I'm beginning, for this blog, a series of short utility scripts and essays that relate, in one way or another, to the general subject of indexing and data retrieval.
The first entry is a short Perl script (just 18 command lines) that extracts the names (of people) wherever the names may occur within a provided text file. The output consists of an alphabetized list of non-repeating names. The script is so simple that it can be easily be translated into any language that supports regular expressions (regex).
The script is available at:
http://www.julesberman.info/factoids/namesget.htm
Blog readers who are uninterested in indexing and data retrieval may want to visit my two other blogs,
Machiavelli's Laboratory (scientific ethics taught from the perspective on an unethical scientist)
and
Neoplasms (essays on tumor biology)
- © 2010 Jules Berman
key words: indices, indexing, indexes, index, data retrieval, information retrieval, informatics
Wednesday, October 27, 2010
Thursday, October 14, 2010
Germ cell tumor web page available
The recent blog series on germ cell tumors has been packaged into a single web page available at:
http://www.julesberman.info/factoids/germcell.htm
- © 2010 Jules Berman
key words: carcinogenesis, neoplasia, neoplasms, tumor development, tumour development, tumor biology, tumour biology, carcinogenesis
http://www.julesberman.info/factoids/germcell.htm
- © 2010 Jules Berman
key words: carcinogenesis, neoplasia, neoplasms, tumor development, tumour development, tumor biology, tumour biology, carcinogenesis
Monday, October 11, 2010
New blog site on Neoplasms
Readers who are primarily interested in medical informatics may have found the past week's blogs on germ cell tumors to be a bit off-track. I agree. I've created a new blog site, Neoplasms, to cover my interests in tumor biology.
Henceforth, for the Specified Life blog, I'll stick to issues of data retrieval, organization, indexing, annotation, and analysis.
For readers who have been following the germ cell series, you might be interested in a new blog series I'll be starting, on "epigenomic tumors", in the Neoplasms blog site. I'll be starting with a discussion of malignant rhabdoid tumors.
- © 2010 Jules Berman
key words: carcinogenesis, neoplasia, neoplasms, tumor development, tumour development, tumor biology, tumour biology, carcinogenesis
Henceforth, for the Specified Life blog, I'll stick to issues of data retrieval, organization, indexing, annotation, and analysis.
For readers who have been following the germ cell series, you might be interested in a new blog series I'll be starting, on "epigenomic tumors", in the Neoplasms blog site. I'll be starting with a discussion of malignant rhabdoid tumors.
- © 2010 Jules Berman
key words: carcinogenesis, neoplasia, neoplasms, tumor development, tumour development, tumor biology, tumour biology, carcinogenesis
Thursday, October 7, 2010
Germ cell cancers of testes: conclusion
This is the last entry on a series of blogs on germ cell cancers of the testes.
I've added forward and backward links for each of the blogs in the series, so you can visit the first blog in the series and click forward or backward through the sequential entries.
Basically, in this series, we showed, using the SEER public use data files, that there has been a large increase in the incidence of germ cell cancers of the testis in white non-Hispanic males since the first SEER observation year (1973) up to the most recent data year (2007).
Along with the increase in seminomatous germ cell cancers was a lesser but parallel increase in the non-seminomatous germ cell cancers of the testis, when compared in birth cohort populations.
The seminomatous and non-seminomatous germ cell cancers, though derived from very different cell types (germ cells versus embryonic/extra-embryonic primitive cells) develop from the same precanceous lesion (usually intratubular germ cell neoplasia and sometimes gonadoblastoma). Precancerous germ cells are characterized by epigenomic erasure, and this "erased" state seems to allow precancerous germ cells to develop into seminomas or into tumors derived from totipotent stem cells.
Testicular precancers develop from disorders of sex development. The incidence of disorders of sex development, like the incidence of testicular germ cell cancers, has been rising. The cause for the rise of disorders of sex development (and the concomitant rise in testicular germ cell cancers) is unknown. However, the ubiquitous appearance of the platicizer and endocrine disruptor, Bisphenol A, has captured the interest of toxicologists and cancer researchers.
All of these issues were discussed in this completed series of blogs on testicular germ cell cancers.
- © 2010 Jules Berman
key words: carcinogenesis, neoplasia, neoplasms, tumor development, tumour development, germ cell tumor, germ cell tumour, tumor epidemiology, increasing germ cell cancer rates, germ cell cancer, seminomas, seminomatous, non-seminomatous, non-germinomatous, embryonal carcinoma, choriocarcinoma, testis, testes, itgcn, intratubular germ cell neoplasm, plasticizers, endocrine disruptors
I've added forward and backward links for each of the blogs in the series, so you can visit the first blog in the series and click forward or backward through the sequential entries.
Basically, in this series, we showed, using the SEER public use data files, that there has been a large increase in the incidence of germ cell cancers of the testis in white non-Hispanic males since the first SEER observation year (1973) up to the most recent data year (2007).
Along with the increase in seminomatous germ cell cancers was a lesser but parallel increase in the non-seminomatous germ cell cancers of the testis, when compared in birth cohort populations.
The seminomatous and non-seminomatous germ cell cancers, though derived from very different cell types (germ cells versus embryonic/extra-embryonic primitive cells) develop from the same precanceous lesion (usually intratubular germ cell neoplasia and sometimes gonadoblastoma). Precancerous germ cells are characterized by epigenomic erasure, and this "erased" state seems to allow precancerous germ cells to develop into seminomas or into tumors derived from totipotent stem cells.
Testicular precancers develop from disorders of sex development. The incidence of disorders of sex development, like the incidence of testicular germ cell cancers, has been rising. The cause for the rise of disorders of sex development (and the concomitant rise in testicular germ cell cancers) is unknown. However, the ubiquitous appearance of the platicizer and endocrine disruptor, Bisphenol A, has captured the interest of toxicologists and cancer researchers.
All of these issues were discussed in this completed series of blogs on testicular germ cell cancers.
- © 2010 Jules Berman
key words: carcinogenesis, neoplasia, neoplasms, tumor development, tumour development, germ cell tumor, germ cell tumour, tumor epidemiology, increasing germ cell cancer rates, germ cell cancer, seminomas, seminomatous, non-seminomatous, non-germinomatous, embryonal carcinoma, choriocarcinoma, testis, testes, itgcn, intratubular germ cell neoplasm, plasticizers, endocrine disruptors
Wednesday, October 6, 2010
Explaining the rise in testicular germ cell tumors
In yesterday's blog we saw that the rise in testicular cancer rates in white males showed a parallel increase in seminomatous and non-seminomatous germ cell cancers among birth cohorts.
What can explain this increase?
There is one class of conditions that is overwhelmingly associated with the development of germ cell tumors of the testis: disorders of sex development of the testes.[1] Among the conditions within this general group are testicular dysgenesis, testicular feminization (insensitivity to androgens), and cryptorchidism. Disorders of sex development of the testis raise the incidence of intratubular germ cell neoplasia or of gonadoblastoma, both of which are testicular precancers.
As you might expect, along with the observed increase in testicular germ cell cancers in white males, there has been an observed increase in the incidence of disorders of sex development in the same population. [1,2] These disorders are characterized by a retardation in the maturation of primordial germ cells, along with an apparent mitotic over-stimulation of these same cells: leading to a proliferative, precancerous condition.
Though there is no proof at the moment, we might expect that males who develop testicular germ cell cancer who have clinically normal testes, may harbor small foci of [clinically unobserved] germ cell proliferative lesions.
What has caused the increased incidence of disorders of sex development in the testes? We don't know, but we have a candidate: the ubiquitous plasticizer and endocrine disruptor, Bisphenol A.
Bisphenol A is a synthetic estrogen used in the process of manufacturing plastics, and has been detected in the serum, milk, saliva, urine, and amniotic fluid of humans.[3] Because we get our daily dose of Bisphenol A from plastic bottles, one would expect that the levels of Bisphenol A in our blood would have increased steadily over the past several decades [coinciding with our increased dependence of plastic food and drink containers]. You might also expect that if Bisphenol A produced testicular cancers, you would see the largest increases in incidence among the wealthiest populations in the most industrialized nations [as we do].
Can we assume that Bisphenol A is causing the rise of incidence of testicular germ cell cancers? Absolutely not. All of the evidence, so far, is very weak (if it can be called evidence at all!). Still, nobody would suggest that Bisphenol A has much to recommend itself as a healthy addition to our diets. It seems prudent to try to limit our exposure to this compound when feasible, particularly among infants and pregnant women.
1. Pleskacova J, Hersmus R, Oosterhuis JW, Setyawati BA, Faradz SM, Cools M, Wolffenbuttel KP, Lebl J, Drop SL, Looijenga LH. Tumor Risk in Disorders of Sex Development. Sex Dev 4:259-269, 2010.
2. Skakkebaek NE, Rajpert-De Meyts E, Jorgensen N, Main KM, Leffers H, Andersson AM, Juul A, Jensen TK, Toppari J. Testicular cancer trends as 'whistle blowers' of testicular developmental problems in populations. Int J Androl 30:198-204, 2007.
