Prognostic impact of mismatch repair genes germline defects in colorectal cancer patients: are all mutations equal?
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.
Clinica di Oncologia Medica e Centro Regionale di Genetica Oncologica, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti, Ancona, Italy.
Elena
E
Maccaroni
Clinica di Oncologia Medica e Centro Regionale di Genetica Oncologica, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti, Ancona, Italy.
Raffaella
R
Bracci
Clinica di Oncologia Medica e Centro Regionale di Genetica Oncologica, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti, Ancona, Italy.
Riccardo
R
Giampieri
Clinica di Oncologia Medica e Centro Regionale di Genetica Oncologica, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti, Ancona, Italy.
Francesca
F
Bianchi
Clinica di Oncologia Medica e Centro Regionale di Genetica Oncologica, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti, Ancona, Italy.
Laura
L
Belvederesi
Clinica di Oncologia Medica e Centro Regionale di Genetica Oncologica, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti, Ancona, Italy.
Cristiana
C
Brugiati
Clinica di Oncologia Medica e Centro Regionale di Genetica Oncologica, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti, Ancona, Italy.
Silvia
S
Pagliaretta
Clinica di Oncologia Medica e Centro Regionale di Genetica Oncologica, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti, Ancona, Italy.
Michela
M
Del Prete
Medical Oncology, Azienda Ospedaliero-Universitaria di Cagliari, Monserrato (CA), Cagliari, Italy.
Mario
M
Scartozzi
Clinica di Oncologia Medica e Centro Regionale di Genetica Oncologica, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti, Ancona, Italy.
Stefano
S
Cascinu
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D053843:DNA Mismatch Repair; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D011379:Prognosis; D055815:Young Adult
Lynch syndrome; colorectal cancer; genetic testing; germline mutation; prognosis