The prototypical epigenomic cancer

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.

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-© 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

Rhabdoid tumors: the first clue

This post continues a discussion of rhabdoid tumors, begun in yesterday's blog.

One of the most important clues concerning the fundemantal nature of rhabdoid tumors is revealed when we compare its nuclear morphology with its genetic structure. When we make this comparison, we discover that much of what we thought we knew about cancer cells, in general, is simply incorrect.

Here is a photomicroscopic image of a rhabdoid tumor, available in the public domain, from wikipedia:


Look closely at all the nuclei in this very typical image of a rhabdoid tumor.
What can say about the nuclei?

1. They vary in shape and size from one cancer cell to another.
   
   
2. The nuclei are mottled, with areas of light and of dark, and the sizes and locations of these light and dark areas varies from nucleus to nucleus.
   
   
3. Some nuclei have large nucleoli; the number of nucleoli vary from nucleus to nucleus, ranging from 0 to 3; the nucleoli are not uniform in size or contour, or color.
   
   
4. The nuclei are outlined by a highly irregular membrane, with thick, dark borders in some areas, alternating with light borders elsewhere, with no constant pattern from nucleus to nucleus.
   
   
5. The nuclei are not consistently round, or oval or bean-shaped. Numerous sharp puckerings are seen on the nuclear boder; some nuclei seem to have tails and protrusions; others have focally straight edges.
   

Though you can't judge it from this image, which exclusively shows malignant cells, the nuclei of the rhabdoid tumor cells are larger than the nuclei of normal cells.

What do all of these nuclear observations indicate? The nuclear morphology of rhabdoid cells conforms to the classic cytologic features that characterize malignant cells.

Pathologists assume, when they see highly abnormal nuclei, that the observed abnormalities indicate genetic alterations in chromosome number (aneuploidy) and arrangements (cytogenetic abnormalities) resulting from genetic instability; all hallmarks of cancer.

But this is not the case with rhabdoid tumors.

Rhabdoid tumors are genetically stable, and have a normal karyotype (i.e., are diploid, not aneuploid).[1] The morphologic nuclear changes in malignant rhabdoid cells do not correlate with cytogenetic defects.

How is this remotely possible? Is everything we think we know about tumor cytology incorrect?

Yes and no. The nuclei of rhabdoid cells are highly abnormal, but the abnormalities are not the result of genetic alterations. The abnormalities are due to epigenetic alterations. Histologic stains do not bind to DNA. The routine nuclear stains used by pathologists will bind to chromosomal and nuclear proteins. Basically, routine nuclear stains provide pathologists with a view of the epigenome, not the genome. In most types of cancer, cells have profound changes in both the epigenome and the genome, so the kinds of nuclear abnormalities associated with malignant cells will almost always correlate with aneuploidy and genetic instability. But not so in the case of rhabdoid tumors.

When we look at the nuclei of a rhaboid tumor, using standard histologic stains, we are seeing the ravages of profound epigenomic alterations in a unique type of cancer.

In the next blog, we'll explain the biologic basis for rhabdoid tumors, and we will show that malignant rhabdoid tumor is the prototype for epigenomic (not genomic) carcinogenesis. In subsequent blogs, we will discuss the consequences of this finding for tumor classification and for cancer treatment, in general.

1. McKenna ES, Sansam CG, Cho YJ, Greulich H, Evans JA, Thom CS, Moreau LA, Biegel JA, Pomeroy SL, Roberts CW. Loss of the epigenetic tumor suppressor SNF5 leads to cancer without genomic instability. Mol Cell Biol 28:6223-6333, 2008.
   

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-© 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