3. Bouskine A, Nebout M, Brucker-Davis F, Benahmed M, Fenichel P. Low Doses of Bisphenol A Promote Human Seminoma Cell Proliferation by Activating PKA and PKG via a Membrane G-Protein-Coupled Estrogen Receptor. Environ Health Perspect 117:1053-1058, 2009.
This series of blogs has drawn heavily from the public use SEER data sets produced by the U.S. National Cancer Institute's Surveillance, Epidemiology and End Results project. In the next blog, I'll discuss how this data can be obtained and used by the science-minded public.
Jump to Tomorrow's blog
- © 2010 Jules Berman
key words: carcinogenesis, neoplasia, neoplasms, tumor development, tumour development, germ cell tumor, germ cell tumour, tumor epidemiology, increasing germ cell cancer rates, germ cell cancer, seminomas, seminomatous, non-seminomatous, non-germinomatous, embryonal carcinoma, choriocarcinoma, testis, testes, itgcn, intratubular germ cell neoplasm, plasticizers, endocrine disruptors
About my book, Precancer: The Beginning and the End of Cancer. Nearly every type of cancer passes through a precancer phase, during which it cannot metastasize or invade other tissues. While medicine is not always successful in treating or curing advanced stages of cancers, recent advances in our understanding of carcinogenesis have helped us to develop strategies to prevent, diagnose, and treat many cancers at the precancer stage. Research in this field is escalating rapidly as the evidence increasingly shows that the number of annual cancer deaths could be drastically reduced through the effective treatment and cure of precancer lesions. This book begins by explaining why it has been so difficult to cure cancers, followed by a review of precancer biology, with descriptions of the most common precancer lesions. The final chapters provide practical socio-political and medical goals for precancer treatment, including discussions of the economics and politics of treating precancers.
I urge you to read more about this important topic. Google Books has provided a generous preview of this book.
What can explain this increase?
There is one class of conditions that is overwhelmingly associated with the development of germ cell tumors of the testis: disorders of sex development of the testes.[1] Among the conditions within this general group are testicular dysgenesis, testicular feminization (insensitivity to androgens), and cryptorchidism. Disorders of sex development of the testis raise the incidence of intratubular germ cell neoplasia or of gonadoblastoma, both of which are testicular precancers.
As you might expect, along with the observed increase in testicular germ cell cancers in white males, there has been an observed increase in the incidence of disorders of sex development in the same population. [1,2] These disorders are characterized by a retardation in the maturation of primordial germ cells, along with an apparent mitotic over-stimulation of these same cells: leading to a proliferative, precancerous condition.
Though there is no proof at the moment, we might expect that males who develop testicular germ cell cancer who have clinically normal testes, may harbor small foci of [clinically unobserved] germ cell proliferative lesions.
What has caused the increased incidence of disorders of sex development in the testes? We don't know, but we have a candidate: the ubiquitous plasticizer and endocrine disruptor, Bisphenol A.
Bisphenol A is a synthetic estrogen used in the process of manufacturing plastics, and has been detected in the serum, milk, saliva, urine, and amniotic fluid of humans.[3] Because we get our daily dose of Bisphenol A from plastic bottles, one would expect that the levels of Bisphenol A in our blood would have increased steadily over the past several decades [coinciding with our increased dependence of plastic food and drink containers]. You might also expect that if Bisphenol A produced testicular cancers, you would see the largest increases in incidence among the wealthiest populations in the most industrialized nations [as we do].
Can we assume that Bisphenol A is causing the rise of incidence of testicular germ cell cancers? Absolutely not. All of the evidence, so far, is very weak (if it can be called evidence at all!). Still, nobody would suggest that Bisphenol A has much to recommend itself as a healthy addition to our diets. It seems prudent to try to limit our exposure to this compound when feasible, particularly among infants and pregnant women.
1. Pleskacova J, Hersmus R, Oosterhuis JW, Setyawati BA, Faradz SM, Cools M, Wolffenbuttel KP, Lebl J, Drop SL, Looijenga LH. Tumor Risk in Disorders of Sex Development. Sex Dev 4:259-269, 2010.
2. Skakkebaek NE, Rajpert-De Meyts E, Jorgensen N, Main KM, Leffers H, Andersson AM, Juul A, Jensen TK, Toppari J. Testicular cancer trends as 'whistle blowers' of testicular developmental problems in populations. Int J Androl 30:198-204, 2007.
3. Bouskine A, Nebout M, Brucker-Davis F, Benahmed M, Fenichel P. Low Doses of Bisphenol A Promote Human Seminoma Cell Proliferation by Activating PKA and PKG via a Membrane G-Protein-Coupled Estrogen Receptor. Environ Health Perspect 117:1053-1058, 2009.
This series of blogs has drawn heavily from the public use SEER data sets produced by the U.S. National Cancer Institute's Surveillance, Epidemiology and End Results project. In the next blog, I'll discuss how this data can be obtained and used by the science-minded public.
Jump to Tomorrow's blog
- © 2010 Jules Berman
key words: carcinogenesis, neoplasia, neoplasms, tumor development, tumour development, germ cell tumor, germ cell tumour, tumor epidemiology, increasing germ cell cancer rates, germ cell cancer, seminomas, seminomatous, non-seminomatous, non-germinomatous, embryonal carcinoma, choriocarcinoma, testis, testes, itgcn, intratubular germ cell neoplasm, plasticizers, endocrine disruptors
About my book, Precancer: The Beginning and the End of Cancer. Nearly every type of cancer passes through a precancer phase, during which it cannot metastasize or invade other tissues. While medicine is not always successful in treating or curing advanced stages of cancers, recent advances in our understanding of carcinogenesis have helped us to develop strategies to prevent, diagnose, and treat many cancers at the precancer stage. Research in this field is escalating rapidly as the evidence increasingly shows that the number of annual cancer deaths could be drastically reduced through the effective treatment and cure of precancer lesions. This book begins by explaining why it has been so difficult to cure cancers, followed by a review of precancer biology, with descriptions of the most common precancer lesions. The final chapters provide practical socio-political and medical goals for precancer treatment, including discussions of the economics and politics of treating precancers.
I urge you to read more about this important topic. Google Books has provided a generous preview of this book.
Tuesday, October 5, 2010
Explaining the germ cell cancer rates
In yesterday's blog we explained how the precancer of testicular germ cell tumors, intratubular germ cell neoplasia, gives rise to seminomas (differentiated germinomatous lineage) and non-seminomas (tumors of pluripotent progenitor cells that are not of germ cell lineage).
In the first blog of this series on germ cell tumors , we noted that the increase in occurrences of seminomas has outpaced the occurrences of the nonseminomatous germ cell tumors.
Here is a graph, produced from the SEER public use data sets, of the crude occurrences of seminoma and non-seminoma testicular germ cell tumors, in white males, since 1973.
The light blue bars are the seminomas, and the maroon bars are the non-seminomatous germ cell tumors of the testes. Since 1973, the seminomas increased from a number much lower than the occurrences of the non-seminomatous germ cell tumors; exceeding them in 1977. Since 1977, the crude occurrences of seminomas has greatly outpaced the occurrences of the non-seminomatous germ cell tumors of testes in white males.
Why? If both types of tumors are coming from the same precancer, why are their trends of occurrence non-parallel?
Well, there are several possible answers. It is possible that some external influence has modified the step in the progression of precancer to cancer, to favor the occurrence of seminomas.
However, it is also possible that their increases in occurrence are indeed parallel, and we're just not seeing it in our graph. Bray et al have looked at the incidence of testicular seminoma and non-seminoma germ cell tumors, by cohort (i.e., year of birth), not by year of occurrence.[1]
Bray F, Richiardi L, Ekbom A, Forman D,Pukkala E, Cuninkova M, Moller H. Do Testicular Seminoma and Nonseminoma Share the Same Etiology? Evidence from an Age-Period-Cohort Analysis of Incidence Trends in Eight European Countries. Cancer Epidemiol Biomarkers Prev 15:652–658, 2006.
When the comparisons are based on cohort (comparing incidence for people born the same year), most of the differences vanish [between the incidence of seminomas and non-seminomatous germ cell tumors].
When do we see a birth corhort effect on tumor incidence? For cancers, a cohort effect is best observed when individuals born in one year are exposed (as a population group) to a causal agent that is different from the exposure of individuals born in other years. The cancers that result may occur at many different ages, thus erasing the cohort effect when the data is stratified by year of occurrence (as we had done the graph above). Only when you look at the birth cohort will you find a trend that may relate to a carcinogenic exposure.
OK. The birth cohort data reported by Bray et al would seem to indicate that some generational effect is acting on succeeding cohorts to produce a shared increase in the incidence of all testicular germ cell cancers. Furthermore, whatever is causing the generational effect is likely to be of short duration or differ significantly from year to year. Why is that? If the exposure of a carcinogen were of long duration or were the same from year to year, then every cohort would be exposed similarly, and there would be no birth-year specific effect.
