Herein, we investigate the clinical meaning of MMR deficiency in breast cancer by immunohistochemical assessment of MSH2, MSH6, MLH1 and PMS2 on a large series of breast cancers linked to detailed biomarker and long-term outcome data.
Mismatch repair deficiency was associated with tumor development and progression therefore, current study was aimed to investigate MLH1 and MSH2 expression in breast cancer and correlate patients' clinicopathological factors with status of mismatch repair genes.
Six (7%) tumors were p53 abnormal, 82 (91%) were p53 normal, and 2 (2%) tumors had MMR deficiency (1 MSH6 loss and 1 MSH2/6 loss; both were p53 normal).
Patients whose tumors showed MMR deficiency (MMR-D) and wild-type BRAF were selected to undergo mutational analysis of the MLH1 and MSH2 genes using Sanger sequencing.
The patient harboring a MSH2 mutation experienced a long-term complete response after pembrolizumab, while the patient with high mutational burden and absence of mismatch repair deficiency did not have any response.
Tumor MMR-deficiency was observed for 22 cases [69 %; 95 % confidence interval (CI) 50-83 %], with the highest prevalence of MMR-deficiency in tumors from MSH2 mutation carriers (19/23, 83 %) compared with MLH1 and MSH6 carriers combined (3/9, 33 %; p = 0.01).
A somatic rearrangement in trans affecting MSH2 is responsible for the final mismatch repair deficiency in the corresponding tumors but the mechanisms are not well documented.
We show that silencing of the PTEN-induced putative kinase 1 (PINK1), is synthetically lethal with MMR deficiency in cells with MSH2, MLH1, or MSH6 dysfunction.
Only one patient showed MMR deficiency, as evidenced by microsatellite instability, which was acquired at relapse and was associated with reduced expression of both MLH1 and MSH2.
Currently, testing for mismatch repair deficiency in colorectal cancers is initiated by performing immunohistochemistry with four antibodies (MLH1, PMS2, MSH2 and MSH6).
All patients underwent tumor microsatellite instability analysis and immunostaining for MLH1 and MSH2, and those with MMR deficiency (n = 91) underwent tumor BRAF V600E mutation analysis and MLH1/MSH2 germline testing.
Sensitivity, specificity and positive predictive value (PPV) of the PREMM(1,2) and the Barnetson models for identification of MLH1/MSH2 mutation carriers were evaluated and compared with the revised Bethesda guidelines (RBG), Amsterdam II criteria, and tumour analysis for MMR deficiency.
The immunohistochemical analysis has proven to be an effective and sensitive approach for screening MMR deficiency regardless of somatic inactivation or promoter hypermethylation of hMSH2 and/or hMLH1 gene.
IHC analysis had a sensitivity of 100% in detecting MMR deficiency in carriers of a pathogenic MMR mutation, and can be used to predict which gene is expected to harbor the mutation for MLH1, MSH2 and MSH6.
In conclusion, immunohistochemistry of hMLH1 and hMSH2 proteins is a useful method to predict the presence of mismatch repair deficiency, although its sensitivity is lower than that of MSI analysis.
In contrast, we did not identify frameshift mutations in the (A)8 tract of MSH3 in a control group of 18 colorectal carcinomas in which the MMR deficiency was based on the inactivation of MSH2.
In the present investigation, hMLH1 and hMSH2 immunohistochemistry was tested in order to evaluate the utility of this method in predicting MMR deficiency.
Microsatellite instability is a hallmark of mismatch repair deficiency in hereditary nonpolyposis colorectal cancer and results from mutations in the mismatch repair genes MLH1 or MSH2 or from gene inactivation associated with DNA methylation.