P19: Identification of germline FAN1 variants in MSH2-deficient Lynch-like syndrome patients

Gardenia Vargas1, Estela Dámaso1, Matilde Navarro1, Tirso Pons2, Leonardo Mina3, Anna Fernández1, Lídia Feliubadaló1, Ares Solanes4, Silvia Iglesias1, Àngela Velasco5, Judith Balmaña6, Teresa Ramón y Cajal7,  Alfonso Valencia8, Joan Brunet5, Jordi Surrallés3, Conxi Lázaro1, Laura Valle1, 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 – Genome Instability and DNA Repair Group, Department of Genetics and Microbiology, Universitat Autònoma de Barcelona, Spain. 4 – Hereditary Cancer Program, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain. 5 – Hereditary Cancer Program, Catalan Institute of Oncology, IDIBGI, Girona, Spain. 6 – Medical Oncology Department, University Hospital of Vall d’Hebron and Vall d’Hebron Institute of Oncology, Barcelona, Spain. 7 – Medical Oncology Service, Santa Creu i Sant Pau Hospital, Barcelona, Spain. 8 – Structural Biology and Biocomputing Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain.

Aim

In about 55% of individuals harboring mismatch repair (MMR) deficient tumours, germline mutations or somatic methylation in MMR genes are not identified, being referred as Lynch-like syndrome (LLS) patients. Recently FAN1 germline mutations have been associated to MMR proficient colorectal cancer (CRC) and pancreatic cancer predisposition. The aim of this study was to determine whether germline FAN1 play also a role in LLS.

Method

Germline analysis of FAN1 was performed in 30 LLS unrelated individuals showing MSH2 loss of expression in tumours. Pathogenicity assessment of identified variants was performed using computational and cosegregation analyses.

Results

We identified three rare missense variants in 3 unrelated LLS patients (10% of the studied sample). Two of the 3 identified variants, c.434G>A [p.(R145H)] and c.1129C>T [p.(R377W)], cosegregated with colorectal cancer-affected relatives. The remaining variant, c.1856T>A (p.M619K), for which no cosegregation data was available, was classified as likely pathogenic based on functional and computational analyses.

Conclusion

The obtained results suggest the involvement of the FAN1 gene in MSH2-deficient LLS.

Funding: SAF2012-33636, AECC, 2014SGR388.

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