So, now the mystery is: What are the conditions and carcinogens that might cause testicular germ cell tumors, which have changed, year-by-year, to produce the observed rise in these cancers in white males? This will be the topic of the next blog.
Jump to Tomorrow's Blog
- © 2010 Jules Berman
key words: carcinogenesis, neoplasia, neoplasms, tumor development, tumour development, germ cell tumor, germ cell tumour, tumor epidemiology, increasing germ cell cancer rates, germ cell cancer, seminomas, seminomatous, non-seminomatous, non-germinomatous, embryonal carcinoma, choriocarcinoma, testis, testes, itgcn, intratubular germ cell neoplasm
Science is not a collection of facts. Science is what facts teach us; what we can learn about our universe, and ourselves, by deductive thinking. From observations of the night sky, made without the aid of telescopes, we can deduce that the universe is expanding, that the universe is not infinitely old, and why black holes exist. Without resorting to experimentation or mathematical analysis, we can deduce that gravity is a curvature in space-time, that the particles that compose light have no mass, that there is a theoretical limit to the number of different elements in the universe, and that the earth is billions of years old. Likewise, simple observations on animals tell us much about the migration of continents, the evolutionary relationships among classes of animals, why the nuclei of cells contain our genetic material, why certain animals are long-lived, why the gestation period of humans is 9 months, and why some diseases are rare and other diseases are common. In “Armchair Science”, the reader is confronted with 129 scientific mysteries, in cosmology, particle physics, chemistry, biology, and medicine. Beginning with simple observations, step-by-step analyses guide the reader toward solutions that are sometimes startling, and always entertaining. “Armchair Science” is written for general readers who are curious about science, and who want to sharpen their deductive skills.
In the first blog of this series on germ cell tumors , we noted that the increase in occurrences of seminomas has outpaced the occurrences of the nonseminomatous germ cell tumors.
Here is a graph, produced from the SEER public use data sets, of the crude occurrences of seminoma and non-seminoma testicular germ cell tumors, in white males, since 1973.
The light blue bars are the seminomas, and the maroon bars are the non-seminomatous germ cell tumors of the testes. Since 1973, the seminomas increased from a number much lower than the occurrences of the non-seminomatous germ cell tumors; exceeding them in 1977. Since 1977, the crude occurrences of seminomas has greatly outpaced the occurrences of the non-seminomatous germ cell tumors of testes in white males.
Why? If both types of tumors are coming from the same precancer, why are their trends of occurrence non-parallel?
Well, there are several possible answers. It is possible that some external influence has modified the step in the progression of precancer to cancer, to favor the occurrence of seminomas.
However, it is also possible that their increases in occurrence are indeed parallel, and we're just not seeing it in our graph. Bray et al have looked at the incidence of testicular seminoma and non-seminoma germ cell tumors, by cohort (i.e., year of birth), not by year of occurrence.[1]
Bray F, Richiardi L, Ekbom A, Forman D,Pukkala E, Cuninkova M, Moller H. Do Testicular Seminoma and Nonseminoma Share the Same Etiology? Evidence from an Age-Period-Cohort Analysis of Incidence Trends in Eight European Countries. Cancer Epidemiol Biomarkers Prev 15:652–658, 2006.
When the comparisons are based on cohort (comparing incidence for people born the same year), most of the differences vanish [between the incidence of seminomas and non-seminomatous germ cell tumors].
When do we see a birth corhort effect on tumor incidence? For cancers, a cohort effect is best observed when individuals born in one year are exposed (as a population group) to a causal agent that is different from the exposure of individuals born in other years. The cancers that result may occur at many different ages, thus erasing the cohort effect when the data is stratified by year of occurrence (as we had done the graph above). Only when you look at the birth cohort will you find a trend that may relate to a carcinogenic exposure.
OK. The birth cohort data reported by Bray et al would seem to indicate that some generational effect is acting on succeeding cohorts to produce a shared increase in the incidence of all testicular germ cell cancers. Furthermore, whatever is causing the generational effect is likely to be of short duration or differ significantly from year to year. Why is that? If the exposure of a carcinogen were of long duration or were the same from year to year, then every cohort would be exposed similarly, and there would be no birth-year specific effect.
So, now the mystery is: What are the conditions and carcinogens that might cause testicular germ cell tumors, which have changed, year-by-year, to produce the observed rise in these cancers in white males? This will be the topic of the next blog.
Jump to Tomorrow's Blog
- © 2010 Jules Berman
key words: carcinogenesis, neoplasia, neoplasms, tumor development, tumour development, germ cell tumor, germ cell tumour, tumor epidemiology, increasing germ cell cancer rates, germ cell cancer, seminomas, seminomatous, non-seminomatous, non-germinomatous, embryonal carcinoma, choriocarcinoma, testis, testes, itgcn, intratubular germ cell neoplasm
Science is not a collection of facts. Science is what facts teach us; what we can learn about our universe, and ourselves, by deductive thinking. From observations of the night sky, made without the aid of telescopes, we can deduce that the universe is expanding, that the universe is not infinitely old, and why black holes exist. Without resorting to experimentation or mathematical analysis, we can deduce that gravity is a curvature in space-time, that the particles that compose light have no mass, that there is a theoretical limit to the number of different elements in the universe, and that the earth is billions of years old. Likewise, simple observations on animals tell us much about the migration of continents, the evolutionary relationships among classes of animals, why the nuclei of cells contain our genetic material, why certain animals are long-lived, why the gestation period of humans is 9 months, and why some diseases are rare and other diseases are common. In “Armchair Science”, the reader is confronted with 129 scientific mysteries, in cosmology, particle physics, chemistry, biology, and medicine. Beginning with simple observations, step-by-step analyses guide the reader toward solutions that are sometimes startling, and always entertaining. “Armchair Science” is written for general readers who are curious about science, and who want to sharpen their deductive skills.
Sunday, October 3, 2010
Germ cell precancers and epigenetic erasure
In yesterday's blog , we left off with a question: "How it is possible for intratubular germ cell neoplasia to be the precursor for both germinomatous germ cell cancers (i.e., seminoma) and non-germinomatous germ cell cancers (e.g. embryonal carcinoma, choriocarcinoma)?
The key is epigenetic erasure, a phenomenon unique to germ cells.
As an organism develops, cells specialize into about 200 differentiated cell types. All these different types of cells have the same genetic sequence (genome). Cell types are distingued, one from the other, by epigenetic modifications. Epigenetic modifications to genes involve base methylation, conformational changes in chromosomes, protein modifications... anything other than changes in DNA sequence.
Germ cells, like all other differentiated cells, have epigenetic modifications. The unique thing about germ cells is that they must undergo epigenetic erasure prior to the production of gametes; otherwise the gametes would be imprinted with the epigenetic modifications characteristic of the parent organism and would not be capable of recombining during fertilization to produce a fully de-differentiated, totipotent product.[1]
The cells of intratubular germ cell neoplasia (the precancer of most male germ cell tumors) and of seminomas, are all characterized by DNA hypomethylation; not so for the cells of non-germinomatous germ cell tumors.[2,3] DNA Hypomethylation is seen in epigenomic erasure [of germ cells].
"Erased" germ cells are capable of developing into totipotent embryonic cells.[4] It would seem that a plausible mechanism for the development of non-germinomatous germ cell cancers from a germ cell precursor (intratubular germ cell neoplasia, itgcn) is that the "erased" itgcn cells, during cancer development, transform into totipotent cells, capable of differentiating into cells from any embryonic layer (e.g., embryonal carcinoma), or into extra-embryonic tissue (e.g., choriocarcinoma).
This explains why the itgcn, the germ cell precancer, can give rise to both germinomatous (erased) and non-germinomatous (epigenetic-modified) cancers.
There is only one mystery left to solve (the original mystery that we started with, about 4 blog entries back ). If germinomatous and non-germinomatous germ cell cancers both arise from the same precursor, why is there a much greater increase in the rate of occurrence of seminomas compared with the rate of occurrence of non-germinomatous cancers, since 1973?
1. Allegrucci C, Thurston A, Lucas E, Young L. Epigenetics and the germline. Reproduction 129:137-149, 2005.
2. Netto GJ et al.Global DNA hypomethylation in intratubular germ cell neoplasia and seminoma, but not in nonseminomatous male germ cell tumors. Modern Pathology 21: 1337-1344, 2008.
3. Lind GE, Skotheim RI, Lothe RA. The epigenome of testicular germ cell tumors. APMIS (Acta Pathologica, Microbiologica et Immunologica Scandinavica) 115:1147-1160, 2007.
4. Turnpenny L. Derivation of human embryonic germ cells: an alternative source of pluripotent stem cells. Stem Cells 21:598-609, 2003.
Jump to Tomorrow's Blog
- © 2010 Jules Berman
key words: carcinogenesis, neoplasia, neoplasms, tumor development, tumour development, germ cell tumor, germ cell tumour, tumor epidemiology, increasing germ cell cancer rates, germ cell cancer, seminomas, seminomatous, non-seminomatous, non-germinomatous, embryonal carcinoma, choriocarcinoma, testis, testes, itgcn, intratubular germ cell neoplasm
In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.
