Immunohistochemistry (IHC) for DNA mismatch repair proteins MLH1, PMS2, MSH2, and MSH6 is used for microsatellite instability (MSI) screening in colorectal carcinoma (CRC) and endometrial carcinoma (EC).
Pathogenic MSH6 variants caused a sex-limited trait with high endometrial cancer risk but only modestly increased colorectal cancer risk in both genders.
Overall, 15% (7/50) of microsatellite instability high endometrial carcinomas showed isolated loss of MSH6 in contrast to 7% (1/15) seen in microsatellite instability high colorectal carcinomas.
The three pathogenic variants included two colorectal cancers with MLH1 loss and high MSI and one endometrial cancer with MSH6 loss and microsatellite stability.
Lynch syndrome due to pathogenic variants in the DNA mismatch repair genes MLH1, MSH2, and MSH6 is predominantly associated with colorectal and endometrial cancer, although extracolonic cancers have been described within the Lynch tumor spectrum.
Mutations in MSH6 were less prevalent, and MSH6 mutation carriers presented with colorectal and endometrial cancer at later ages than carriers of mutations in MSH2 or MLH1.
Here we describe our institution's experience with a prospective universal screening protocol in which all ECs resected over a period of 19 months (n=242) were screened for MLH1, PMS2, MSH2, and MSH6 deficiencies using IHC, followed by MLH1 promoter methylation testing when appropriate.
We analyzed immunohistochemistry of MMR proteins (MLH1/MSH2/MSH6/PMS2) and MLH1 promoter methylation in primary endometrial carcinomas from 221 consecutive patients.
Multivariate survival analysis revealed that MSH6 gene expression was associated with outcome of endometrial cancer patients independently from traditional prognostic clinicopathologic parameters, which was confirmed in an independent cohort at the protein level.
Analysis of the MMR genes, in particular MSH6, seems to be appropriate in women with endometrial cancer and a family history of tumours associated with LS.
Lynch syndrome (LS) is an autosomal-dominant inherited disorder mainly caused by a germline mutation in the DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) and is associated with increased risk for various cancers, particularly colorectal cancer and endometrial cancer (EC).
Endometrial cancer of the proband was investigated for microsatellite instability (MSI) and immunohistochemical expression of MLH1, MSH2 and MSH6 proteins.
In this study, we investigated the frequency of BAF250a immunohistochemical loss in a cohort of high-grade endometrial cancers (n=190) and correlated it with mismatch repair (hMLH1, hMSH2, hMSH6, and hPMS2) and p53 protein expression.
Endometrial cancers from 173 patients recruited to the Nanchong Central Hospital were tested for MMR (MLH1, MSH2, PMS2, and MSH6) protein expression using immunohistochemistry (IHC).
Furthermore, the mean age at diagnosis of endometrial cancer in Japanese MSH6 mutation carriers (49.2 years) was earlier than previous reports from Western countries (56.5 years).
Therefore, a cohort of 187 pure endometrioid and non-endometrioid endometrial carcinomas, carefully characterized as to clinical and pathological features, was examined for PTEN sequence abnormalities and the immunohistochemical expression of PTEN and the DNA mismatch repair proteins MLH1, MSH2, MSH6, and PMS2.
Lynch syndrome, which is associated with mutations in 1 of 4 mismatch repair genes (MLH1, MSH2, MSH6, and PMS2), is a well-described hereditary cancer predisposition syndrome associated with a substantial risk of colon, rectum, and endometrial cancer.
We identified germline mutations in BRCA1 and in MSH6 in a patient with increased risk for HBOC diagnosed with endometrial cancer at the age of 46 years.