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Mismatch repair analysis of inherited MSH2 and/or MSH6 variation pairs found in cancer patients - Kantelinen - Human Mutation
Abstract
Mismatch
repair (MMR) malfunction causes the accumulation of mismatches in the
genome leading to genomic instability and cancer. The inactivation of an
MMR gene (MSH2, MSH6, MLH1 or PMS2) with an inherited
mutation causes Lynch syndrome (LS), a dominant susceptibility to
cancer. MMR gene variants of uncertain significance (VUS) may be
pathogenic mutations which cause LS, may result in moderately increased
cancer risks, or may be harmless polymorphisms. Our study suggests that
an inherited MMR VUS individually assessed as proficient may, however,
in a pair with another MMR VUS found in the same colorectal cancer (CRC)
patient have a concomitant contribution to the MMR deficiency. Here,
eight pairs of MMR gene variants found in cancer patients were
functionally analyzed in an in vitro MMR assay. Although the other pairs do not suggest a compound deficiency, the MSH2 VUS pair c.380A>G/c.982G>C (p.Asn127Ser/p.Ala328Pro), which nearly halves the repair capability of the wild type MSH2
protein, is presumed to increase the cancer risk considerably.
Moreover, two MSH6 variants, c.1304T>C (p.Leu435Pro) and c.1754T>C
(p.Leu585Pro), were shown to be MMR deficient. The role of one of the
most frequently reported MMR gene VUS, MSH2 c.380A>G
(p.Asn127Ser), is especially interesting, since its concomitant defect
with another variant could finally explain its recurrent occurrence in
CRC patients.
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