I urge you to read more about my book. There's a generous preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy of this book for your library or reading room.
The key is epigenetic erasure, a phenomenon unique to germ cells.
As an organism develops, cells specialize into about 200 differentiated cell types. All these different types of cells have the same genetic sequence (genome). Cell types are distingued, one from the other, by epigenetic modifications. Epigenetic modifications to genes involve base methylation, conformational changes in chromosomes, protein modifications... anything other than changes in DNA sequence.
Germ cells, like all other differentiated cells, have epigenetic modifications. The unique thing about germ cells is that they must undergo epigenetic erasure prior to the production of gametes; otherwise the gametes would be imprinted with the epigenetic modifications characteristic of the parent organism and would not be capable of recombining during fertilization to produce a fully de-differentiated, totipotent product.[1]
The cells of intratubular germ cell neoplasia (the precancer of most male germ cell tumors) and of seminomas, are all characterized by DNA hypomethylation; not so for the cells of non-germinomatous germ cell tumors.[2,3] DNA Hypomethylation is seen in epigenomic erasure [of germ cells].
"Erased" germ cells are capable of developing into totipotent embryonic cells.[4] It would seem that a plausible mechanism for the development of non-germinomatous germ cell cancers from a germ cell precursor (intratubular germ cell neoplasia, itgcn) is that the "erased" itgcn cells, during cancer development, transform into totipotent cells, capable of differentiating into cells from any embryonic layer (e.g., embryonal carcinoma), or into extra-embryonic tissue (e.g., choriocarcinoma).
This explains why the itgcn, the germ cell precancer, can give rise to both germinomatous (erased) and non-germinomatous (epigenetic-modified) cancers.
There is only one mystery left to solve (the original mystery that we started with, about 4 blog entries back ). If germinomatous and non-germinomatous germ cell cancers both arise from the same precursor, why is there a much greater increase in the rate of occurrence of seminomas compared with the rate of occurrence of non-germinomatous cancers, since 1973?
1. Allegrucci C, Thurston A, Lucas E, Young L. Epigenetics and the germline. Reproduction 129:137-149, 2005.
2. Netto GJ et al.Global DNA hypomethylation in intratubular germ cell neoplasia and seminoma, but not in nonseminomatous male germ cell tumors. Modern Pathology 21: 1337-1344, 2008.
3. Lind GE, Skotheim RI, Lothe RA. The epigenome of testicular germ cell tumors. APMIS (Acta Pathologica, Microbiologica et Immunologica Scandinavica) 115:1147-1160, 2007.
4. Turnpenny L. Derivation of human embryonic germ cells: an alternative source of pluripotent stem cells. Stem Cells 21:598-609, 2003.
Jump to Tomorrow's Blog
- © 2010 Jules Berman
key words: carcinogenesis, neoplasia, neoplasms, tumor development, tumour development, germ cell tumor, germ cell tumour, tumor epidemiology, increasing germ cell cancer rates, germ cell cancer, seminomas, seminomatous, non-seminomatous, non-germinomatous, embryonal carcinoma, choriocarcinoma, testis, testes, itgcn, intratubular germ cell neoplasm
In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.
I urge you to read more about my book. There's a generous preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy of this book for your library or reading room.
Germ cell tumor common precancer: itgcn
In yesterday's blog , we discussed the terminology problem with the germ cell tumors. Basically, if you have a sub-class of germ cell tumors that are called "non-germinomatous germ cell tumors," isn't that a contradiction in terms? Isn't it like saying that dehydrated water is a subclass of water?
The answer is simple: the classic germ cell tumor of the testes (seminoma), as well as most of the malignant non-germinomatous germ cell tumors of the testes, arise from the same precancer: intratubular germ cell neoplasia (itgcn). Because itgcn is composed of dysplastic (early neoplastic) germ cells, both the germinomatous and non-germinomatous tumors have a germ cell origin.
You can easily appreciate the morphologic similarity between itgcn and seminoma by looking at a histologic preparation of each.
Image of Intratubular Germ Cell neoplasia
Distributed by Wikimedia
under a Creative Commons License
The germ cell precancer, itgcn, is a collection of atypical gonocytic cells lining seminiferous tubules in the testis.
Image of Seminoma
Distributed by Wikimedia
under a GNU License
Seminoma cells closely resemble the cells of itgcn, from which they derive (with the rare exception of the so-called spermatocytic seminoma, which behaves unlike the other types of seminomas).
The same precancer (itgcn) precedes the development of most of the invasive non-germinomatous germ cell tumors of the testis.
So, the terminologic mystery is solved. The germinomatous and the non-germinomatous germ cell tumors are classified together because most of them are derived from neoplastic intratubular germ cells (i.e., intratubular germ cell neoplasia).
But solving the terminologic mystery does not help us understand the biology of what's happening. Why does itgcn give rise to tumors of germ cells (e.g., seminomas) and to tumors of primimitive non-germ cells (e.g., embryonal carcinoma, choriocarcinoma)? How can a tumor be derived from cells that have a committed lineage (i.e., sperm cells in the case of males) that is completely unrelated to the lineages found in the tumor?
There's an answer. It has a lot to do with a phenomenon unique to germ cells called epigenomic erasure. This will be the topic of the next blog in our series on germ cell tumors.
Jump to Tomorrow's Blog
- © 2010 Jules Berman
key words: carcinogenesis, neoplasia, neoplasms, tumor development, tumour development, germ cell tumor, germ cell tumour, tumor epidemiology, increasing germ cell cancer rates, germ cell cancer, seminomas, seminomatous, non-seminomatous, non-germinomatous, embryonal carcinoma, choriocarcinoma, testis, testes, itgcn, intratubular germ cell neoplasm
In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.
I urge you to read more about my book. There's a generous preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy of this book for your library or reading room.
The answer is simple: the classic germ cell tumor of the testes (seminoma), as well as most of the malignant non-germinomatous germ cell tumors of the testes, arise from the same precancer: intratubular germ cell neoplasia (itgcn). Because itgcn is composed of dysplastic (early neoplastic) germ cells, both the germinomatous and non-germinomatous tumors have a germ cell origin.
You can easily appreciate the morphologic similarity between itgcn and seminoma by looking at a histologic preparation of each.
Distributed by Wikimedia
under a Creative Commons License
The germ cell precancer, itgcn, is a collection of atypical gonocytic cells lining seminiferous tubules in the testis.
_nodal_metastasis.jpg){kind=link}
Distributed by Wikimedia
under a GNU License
Seminoma cells closely resemble the cells of itgcn, from which they derive (with the rare exception of the so-called spermatocytic seminoma, which behaves unlike the other types of seminomas).
The same precancer (itgcn) precedes the development of most of the invasive non-germinomatous germ cell tumors of the testis.
So, the terminologic mystery is solved. The germinomatous and the non-germinomatous germ cell tumors are classified together because most of them are derived from neoplastic intratubular germ cells (i.e., intratubular germ cell neoplasia).
But solving the terminologic mystery does not help us understand the biology of what's happening. Why does itgcn give rise to tumors of germ cells (e.g., seminomas) and to tumors of primimitive non-germ cells (e.g., embryonal carcinoma, choriocarcinoma)? How can a tumor be derived from cells that have a committed lineage (i.e., sperm cells in the case of males) that is completely unrelated to the lineages found in the tumor?
There's an answer. It has a lot to do with a phenomenon unique to germ cells called epigenomic erasure. This will be the topic of the next blog in our series on germ cell tumors.
Jump to Tomorrow's Blog
- © 2010 Jules Berman
key words: carcinogenesis, neoplasia, neoplasms, tumor development, tumour development, germ cell tumor, germ cell tumour, tumor epidemiology, increasing germ cell cancer rates, germ cell cancer, seminomas, seminomatous, non-seminomatous, non-germinomatous, embryonal carcinoma, choriocarcinoma, testis, testes, itgcn, intratubular germ cell neoplasm
In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.
I urge you to read more about my book. There's a generous preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy of this book for your library or reading room.
Saturday, October 2, 2010
Germ cell tumors: definition problems
OK, getting back to the prior post on germ cell tumors, we found that the rate of occurrence of seminomatous germ cell tumors of the testes has been greatly increasing, in the white male population, since (at least) 1973. During the same period, the rate of occurrence of the other type of germ cell tumors (non-seminomatous) has hardly increased at all, for white men.
Why has the rate of occurrence of seminomas increased since 1973, in the white male population? Also, if seminomatous and non-seminomatous germ cell tumors are just morphologic variants of the same basic tumor (i.e., germ cell tumor), why wouldn't they both increase to the same extent?
Perhaps some of the problem relates to the definition of these two tumors.
Seminomas are tumors of gonocytes, a differentiated cell committed to producing gametes (sperm in males, eggs in females), or a committed progenitor cell of gamete-producing cells (i.e., an ancestral cell of a gamete-producing cell). Since seminomas are considered the neoplastic equivalent of gonocytes, there seems to be little leeway in their classification: they must be included among the germ cell tumors.
