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When a cell loses its DNA spell-checker, short repeated stretches of DNA slip. This paper found that one of the genes destroyed that way is the brake that stops bowel cells growing, which is how a repair defect becomes a cancer.
Human colon cancer cell lines with high rates of microsatellite instability were found to harbour mutations in the type II TGF-beta receptor gene. Eight such examples, from three different mutations, were identified. The mutations clustered within small repeated sequences in the gene, were accompanied by the absence of cell surface receptors, and were usually associated with small amounts of transcript. Receptor mutation, by allowing cells to escape TGF-beta-mediated growth control, links DNA repair defects to a specific pathway of tumour progression.
It showed how mismatch repair failure selects for cancer: coding microsatellites in tumour suppressors are the targets, which is why TGFBR2, ACVR2A, RNF43 and B2M frameshifts are the signature of MSI-high bowel cancer.
Shares Kenneth W. Kinzler, Bert Vogelstein, Mismatch repair & microsatellite instability, Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center.
Shares Kenneth W. Kinzler, Bert Vogelstein, Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), Mismatch repair & microsatellite instability.
Shares Kenneth W. Kinzler, Science, Bert Vogelstein, Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center.
Shares Kenneth W. Kinzler, Bert Vogelstein, Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center.
Shares Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), Mismatch repair & microsatellite instability, Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR), Colorectal cancer.
Shares Kenneth W. Kinzler, Science, Bert Vogelstein, Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center.
Shares Kenneth W. Kinzler, Bert Vogelstein, Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center.
Shares Science, Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center, Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR).