We have also noted that in these cancers both the maternally and the paternally inherited MLH1 genes are methylated and that the genes remethylate after 5-azacytidine is removed. We hypothesize that in these cancers MLH1 is actively targeted for methylation by a specific aberrant mechanism, which we hope to elucidate in the near future. Perhaps as a primitive defense against cancer, the epithelial cells of the colon that are exposed to food and other environmental mutagens are killed off on a weekly basis and renewed by a process of cell death and shedding called apoptosis. In the absence of effective mismatch repair, this segment is specifically destabilized and becomes a hot spot for insertion and deletion frameshift mutations, generally in both alleles. As they encode for truncated receptors that lack the cytoplasmic signaling domains, these mutant receptors are inactive for TGF b signaling.
Colon cancers develop from premalignant neoplastic growths known as adenomatous polyps.
Our studies of the timing of RII mutation show that the RII mutations arise in very late adenomatous polyps at exactly the time when the polyps first demonstrate areas of frank colon cancer. This suggests that TGF b regulates an important progression step that allows neoplastic adenoma cells to acquire the invasive capability that is the defining trait of frank cancers. Consistent with this hypothesis, we find that transfer of normal RII genes back into colon cancer cells in which endogenous RII is mutant abrogates the ability of these cancers to form tumors when injected into immune-deficient mice. Thus, structurally and functionally, RII acts as a tumor-suppressor gene. Indeed, by functional assay we find that 80 percent of these colon cancers have inactivated the TGF b signaling pathway.