But what about the other type of germ cell tumors. This other type is known by two different names that tell us a lot about the ambivalent nature of the tumor:
From wikipedia:
"The nongerminomatous or nonseminomatous germ cell tumors (NGGCT, NSGCT) include all other germ cell tumors, pure and mixed."
How can a germ cell tumor be non-germinomatous? Wouldn't the adjective "non-germinomatous" pretty much tell you that the tumor can't be a germ cell tumor?
It reminds me of one of my favorite limericks.
As I was sitting in my chair,
I sensed the bottom was not there.
Nor legs, nor back,
But I just sat,
Ignoring little things like that.
- Anonymous
Well, what are the non-germinomatous germ cell tumors? These are tumors that usually arise in the gonads and are composed of primitive pluripotent cells. We can find pure or mixed populations of embryonal carcinoma, teratomatous tissue, and choriocarcinoma in the non-germinomatous germ cell tumors. These are the same cells that are found in the very earliest embryo and placenta. But these primitive cell types are not gonocytes (i.e., they are not differentiated cells committed to producing sperm or eggs). These tumors are composed of primitive non-germ cells.
So why are the primitive non-germ cell tumors included among the germ cell tumors?
The answer to this question comes from our understanding of the common precancer of most of the seminomatous and non-seminomatous germ cell tumors: intratubular germ cell neoplasia.
In the next several blogs, we'll discuss germ cell precancer, and we'll explain the unifying concept of germ cell neoplasia. We'll also see how a study of precancers is crucial to our understanding of neoplasia, in general.
Jump to Tomorrow's Blog
- © 2010 Jules Berman
key words: carcinogenesis, neoplasia, neoplasms, tumor development, tumour development, germ cell tumor, germ cell tumour, tumor epidemiology, increasing germ cell cancer rates, germ cell cancer, seminomas, seminomatous
In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.
I urge you to read more about my book. There's a generous preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy of this book for your library or reading room.
Why has the rate of occurrence of seminomas increased since 1973, in the white male population? Also, if seminomatous and non-seminomatous germ cell tumors are just morphologic variants of the same basic tumor (i.e., germ cell tumor), why wouldn't they both increase to the same extent?
Perhaps some of the problem relates to the definition of these two tumors.
Seminomas are tumors of gonocytes, a differentiated cell committed to producing gametes (sperm in males, eggs in females), or a committed progenitor cell of gamete-producing cells (i.e., an ancestral cell of a gamete-producing cell). Since seminomas are considered the neoplastic equivalent of gonocytes, there seems to be little leeway in their classification: they must be included among the germ cell tumors.
But what about the other type of germ cell tumors. This other type is known by two different names that tell us a lot about the ambivalent nature of the tumor:
From wikipedia:
"The nongerminomatous or nonseminomatous germ cell tumors (NGGCT, NSGCT) include all other germ cell tumors, pure and mixed."
How can a germ cell tumor be non-germinomatous? Wouldn't the adjective "non-germinomatous" pretty much tell you that the tumor can't be a germ cell tumor?
It reminds me of one of my favorite limericks.
As I was sitting in my chair,
I sensed the bottom was not there.
Nor legs, nor back,
But I just sat,
Ignoring little things like that.
- Anonymous
Well, what are the non-germinomatous germ cell tumors? These are tumors that usually arise in the gonads and are composed of primitive pluripotent cells. We can find pure or mixed populations of embryonal carcinoma, teratomatous tissue, and choriocarcinoma in the non-germinomatous germ cell tumors. These are the same cells that are found in the very earliest embryo and placenta. But these primitive cell types are not gonocytes (i.e., they are not differentiated cells committed to producing sperm or eggs). These tumors are composed of primitive non-germ cells.
So why are the primitive non-germ cell tumors included among the germ cell tumors?
The answer to this question comes from our understanding of the common precancer of most of the seminomatous and non-seminomatous germ cell tumors: intratubular germ cell neoplasia.
In the next several blogs, we'll discuss germ cell precancer, and we'll explain the unifying concept of germ cell neoplasia. We'll also see how a study of precancers is crucial to our understanding of neoplasia, in general.
Jump to Tomorrow's Blog
- © 2010 Jules Berman
key words: carcinogenesis, neoplasia, neoplasms, tumor development, tumour development, germ cell tumor, germ cell tumour, tumor epidemiology, increasing germ cell cancer rates, germ cell cancer, seminomas, seminomatous
In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.
I urge you to read more about my book. There's a generous preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy of this book for your library or reading room.
Friday, October 1, 2010
Povray script for book cover
Currently, I'm writing a series of blogs on germ cell tumors. But I took a break today to prepare a web page that provides the PovRay script for the cover image of my new book, Methods in Medical Informatics, Fundamental of Healthcare Programming in Perl, Python, and Ruby.
The PovRay script and a high-resoluion version of the image used in the book cover, are available at:
http://www.julesberman.info/book/coverhow.htm
I'll resume the germ cell tumor series soon.
- Jules Berman
Science is not a collection of facts. Science is what facts teach us; what we can learn about our universe, and ourselves, by deductive thinking. From observations of the night sky, made without the aid of telescopes, we can deduce that the universe is expanding, that the universe is not infinitely old, and why black holes exist. Without resorting to experimentation or mathematical analysis, we can deduce that gravity is a curvature in space-time, that the particles that compose light have no mass, that there is a theoretical limit to the number of different elements in the universe, and that the earth is billions of years old. Likewise, simple observations on animals tell us much about the migration of continents, the evolutionary relationships among classes of animals, why the nuclei of cells contain our genetic material, why certain animals are long-lived, why the gestation period of humans is 9 months, and why some diseases are rare and other diseases are common. In “Armchair Science”, the reader is confronted with 129 scientific mysteries, in cosmology, particle physics, chemistry, biology, and medicine. Beginning with simple observations, step-by-step analyses guide the reader toward solutions that are sometimes startling, and always entertaining. “Armchair Science” is written for general readers who are curious about science, and who want to sharpen their deductive skills.
The PovRay script and a high-resoluion version of the image used in the book cover, are available at:
http://www.julesberman.info/book/coverhow.htm
I'll resume the germ cell tumor series soon.
- Jules Berman
Science is not a collection of facts. Science is what facts teach us; what we can learn about our universe, and ourselves, by deductive thinking. From observations of the night sky, made without the aid of telescopes, we can deduce that the universe is expanding, that the universe is not infinitely old, and why black holes exist. Without resorting to experimentation or mathematical analysis, we can deduce that gravity is a curvature in space-time, that the particles that compose light have no mass, that there is a theoretical limit to the number of different elements in the universe, and that the earth is billions of years old. Likewise, simple observations on animals tell us much about the migration of continents, the evolutionary relationships among classes of animals, why the nuclei of cells contain our genetic material, why certain animals are long-lived, why the gestation period of humans is 9 months, and why some diseases are rare and other diseases are common. In “Armchair Science”, the reader is confronted with 129 scientific mysteries, in cosmology, particle physics, chemistry, biology, and medicine. Beginning with simple observations, step-by-step analyses guide the reader toward solutions that are sometimes startling, and always entertaining. “Armchair Science” is written for general readers who are curious about science, and who want to sharpen their deductive skills.
Monday, September 27, 2010
Non-seminomatous germ cell tumors
In yesterday's blog, we examined the enormous increase in the incidence of seminomatous germ cell tumors occurring in white non-Hispanic males.
There are two categories of germ cell tumors: seminomatous and non-seminomatous.
The seminomatous tumors are tumors composed predominantly of a single cell type, the gonocyte. The non-neoplastic gonocyte would normally produce sperm cell in the testis. Seminomas are permitted to contain a few neoplastic trophoblasts, but otherwise, seminomas are composed of a population of large, round, monomorphic cells.
The other type of germ cell tumors is the non-seminomatous tumors, and these tumors are composed of malignant cells resembling those of the pluripotent primitive embryonic (from the early embryo) or extra-embryonic (from the placenta) malignant cells. Consequently, the non-seminomatous germ cell tumors may be teratomatous, primative embryonic, choriocarcinomatous, or some mixture of these. Non-seminomatous germ cell tumors may even contain foci of seminoma! The key characteristic of non-seminomatous germ cell tumors of the testis is that they must have a component of primitive neoplastic cells that are not seminoma cells.
Can we observe the same increased incidence of non-seminomatous germ cell tumors as we saw (yesterday) in the seminomatous germ cell tumors.
NO. Here are the numbers, computed from the SEER (the U.S. National Cancer Institute's Surveillance Epidemiology and End Results) public use data files. The first column is the crude number of occurrences of non-seminomatous germ cell tumors of testes in white, non-Hispanic males. The second column is the number of occurrences expressed as a proportion of all of the seer cases for the year examined, and the third column is the number of occurrences expressed as a proportion of the U.S. population for the year examined.
