Prognostic impact of mismatch repair genes germline defects in colorectal cancer patients: are all mutations equal?

Abstract

BackgroundLynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) syndrome, caused by germline mutations in MisMatch Repair (MMR) genes, particularly in MLH1, MSH2 and MSH6. Patients with LS seem to have a more favourable prognosis than those with sporadic CRC, although the prognostic impact of different mutation types is unknown.Aim of our study is to compare survival outcomes of different types of MMR mutations in patients with LS-related CRC.Methods302 CRC patients were prospectively selected on the basis of Amsterdam or Revised Bethesda criteria to undergo genetic testing: direct sequencing of DNA and MLPA were used to examine the entire MLH1, MSH2 and MSH6 coding sequence.Patients were classified as mutation-positive or negative according to the genetic testing result.ResultsA deleterious MMR mutation was found in 38/302 patients. Median overall survival (OS) was significantly higher in mutation-positive vs mutation-negative patients (102.6 vs 77.7 months, HR:0.63, 95%CI:0.46–0.89, p = 0.0083). Different types of mutation were significantly related with OS: missense or splicing-site mutations were associated with better OS compared with rearrangement, frameshift or non-sense mutations (132.5 vs 82.5 months, HR:0.46, 95%CI:0.16–0.82, p = 0.0153).ConclusionsOur study confirms improved OS for LS-patients compared with mutation-negative CRC patients. In addition, not all mutations could be considered equal: the better prognosis in CRC patients with MMR pathogenic missense or splicing site mutation could be due to different functional activity of the encoded MMR protein. This matter should be investigated by use of functional assays in the future.

Mismatch repair deficiency may affect clinical outcome through immune response activation in metastatic gastric cancer patients receiving first-line chemotherapy

“…Similar data have been found in other tumor types, such as colorectal [5][6][7][8] and ovarian cancers, thus supporting the observation that MMR-deficient tumors have distinctive biological and clinical characteristics. Intriguingly, recent findings also hypothesized that this favorable clinical behavior might be related to immune response induced by tumor cells in the presence of MMR deficiency.…”

High microsatellite instability (MSI-H) colorectal carcinoma: a brief review of predictive biomarkers in the era of personalized medicine

“…In addition, patients with Lynch syndrome have an increased risk of synchronous or metachronous tumors that include extracolonic sites (small bowel, stomach, endometrium, skin, genitourinary tract) [ 5 , 13 ]. Prognostically, patients with HNPCC have a more favorable outcome (overall survival) in comparison with stage-matched sporadic CRCs [ 14 , 15 ].…”

Molecular subtype classification of urothelial carcinoma in Lynch syndrome

“…Colorectal cancers that develop in Lynch syndrome show a better disease-specific survival than sporadic colorectal cancer, most likely due to the immunogenic signatures in MMR-defective tumors (Boland, 2016;Maccaroni et al, 2015). This hypothesis is further supported by the finding that MMR status predicts clinical benefit from PD-1 blockade in colorectal cancer (Le et al, 2015).…”