Background and aims Individuals with tumours showing mismatch repair (MMR) deficiency not linked to germline mutations or somatic methylation of MMR genes have been recently referred as having 'Lynch-like syndrome' (LLS). The genetic basis of these LLS cases is unknown. MUTYH-associated polyposis patients show some phenotypic similarities to Lynch syndrome patients. The aim of this study was to investigate the prevalence of germline MUTYH mutations in a large series of LLS patients. Methods Two hundred and twenty-five probands fulfilling LLS criteria were included in this study. Screening of MUTYH recurrent mutations, whole coding sequencing and a large rearrangement analysis were undertaken. Age, sex, clinical, pathological and molecular characteristics of tumours including KRAS mutations were assessed. Results We found a prevalence of 3.1% of MAP syndrome in the whole series of LLS (7/225) and 3.9% when only cases fulfilling clinical criteria were considered (7/178). Patients with MUTYH biallelic mutations had more adenomas than monoallelic (P = 0.02) and wildtype patients (P < 0.0001). Six out of nine analysed tumours from six biallelic MUTYH carriers harboured KRAS-p.G12C mutation. This mutation was found to be associated with biallelic MUTYH germline mutation when compared with reported series of unselected colorectal cancer cohorts (P < 0.0001). Conclusions A proportion of unexplained LLS cases is caused by biallelic MUTYH mutations. The obtained results further justify the inclusion of MUTYH in the diagnostic strategy for Lynch syndrome-suspected patients.
Bibliographical noteFunding Information:
This work was funded by the Spanish Ministry of Economy and Competitiveness (grant SAF2012-33636 ); the Scientific Foundation Asociación Española Contra el Cáncer ; the Government of Catalonia (grant 2009SGR290 ), Fundación Mutua Madrileña (grant AP114252013 ), RTICC MINECO Network RD12/0036/0031 and RD12/0036/0008 , and the Biomedical Research Foundation from the Hospital of Elche (FIBElx-CO11/03). AC and M-IC are funded by Health and Biomedical Research Foundation from the Valencian Region ( FISABIO ). The Mexican National Council for Science and Technology (CONACyT) fellowship to GV. EH-I is recipient of a fellowship from the Fondo Investigación Sanitaria ISCIII (FI12/00233).
- KRAS mutations
- Lynch syndrome
- MAP syndrome