Here's the graph. The blue columns are the crude occurrences. The maroon columns are the numbers as a proportion of the year's seer records, and the white column are the numbers as a porportion of the U.S. population in the examined year.
There's a small increase since 1973, but much of the increase is accounted for by the increase in the SEER population and the increase in the U.S. population for the same years. The relative (population adjusted) rate of occurrence of non-seminomatous germ cell tumors has not increased by much; certainly nothing like the increase seen yesterday, for the seminomatous germ cell tumors.
What about the germ cell tumors that occur outside the gonads? Are they increasing in occurrence since 1973? Though germ cell tumors can occur outside the gonads, they are very rare. Here are the SEER numbers for non-seminomatous non-testicular germ cell tumors in white non-Hispanic males.
Here are the numbers for seminomatous non-testicular germ cell tumors in white non-Hispanic males.
Non-testicular germ cell tumors represent a tiny fraction of the germ cell tumors occurring in men. For the purposes of analysis, there's not much you can do with these tumors. They're not going to give you statistically significant results when you try to test a hypothesis; some of them may represent misdiagnoses (e.g., colon cancer mistaken for monomorphic teratoma in a peri-testicular appendage), or a conservative topographic assignment (peri-testicular metastasis from a regressed primary germ cell tumor).
So, for the purposes of this blog, where we're trying to find a biological explanation for the rise in seminomas in non-Hispanic white males, we'll ignore the non-testicular germ cell tumors.
Jump to Tomorrow's Blog
- © 2010 Jules Berman
key words: carcinogenesis, neoplasia, neoplasms, tumor development, tumour development, germ cell tumor, germ cell tumour, tumor epidemiology, increasing germ cell cancer rates, germ cell cancer, seminomas, seminomatous, common disease, orphan disease, orphan drugs, genetics of disease, disease genetics, rules of disease biology, rare disease, pathology
In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.
I urge you to read more about my book. There's a generous preview of the book at the Google Books site.
There are two categories of germ cell tumors: seminomatous and non-seminomatous.
The seminomatous tumors are tumors composed predominantly of a single cell type, the gonocyte. The non-neoplastic gonocyte would normally produce sperm cell in the testis. Seminomas are permitted to contain a few neoplastic trophoblasts, but otherwise, seminomas are composed of a population of large, round, monomorphic cells.
The other type of germ cell tumors is the non-seminomatous tumors, and these tumors are composed of malignant cells resembling those of the pluripotent primitive embryonic (from the early embryo) or extra-embryonic (from the placenta) malignant cells. Consequently, the non-seminomatous germ cell tumors may be teratomatous, primative embryonic, choriocarcinomatous, or some mixture of these. Non-seminomatous germ cell tumors may even contain foci of seminoma! The key characteristic of non-seminomatous germ cell tumors of the testis is that they must have a component of primitive neoplastic cells that are not seminoma cells.
Can we observe the same increased incidence of non-seminomatous germ cell tumors as we saw (yesterday) in the seminomatous germ cell tumors.
NO. Here are the numbers, computed from the SEER (the U.S. National Cancer Institute's Surveillance Epidemiology and End Results) public use data files. The first column is the crude number of occurrences of non-seminomatous germ cell tumors of testes in white, non-Hispanic males. The second column is the number of occurrences expressed as a proportion of all of the seer cases for the year examined, and the third column is the number of occurrences expressed as a proportion of the U.S. population for the year examined.
crude of SEER of U.S. Pop
1973 000109 000196 000051
1974 000147 000218 000068
1975 000157 000213 000072
1976 000165 000218 000075
1977 000189 000246 000085
1978 000167 000214 000075
1979 000182 000226 000080
1980 000216 000260 000095
1981 000222 000259 000096
1982 000203 000234 000087
1983 000226 000251 000096
1984 000219 000234 000092
1985 000238 000243 000100
1986 000233 000232 000097
1987 000253 000238 000104
1988 000222 000206 000090
1989 000263 000238 000106
1990 000243 000209 000097
1991 000237 000192 000094
1992 000237 000185 000092
1993 000245 000194 000095
1994 000222 000176 000085
1995 000216 000169 000082
1996 000247 000202 000093
1997 000225 000178 000084
1998 000234 000180 000086
1999 000245 000185 000089
2000 000237 000177 000084
2001 000223 000162 000078
2002 000258 000185 000089
2003 000230 000166 000079
2004 000278 000192 000094
2005 000275 000188 000092
2006 000251 000169 000084
2007 000277 000182 000091
Here's the graph. The blue columns are the crude occurrences. The maroon columns are the numbers as a proportion of the year's seer records, and the white column are the numbers as a porportion of the U.S. population in the examined year.
There's a small increase since 1973, but much of the increase is accounted for by the increase in the SEER population and the increase in the U.S. population for the same years. The relative (population adjusted) rate of occurrence of non-seminomatous germ cell tumors has not increased by much; certainly nothing like the increase seen yesterday, for the seminomatous germ cell tumors.
What about the germ cell tumors that occur outside the gonads? Are they increasing in occurrence since 1973? Though germ cell tumors can occur outside the gonads, they are very rare. Here are the SEER numbers for non-seminomatous non-testicular germ cell tumors in white non-Hispanic males.
crude of SEER of U.S. Pop
1973 000011 000019 000005
1974 000008 000011 000003
1975 000014 000019 000006
1976 000011 000014 000005
1977 000011 000014 000004
1978 000011 000014 000004
1979 000019 000023 000008
1980 000021 000025 000009
1981 000016 000018 000006
1982 000019 000021 000008
1983 000018 000020 000007
1984 000012 000012 000005
1985 000019 000019 000007
1986 000014 000013 000005
1987 000025 000023 000010
1988 000016 000014 000006
1989 000020 000018 000008
1990 000011 000009 000004
1991 000023 000018 000009
1992 000011 000008 000004
1993 000018 000014 000006
1994 000012 000009 000004
1995 000010 000007 000003
1996 000009 000007 000003
1997 000018 000014 000006
1998 000010 000007 000003
1999 000013 000009 000004
2000 000005 000003 000001
2001 000015 000010 000005
2002 000013 000009 000004
2003 000010 000007 000003
2004 000017 000011 000005
2005 000020 000013 000006
2006 000011 000007 000003
2007 000012 000007 000003
Here are the numbers for seminomatous non-testicular germ cell tumors in white non-Hispanic males.
crude of SEER of U.S. Pop
1973 000002 000003 000000
1974 000001 000001 000000
1975 000005 000006 000002
1976 000004 000005 000001
1977 000010 000013 000004
1978 000008 000010 000003
1979 000004 000004 000001
1980 000014 000016 000006
1981 000016 000018 000006
1982 000011 000012 000004
1983 000011 000012 000004
1984 000011 000011 000004
1985 000013 000013 000005
1986 000016 000015 000006
1987 000014 000013 000005
1988 000011 000010 000004
1989 000016 000014 000006
1990 000010 000008 000004
1991 000011 000008 000004
1992 000014 000010 000005
1993 000013 000010 000005
1994 000023 000018 000008
1995 000017 000013 000006
1996 000020 000016 000007
1997 000018 000014 000006
1998 000010 000007 000003
1999 000009 000006 000003
2000 000016 000012 000005
2001 000014 000010 000004
2002 000017 000012 000005
2003 000016 000011 000005
2004 000022 000015 000007
2005 000026 000017 000008
2006 000014 000009 000004
2007 000017 000011 000005
Non-testicular germ cell tumors represent a tiny fraction of the germ cell tumors occurring in men. For the purposes of analysis, there's not much you can do with these tumors. They're not going to give you statistically significant results when you try to test a hypothesis; some of them may represent misdiagnoses (e.g., colon cancer mistaken for monomorphic teratoma in a peri-testicular appendage), or a conservative topographic assignment (peri-testicular metastasis from a regressed primary germ cell tumor).
So, for the purposes of this blog, where we're trying to find a biological explanation for the rise in seminomas in non-Hispanic white males, we'll ignore the non-testicular germ cell tumors.
Jump to Tomorrow's Blog
- © 2010 Jules Berman
key words: carcinogenesis, neoplasia, neoplasms, tumor development, tumour development, germ cell tumor, germ cell tumour, tumor epidemiology, increasing germ cell cancer rates, germ cell cancer, seminomas, seminomatous, common disease, orphan disease, orphan drugs, genetics of disease, disease genetics, rules of disease biology, rare disease, pathology
In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.
I urge you to read more about my book. There's a generous preview of the book at the Google Books site.
Germ cell tumors: the problems
Germ cell tumors are very rare neoplasms that occur most often in young adults and children.
For a variety of reasons, which I'll try to explain in the next few blog posts, much of what we think we understand about these tumors is highly confusing and probably wrong.
Considering that these are rare tumors, you might accept a certain degree of ignorance, but sometimes the mysteries that surround rare tumors must be solved before we can make any headway understanding the more common tumors.
Also, for some strange reason, the incidence of seminomatous germ cell tumors of the testes, in the white population, has been increasing over the past 35 years (at least).
