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

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Table 1: Clinical and pathological characteristics of patients according to mutational status

Presence of synchronous, metachronous colorectal or other HNPCC-associated tumours (mutation + vs -)

19 (50%)

59 (23.4%)

....The identification of the “clinical relevance” of the mutation that has been identified will be even more crucial if we consider that, with the introduction of next-generation-sequencing methods, a greater number of mutations of unknown clinical significance will be identified. In particular, recent published works point out at other genes implied in colorectal cancer pathogenesis (APC, MUTYH, STK11 and BRCA1/2) as explanations of familial colorectal cancer syndromes in patients who do not present mutations in standard MMR protein gene system [25]......

BACKGROUND:

Lynch 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.

METHODS:

302 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.

RESULTS:

A 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...). 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...).

CONCLUSIONS:

Our 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.