Tuesday, October 12, 2010

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