SO09: Elucidating the molecular basis of MSH2-deficient tumours  in Lynch syndrome suspected patients

Gardenia Vargas1, Estela Dámaso1, Tirso Pons2, Jesús del Valle1, Silvia Iglesias1, Àngela Velasco3, Ares Solanes4, Alfonso Valencia2, Joan Brunet3, Lídia Feliubadaló1, Conxi Lázaro1, Matilde Navarro1, Marta Pineda1, Gabriel Capellá1.

1 – Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Spain. 2 – Structural Biology and Biocomputing Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain. 3 – Hereditary Cancer Program, Catalan Institute of Oncology, IdIBGI, Girona, Spain. 4 – Hereditary Cancer Program, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain.


Mutations in POLE and MUTYH and mismatch repair (MMR) double somatic events were found in a proportion of Lynch-like syndrome (LLS) patients. The aim of this study was to elucidate the molecular basis of MSH2-deficient LLS cases by means of a comprehensive analysis of colorectal cancer (CRC) associated genes at germline and somatic level.


Eighteen LLS individuals harboring MSH2-deficient tumours were included. A customized NGS subexome panel including CRC associated genes was designed. PBL and matched FFPE DNA from available tumours were analyzed.


Predicted pathogenic germline heterozygous variants in MSH2, BUB1, SETD2, FAN1 and MUTYH were identified in 6 of the 18 (33%) cases analyzed.  The somatic analysis of tumours demonstrated the presence of MMR double somatic hits, apparent MSH2 loss of heterozygozity and coexistence of double somatic mutations in other MMR and/or POLE/POLD1 genes. Also, somatic mutations in other cancer genes coexisted with the above mentioned alterations.  In all, alterations putatively responsible for LLS were detected in 60% of the cases.


The evaluation of germline and somatic mutational status of CRC-associated genes by means of a subexome panel is useful for the elucidation of the molecular basis of LS-suspected cases.

Funding: SAF2012-33636, AECC, 2014SGR388.