In yesterday's blog, we discussed malignant rhabdoid tumors as the prototypical epigenomic cancer (a malignant tumor characterized by massive alterations of the epigenomic landscape with preservation of chromosomal diploidy and genetic (DNA sequence) stability).
Malignant rhabdoid tumors are not the only example of an epigenomic cancer. Germ cell cancers also belong in this group. In the case of germ cell cancers, cell totipotency (ability to differentiate towards any embryonic or extra-embryonic lineage) is achieved after chromosomes lose their epigenetic programming (modifications) through a normal cellular process unique to germ cells: erasure.
I have prepared a separate web page that discusses some of the biological mysteries surrounding germ cell tumors; mysteries that have puzzled cancer researchers and pathologists for decades.
http://www.julesberm.info/factoids/germcell.htm
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-© 2010 Jules J. Berman
key words: cancer, neoplasia, epigenome, epigenetics, cytogenetics, neoplasms, precancer, tumor biology, tumour biology, carcinogenesis, cancer development, epigenomics
Showing posts with label epigenomics. Show all posts
Showing posts with label epigenomics. Show all posts
Saturday, October 16, 2010
Thursday, October 14, 2010
Rhabdoid tumors: a reasonable hypothesis
This blog continues a discussion of malignant rhabdoid tumors, found in yesterday's post.
Most malignant rhabdoid tumors, regardless of their tissues of origin, have bi-allelic loss of the INI1 gene, also known as SNF5, SMARCB1, andBAF47. This gene is a core component of the SWI/SNF complex that plays a crucial role in chromatin remodeling.[1]
Bi-allelic loss of INI1 may cause cancer through a purely epigenomic route, whereby disruption of normal gene transcription, causing alterations in the expression of thousands of genes, and leading to a characteristic malignant phenotype (i.e., malignant rhabdoid cells) in cells of several different developmental lineages. Essenetially, bi-allelic loss of INI1 hijacks cells to create malignant phenotype that circumvents the usual process of cancer development observed in virtually every other type of cancer.
The resulting rhabdoid tumors are epigenomic cancers, marked by aberrant gene transcription without genomic abnormalities (e.g., aneuploidy, chromosome abnormalities, gene mutations, genetic instability).
Here are some of the experimental observations that support this hypothesis:
The exceedingly rapid emergence of cancer in 100% of INI1-deficient mice would suggest that the mechanism of tumor development bypasses the protracted steps of carcinogenesis exhibited by tumors caused by the accumulation of specific genetic mutations (i.e., virtually every other kind of observed cancer).
In tomorrow's post, we'll discuss the implications of these observations on our general approach to cancer classification, cancer treatment, and on our understanding of precancers.
REFERENCES
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
Most malignant rhabdoid tumors, regardless of their tissues of origin, have bi-allelic loss of the INI1 gene, also known as SNF5, SMARCB1, andBAF47. This gene is a core component of the SWI/SNF complex that plays a crucial role in chromatin remodeling.[1]
Bi-allelic loss of INI1 may cause cancer through a purely epigenomic route, whereby disruption of normal gene transcription, causing alterations in the expression of thousands of genes, and leading to a characteristic malignant phenotype (i.e., malignant rhabdoid cells) in cells of several different developmental lineages. Essenetially, bi-allelic loss of INI1 hijacks cells to create malignant phenotype that circumvents the usual process of cancer development observed in virtually every other type of cancer.
The resulting rhabdoid tumors are epigenomic cancers, marked by aberrant gene transcription without genomic abnormalities (e.g., aneuploidy, chromosome abnormalities, gene mutations, genetic instability).
Here are some of the experimental observations that support this hypothesis:
- The only characteristic gene alteration in rhabdoid tumors is bi-allelic loss of INI1. Rhabdoid tumors lack gene amplifications, gene deletions and, aside
from INI1 loss, are indistinguishable from normal cells on single-nucleotide polymorphism arrays.[1] - Oncogenic pathways often found in common cancers were found to be upregulated or amplified in rhabdoid tumors, indicating that the molecular phenotype of cancer can be achieved through an epigenomic mechanism. [1]
- In a mouse tumor model, loss of INI1 results in cancers in 100% of INI1-deficient mice. The cancer arise, on average, in just 11 days.[2] This is much shorter than the time required to develop chemically-induced cancers in mice. Furthermore, very few chemical carcinogen protocols produce cancers in 100% of the treated animals.
The exceedingly rapid emergence of cancer in 100% of INI1-deficient mice would suggest that the mechanism of tumor development bypasses the protracted steps of carcinogenesis exhibited by tumors caused by the accumulation of specific genetic mutations (i.e., virtually every other kind of observed cancer).
In tomorrow's post, we'll discuss the implications of these observations on our general approach to cancer classification, cancer treatment, and on our understanding of precancers.
REFERENCES
- 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.
- Roberts CW, Leroux MM, Fleming MD, Orkin SH.
Highly penetrant, rapid tumorigenesis through conditional inversion of the
Cancer Cell 2:415-425, 2002.
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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
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?
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.
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
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?
- They vary in shape and size from one cancer cell to another.
- 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.
- 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.
- 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.
- 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.
- 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.
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
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