This post continues the discussion of rhabdoid tumors found in yesterday's blog.
Rhabdoid tumors seem to be the prototypical example of an epigenomic cancer; a cancer caused by destabilization of the epigenome.
It is impossible to underestimate the importance of this assertion, if true. For decades, cancer research has been focused on the genetic changes in cancers. It was more or less assumed that every advanced cancer has numerous genetic (DNA sequence) defects that contribute to the phenotype (morphology and biological behavior) of cancer cells. To be confronted with a tumor fueled by epigenetic (i.e., non-sequence non-DNA) alterations, is profoundly shocking.
To be sure, this alleged epigenomic tumor is rare, with only a few dozen reported in the U.S. (compared with about a million new cases of "gene-based" cancers, or two million cases if you count the common skin cancers).
Still, in cancer, we tend to learn the most important lessons from the rarest of cancers.
Observations on the development of rhabdoid tumors in experimental systems, suggest that these tumors can arise incredibly rapidly in mice (11 days). This rapid development would suggest that rhabdoid tumors do not follow the long developmental process that occurs in gene-based cancers.
With an 11-day development time, it seems likely that rhabdoid tumors have no precancerous lesions (lesions that precede the development of gene-based cancers).
How can a cancer NOT have a precancer? A precancer is a sort of natural experiment conducted during carcinogenesis. Basically, the precancer provides a way for developing cancer cells to find an epigenomic pattern (i.e., differentiation phenotype) that can support the cancer that emerges. A single precancer can give rise to several epigenomic patterns available to its lineage (e.g., bronchial dysplasia can give rise to squamous carcinoma or small cell carcinoma or adenocarcinoma). Precancers sometimes regress, and this regression presumably happens when a viable "fit" into an invasive cancer cell type (i.e., epigenomic tumor pattern) fails to occur.
In the case of rhabdoid tumors, there is no "epigenomic pattern" into which the rhabdoid tumor "fits." These tumors can arise from neuroectoderm or nephric mesoderm, or mesenchyme. They don't need to fit into any differentiated lineage. They simply grow, aggressively, when their epigenome is scrambled into a viable cell. If there's no necessity to find a differentiated lieage for the rhabdoid tumor cells, then there is no need for a precancerous stage.
Because there is global alteration of normal gene transcription in rhabdoid tumors, you might expect that a chemotherapeutic intervention aimed at restoring a semblance of normal epigenomic control, might inhibit the growth of this rare tumor.
At present, one of the most promising drugs for epigenomic dysregulation are the
histone deacetylase inhibitors (HDAC inhibitors). These inhibitors block normal remodeling of chromatin structure, and thus change the way that genes are expressed.
HDAC inhibitors, and a few other agents, will probably be studied to see if they are effective agents against tumors whose epigenomes contribute to their malignant phenotypes.
Are there tumors, other than rhabdoid tumors, that are fueled by epigenomic dysregulation? This will be the topic of future posts.
Jump to tomorrow's post
-© 2010 Jules J. Berman
key words: cancer, neoplasia, epigenome, epigenetics, cytogenetics, neoplasms, precancer, tumor biology, tumour biology, carcinogenesis, cancer development, pre-cancer, precancerous lesions, pre-malignant lesions, gene synonyms: Snf5 Ini1 Baf47 SmarcB1, epigenomics
