Research Papers:

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

Elena Maccaroni _, Raffaella Bracci, Riccardo Giampieri, Francesca Bianchi, Laura Belvederesi, Cristiana Brugiati, Silvia Pagliaretta, Michela Del Prete, Mario Scartozzi and Stefano Cascinu

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Oncotarget. 2015; 6:38737-38748. https://doi.org/10.18632/oncotarget.5395

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Elena Maccaroni1, Raffaella Bracci1, Riccardo Giampieri1, Francesca Bianchi1, Laura Belvederesi1, Cristiana Brugiati1, Silvia Pagliaretta1, Michela Del Prete1, Mario Scartozzi2, Stefano Cascinu1

1Clinica di Oncologia Medica e Centro Regionale di Genetica Oncologica, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti, Ancona, Italy

2Medical Oncology, Azienda Ospedaliero-Universitaria di Cagliari, Monserrato (CA), Cagliari, Italy

Correspondence to:

Raffaella Bracci, e-mail: [email protected]

Keywords: Lynch syndrome, germline mutation, colorectal cancer, prognosis, genetic testing

Received: July 23, 2015     Accepted: October 05, 2015     Published: October 15, 2015


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, 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).

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.

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