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.

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- © 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