Lynch Syndrome (LS) is associated with germline mutations in one of the mismatch repair (MMR) genes, including MutL homolog 1 (MLH1), MutS homolog 2 (MSH2), MSH6, PMS1 homolog 2, mismatch repair system component (PMS2), MLH3 and MSH3.
So far, the role of germline MSH3 variants remains unclear, as to our knowledge heterozygous truncating variants are not regarded causative for LS, but were detected in patients with CRC, and recently biallelic MSH3 defects have been identified in two patients with adenomatous polyposis.
To determine a possible role of MSH3 as predisposing to CRC in Lynch syndrome, we screened MSH3 for germ-line mutations in 79 unrelated Lynch patients who were negative for pathogenetic mutations in MLH1, MSH2 and MSH6.
To determine a possible role of MSH3 as predisposing to CRC in Lynch syndrome, we screened MSH3 for germ-line mutations in 79 unrelated Lynch patients who were negative for pathogenetic mutations in MLH1, MSH2 and MSH6.
Two germline mutations in the hMSH6 region have been reported in hereditary nonpolyposis colorectal cancer (HNPCC); however, no germline mutations in the hMSH3 gene have been reported yet.
These data support the notion that these HNPCC-associated mutations may affect some other function of the heterodimeric complexes than simply the static interaction of hMSH2 with hMSH3 or hMSH2 with hMSH6.
To clarify the tumorigenetic role of hMSH3, we screened for somatic mutations at the hMSH3 (A)8 repeat in 29 tumors from 23 hereditary nonpolyposis colorectal cancer patients.
A germ-line mutation of hMSH6 (also called GTBP) was found in a hereditary nonpolyposis colorectal cancer (HNPCC)-like patient in whom germ-line mutations of hMSH2, hMSH3, or hMLH1 had not been detected.