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