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Some families with inherited bowel cancer have no mutation in any repair gene. The fault is in the neighbouring gene: losing its end makes it run on into the repair gene and chemically silence it, but only in the tissues where the neighbour is switched on.
Patients from Dutch and Chinese families with MSH2-deficient tumours were found to carry heterozygous germline deletions of the last exons of TACSTD1 (EPCAM), the gene directly upstream of MSH2. Because of these deletions, transcription of TACSTD1 extends into MSH2. The MSH2 promoter in cis with the deletion was methylated in EpCAM-positive but not in EpCAM-negative normal tissues, showing a correlation between activity of the mutated TACSTD1 allele and epigenetic inactivation of the corresponding MSH2 allele. The authors proposed gene silencing by transcriptional read-through of a neighbouring gene as a general mutational mechanism, producing generalised or mosaic epigenetic inactivation depending on the neighbour's expression pattern.
EPCAM deletion testing is now part of Lynch syndrome panels, and it explains the MSH2-deficient tumours in families where sequencing of the four repair genes comes back clean.
Shares Nature Genetics, Lynch syndrome, Epigenetic reprogramming, Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2).
Shares MSH2, Lynch syndrome, Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), Hereditary cancer syndromes.
Shares Radboudumc Centre for Oncology, Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), Mismatch repair & microsatellite instability, Colorectal cancer.
Shares Nature Genetics, Hereditary cancer syndromes, Germline vs somatic mutations, Germline (hereditary) testing.
Shares Lynch syndrome, Epigenetic reprogramming, Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), Mismatch repair & microsatellite instability.
Shares Lynch syndrome, Hereditary cancer syndromes, Germline (hereditary) testing.
Shares MSH2, Lynch syndrome, Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), Mismatch repair & microsatellite instability.
Shares Epigenetic reprogramming, Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), Mismatch repair & microsatellite instability, Colorectal cancer.