Here are the numbers, computed from the SEER (the U.S. National Cancer Institute's Surveillance Epidemiology and End Results) public use data files. The first column is the crude number of occurrences of seminomatous germ cell tumors of testes in white, non-hispanic males. The second column is the number of occurrences expressed as a proportion of all of the seer cases for the year examined, and the third column is the number of occurrences expressed as a proportion of the U.S. population for the year examined.
Here's the graph. The blue columns are the crude numbers. The maroon columns are the numbers as a proportion of the year's seer records, and the white column are the numbers as a porportion of the U.S. population in the examined year.
When the incidence of a tumor increases almost every year, and we're clueless to explain the increase, it's probably worth thinking about the problem.
Jump to Tomorrow's Blog
- © 2010 Jules Berman
key words: carcinogenesis, neoplasia, neoplasms, tumor development, tumour development, germ cell tumor, germ cell tumour, tumor epidemiology, increasing germ cell cancer rates, germ cell cancer, seminomas, seminomatous, common disease, orphan disease, orphan drugs, genetics of disease, disease genetics, rules of disease biology, rare disease, pathology
In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.
I urge you to read more about my book. There's a generous preview of the book at the Google Books site.
For a variety of reasons, which I'll try to explain in the next few blog posts, much of what we think we understand about these tumors is highly confusing and probably wrong.
Considering that these are rare tumors, you might accept a certain degree of ignorance, but sometimes the mysteries that surround rare tumors must be solved before we can make any headway understanding the more common tumors.
Also, for some strange reason, the incidence of seminomatous germ cell tumors of the testes, in the white population, has been increasing over the past 35 years (at least).
Here are the numbers, computed from the SEER (the U.S. National Cancer Institute's Surveillance Epidemiology and End Results) public use data files. The first column is the crude number of occurrences of seminomatous germ cell tumors of testes in white, non-hispanic males. The second column is the number of occurrences expressed as a proportion of all of the seer cases for the year examined, and the third column is the number of occurrences expressed as a proportion of the U.S. population for the year examined.
crude of SEER of U.S. Pop
1973 000036 000064 000016
1974 000026 000038 000012
1975 000044 000059 000020
1976 000069 000091 000031
1977 000197 000257 000089
1978 000169 000216 000075
1979 000192 000239 000085
1980 000225 000271 000099
1981 000200 000234 000087
1982 000240 000277 000103
1983 000257 000286 000109
1984 000252 000270 000106
1985 000256 000262 000107
1986 000293 000292 000122
1987 000302 000285 000124
1988 000299 000278 000122
1989 000343 000311 000138
1990 000338 000290 000135
1991 000303 000245 000120
1992 000352 000274 000138
1993 000340 000269 000131
1994 000385 000305 000147
1995 000303 000237 000115
1996 000371 000304 000139
1997 000379 000300 000141
1998 000408 000315 000150
1999 000363 000274 000133
2000 000413 000310 000146
2001 000409 000297 000143
2002 000398 000285 000138
2003 000371 000268 000127
2004 000400 000277 000136
2005 000382 000262 000129
2006 000374 000252 000125
2007 000378 000249 000125
Here's the graph. The blue columns are the crude numbers. The maroon columns are the numbers as a proportion of the year's seer records, and the white column are the numbers as a porportion of the U.S. population in the examined year.
When the incidence of a tumor increases almost every year, and we're clueless to explain the increase, it's probably worth thinking about the problem.
Jump to Tomorrow's Blog
- © 2010 Jules Berman
key words: carcinogenesis, neoplasia, neoplasms, tumor development, tumour development, germ cell tumor, germ cell tumour, tumor epidemiology, increasing germ cell cancer rates, germ cell cancer, seminomas, seminomatous, common disease, orphan disease, orphan drugs, genetics of disease, disease genetics, rules of disease biology, rare disease, pathology
In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.
I urge you to read more about my book. There's a generous preview of the book at the Google Books site.
Sunday, September 26, 2010
Tumor speciation revisited
"Things that are new are wont to be set forward rudely and formlessly, and then must be polished and perfected in succeeding centuries."
- Pappus, a Helenistic mathematician (circa 350-300 B.C.E.)
Regular readers of this blog all know that I have a keen interest in the tumor speciation (why we encounter a the set of tumor types that are familiar to all pathologists, and no others). Some examples of different types of tumors are: follicular lymphomas, glioblastomas, oligodendrogliomas, seminomas, hepatocellular carcinomas, etc.)
I find the question of tumor speciation to be profound for the following reason: Research in the genetics of tumors has found that tumors are incredibly complex, with some tumors having thousands of genetic mutations, making each tumor unique from every other tumor that has ever occurred in humans. If every tumor is unique, and if many tumors are genetically complex (many mutations) and internally heterogeneous (a tumor cell may be genetically separable from another tumor cell from the same tumor), then why are there only a finite number of different kinds of tumors? Shouldn't there be a near-infinite number of tumor types?
In a prior post, I tried to answer this question, drawing an analogy from animal speciation, and though the argument seems valid, I can see how it might confuse readers. I spent much of a chapter in my Neoplasms book explaining tumor speciation, but I can't help but wonder if there's a shorter explanation.
Here's my third try:
Basically, cancer is caused by alterations in the genome. Tumor speciation is restricted to a relatively small set of patterns in the epigenome.
That's it! Here's the explanation of what it means and why it makes sense.
When oncogenic mutations occur in cells, a malignant phenotype can only arise in cells that have a specific type of differentiation. The type of differentiation that a cell manifests is determined by the epigenome (the non-sequence modifications to DNA). There are about 200 different cell types in the body. Each cell type within an individual animal has the same exact genome (DNA sequence) as every other cell type in the same animal. Neutrophils, enterocytes, neurons, thyroid cells differ from one another because of differences in their epigenomes.
Because we only observe about 200 different cell types in the body, it's likely that only a finite set of epigenomic patterns "work"; i.e., sustain cell viability. In the case of cancer, the cancer genotype can only manifest itself within a finite set of epigenomic patterns. Specific types of genetic alterations are found in specific types of epigenomic patterns (e.g., the bcr/abl mutation is seen in myeloid lineage cells). Even when cancer mutations become complex, their malignant phenotype can only occur in a restricted epigenomic background.
What happens during the process of carcinogenesis (the period following a carcinogenic mutation and leading to the emergence of an invasive cancer, often years later)? Maybe carcinogenesis requires epigenomic accommodation of the cancer genotype. Over multiple cell generations, the epigenome continuously changes until a stable epigenomic pattern is selected. Because most epigenomic patterns are not viable, most cancer mutations never lead to the emergence of a tumor.
This argument hardly constitutes proof of anything, but in my Neoplasms book, I provide many examples of how tumors develop within the constraints of allowable epigenomic patterns (i.e., the observed differentiated cell types).
Jump to the next Specified Life blog
- © 2010 Jules Berman
In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.
I urge you to read more about my book. There's a generous preview of the book at the Google Books site.
tags: biology of rare diseases, common diseases, genetic disease, disease genetics, orphan diseases, orphan drugs, rare disease organizations, rare disease research, rare diseases,rare disease funding, rare disease research, funding for rare diseases, importance of rare diseases, funding opportunities, books about rare diseases, books about orphan drugs, orphan drug development, pathology of rare diseases, complex diseases, carcinogenesis, neoplasia, neoplasms, oncogenes, cancer development, epigenome, genome, cancer diversity, cancer phenotype, cancer genotype, cancer epigenotype, tumor development, tumour development
- Pappus, a Helenistic mathematician (circa 350-300 B.C.E.)
Regular readers of this blog all know that I have a keen interest in the tumor speciation (why we encounter a the set of tumor types that are familiar to all pathologists, and no others). Some examples of different types of tumors are: follicular lymphomas, glioblastomas, oligodendrogliomas, seminomas, hepatocellular carcinomas, etc.)
I find the question of tumor speciation to be profound for the following reason: Research in the genetics of tumors has found that tumors are incredibly complex, with some tumors having thousands of genetic mutations, making each tumor unique from every other tumor that has ever occurred in humans. If every tumor is unique, and if many tumors are genetically complex (many mutations) and internally heterogeneous (a tumor cell may be genetically separable from another tumor cell from the same tumor), then why are there only a finite number of different kinds of tumors? Shouldn't there be a near-infinite number of tumor types?
In a prior post, I tried to answer this question, drawing an analogy from animal speciation, and though the argument seems valid, I can see how it might confuse readers. I spent much of a chapter in my Neoplasms book explaining tumor speciation, but I can't help but wonder if there's a shorter explanation.
Here's my third try:
Basically, cancer is caused by alterations in the genome. Tumor speciation is restricted to a relatively small set of patterns in the epigenome.
That's it! Here's the explanation of what it means and why it makes sense.
When oncogenic mutations occur in cells, a malignant phenotype can only arise in cells that have a specific type of differentiation. The type of differentiation that a cell manifests is determined by the epigenome (the non-sequence modifications to DNA). There are about 200 different cell types in the body. Each cell type within an individual animal has the same exact genome (DNA sequence) as every other cell type in the same animal. Neutrophils, enterocytes, neurons, thyroid cells differ from one another because of differences in their epigenomes.
Because we only observe about 200 different cell types in the body, it's likely that only a finite set of epigenomic patterns "work"; i.e., sustain cell viability. In the case of cancer, the cancer genotype can only manifest itself within a finite set of epigenomic patterns. Specific types of genetic alterations are found in specific types of epigenomic patterns (e.g., the bcr/abl mutation is seen in myeloid lineage cells). Even when cancer mutations become complex, their malignant phenotype can only occur in a restricted epigenomic background.
What happens during the process of carcinogenesis (the period following a carcinogenic mutation and leading to the emergence of an invasive cancer, often years later)? Maybe carcinogenesis requires epigenomic accommodation of the cancer genotype. Over multiple cell generations, the epigenome continuously changes until a stable epigenomic pattern is selected. Because most epigenomic patterns are not viable, most cancer mutations never lead to the emergence of a tumor.
This argument hardly constitutes proof of anything, but in my Neoplasms book, I provide many examples of how tumors develop within the constraints of allowable epigenomic patterns (i.e., the observed differentiated cell types).
Jump to the next Specified Life blog
- © 2010 Jules Berman
In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.
I urge you to read more about my book. There's a generous preview of the book at the Google Books site.
tags: biology of rare diseases, common diseases, genetic disease, disease genetics, orphan diseases, orphan drugs, rare disease organizations, rare disease research, rare diseases,
Friday, September 24, 2010
Melanoma and the precancer time machine
In an earlier post, I explained the precancer time machine phenomenon. Basically, when you successfully treat precancers, you don't see an immediate drop in the incidence of invasive cancers; you see a drop in invasive cancers at some point in the future, corresponding to the time at which the treated precancers would have developed into invasive cancers.
In the earlier post, I demonstrated that the precancer time machine seemed to apply in the case of dcis and invasive breast cancer.
In today's post, I've used the latest SEER (The U.S. National Cancer Institute's Surveillance Epidemiology and End Results) cancer data to show that there seems to be the same phenomenon going on for melanoma precancers.
The topic of treating melanoma precancers has been somewhat controversial. It would seem to be a no-brainer that we can reduce the incidence of invasive melanomas by treating melanoma precancers (dysplastic nevi and in situ melanomas). Unfortunately, there is no epidemilogiic evidence to support this assertion. Basically, the incidence of invasive melanoma seems to be rising every year, despite our best efforts to stem the tide (through the use of sunscreens, avoiding exposure to strong sunlight, and treating precancers).
The latest SEER data (which covers cancer cases from 1973 to 2007) seems to offer some hope that conditions might be improving.
Here's the graph of invasive melanome incidence in the U.S. SEER population.
The tallest bars (blue) are the crude numbers of occurrences of invasive malignant melanoma. The middle bars (maroon) are the occurrences of invasive melanoma expressed as a proportion of the total number of SEER cases. The bottom bars (white), are the occurrences of melanoma expressed as a proprotion of the total population of the U.S. in the perspective years.
Here are the numbers:
In the last two years studied (2006, 2007), the incidence of invasive malignant melanoma has dropped. Is this just a fluke, or does it indicate a real trend? There's no way to be sure, but inspection of the graph would indicate that it's the first time since 1973 when incidence has dropped two years running.
What about the corresponding incidence of in situ melanoma (the non-invasive precursor for invasive melanoma)?
Here's the graph for in situ melanoma.
Here are the numbers.
The incidence of in situ melanoma keeps going up and up. That's as it should be. When we successfully cure more and more in situ melanomas, we reduce the incidence of invasive melanomas.
The lag between the rise in incidence of the in situ lesions and the drop in incidence of the invasive lesions is due to the precancer time machine phenomenon.
Can we be sure? Not yet. Hopefully, over the next five years or so, the data will become a little more convincing.
- © 2010 Jules Berman
key words: precancer, precancerous, skin cancer, dysplastic nevi, dysplastic nevus, dysplastic naevus, dysplastic naevi, cancer mortality, cancer prevention, carcinogenesis
In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.
I urge you to read more about my book. There's a generous preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy of this book for your library or reading room.
In the earlier post, I demonstrated that the precancer time machine seemed to apply in the case of dcis and invasive breast cancer.
In today's post, I've used the latest SEER (The U.S. National Cancer Institute's Surveillance Epidemiology and End Results) cancer data to show that there seems to be the same phenomenon going on for melanoma precancers.
The topic of treating melanoma precancers has been somewhat controversial. It would seem to be a no-brainer that we can reduce the incidence of invasive melanomas by treating melanoma precancers (dysplastic nevi and in situ melanomas). Unfortunately, there is no epidemilogiic evidence to support this assertion. Basically, the incidence of invasive melanoma seems to be rising every year, despite our best efforts to stem the tide (through the use of sunscreens, avoiding exposure to strong sunlight, and treating precancers).
The latest SEER data (which covers cancer cases from 1973 to 2007) seems to offer some hope that conditions might be improving.
Here's the graph of invasive melanome incidence in the U.S. SEER population.
The tallest bars (blue) are the crude numbers of occurrences of invasive malignant melanoma. The middle bars (maroon) are the occurrences of invasive melanoma expressed as a proportion of the total number of SEER cases. The bottom bars (white), are the occurrences of melanoma expressed as a proprotion of the total population of the U.S. in the perspective years.
Here are the numbers:
crude of SEER of U.S. Pop
1973 001062 001916 000501
1974 001305 001938 000610
1975 001559 002116 000721
1976 001601 002116 000734
1977 001791 002337 000813
1978 001829 002347 000821
1979 001973 002460 000876
1980 002190 002645 000963
1981 002298 002690 001001
1982 002352 002714 001015
1983 002350 002617 001005
1984 002462 002638 001043
1985 002795 002864 001174
1986 002947 002942 001227
1987 003050 002879 001258
1988 002948 002743 001205
1989 003194 002896 001294
1990 003272 002816 001311
1991 003518 002853 001395
1992 003569 002786 001399
1993 003611 002860 001400
1994 003904 003097 001499
1995 004189 003283 001594
1996 004438 003641 001673
1997 004627 003668 001728
1998 004739 003663 001753
1999 004893 003704 001794
2000 005105 003832 001814
2001 005380 003911 001886
2002 005377 003857 001867
2003 005514 003993 001898
2004 005859 004062 001998
2005 006451 004431 002180
2006 006431 004335 002152
2007 006325 004172 002097
In the last two years studied (2006, 2007), the incidence of invasive malignant melanoma has dropped. Is this just a fluke, or does it indicate a real trend? There's no way to be sure, but inspection of the graph would indicate that it's the first time since 1973 when incidence has dropped two years running.
What about the corresponding incidence of in situ melanoma (the non-invasive precursor for invasive melanoma)?
Here's the graph for in situ melanoma.
Here are the numbers.
crude of SEER of U.S. Pop
1973 000035 000063 000016
1974 000059 000087 000027
1975 000081 000109 000037
1976 000096 000126 000044
1977 000155 000202 000070
1978 000177 000227 000079
1979 000177 000220 000078
1980 000263 000317 000115
1981 000276 000323 000120
1982 000326 000376 000140
1983 000384 000427 000164
1984 000466 000499 000197
1985 000638 000653 000268
1986 000723 000721 000301
1987 000782 000738 000322
1988 000824 000766 000337
1989 000976 000885 000395
1990 001127 000970 000451
1991 001192 000966 000472
1992 001373 001072 000538
1993 001375 001089 000533
1994 001599 001268 000614
1995 001920 001504 000730
1996 002091 001715 000788
1997 002258 001790 000843
1998 002533 001957 000937
1999 002765 002093 001013
2000 003202 002404 001137
2001 003508 002550 001230
2002 003656 002622 001269
2003 003429 002483 001180
2004 003604 002499 001229
2005 004060 002788 001372
2006 004048 002728 001354
2007 004291 002831 001422
The incidence of in situ melanoma keeps going up and up. That's as it should be. When we successfully cure more and more in situ melanomas, we reduce the incidence of invasive melanomas.
The lag between the rise in incidence of the in situ lesions and the drop in incidence of the invasive lesions is due to the precancer time machine phenomenon.
Can we be sure? Not yet. Hopefully, over the next five years or so, the data will become a little more convincing.
- © 2010 Jules Berman
key words: precancer, precancerous, skin cancer, dysplastic nevi, dysplastic nevus, dysplastic naevus, dysplastic naevi, cancer mortality, cancer prevention, carcinogenesis
In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.
I urge you to read more about my book. There's a generous preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy of this book for your library or reading room.
Wednesday, September 22, 2010
Methods in Medical Informatics
My new book, Methods in Medical Informatics: Fundamentals of Healthcare Programming in Perl, Python,and Ruby, was published yesterday by CRC Press.
I've prepared web pages with a book description and the Table of Contents for anyone interested.
- Jules Berman
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