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
