Homologous recombination DNA repair gene alterations identify a subset of pancreatic cancers potentially responding to platinum based therapy

Background: The International Cancer Genome Consortium (ICGC) whole genome sequencing effort identified an average of 26 mutations per pancreatic ductal adenocarcinoma (PDAC). KRAS mutations are the hallmark, followed by TP53, SMAD4 and CDKN2A inactivation. A dominating tail of decreasingly mutated genes follows, but individual pathogenic gene alterations aggregate into ten core molecular pathways, one of which is the homologous recombination (HR) DNA repair genes pathway. Aim: Within this framework, the aim of this thesis is to avail of ICGC data and focus on the HR DNA damage repair pathway, as genes in this pathway are involved in cancer predisposition and are targets of specific therapies such as platinum salts and innovative PARP inhibitors. The study also envisaged the creation of patient PDAC xenografts (PDX) as a model for primary cancers in molecular stratification and drug validation. Materials and methods: 100 PDAC and matched PDXs were analysed using targeted next generation sequencing to investigate variants in the genes commonly altered in PDAC and in the homologous recombination (HR) pathway genes.Results: KRAS was mutated in 96% of cases; TP53 in (66%), SMAD4 in 16%, and CDKN2A in 13%. Pathogenic HR mutations were found in 13% of cases: ATM (1%), BARD1 (1%), BRCA1 (1%), BRCA2 (8%), REV3L (1%), and STK11 (1%). These mutations were mutually exclusive. All but those in STK11 and REV3L were germ-line. An additional 13% of cases had variants of unknown significance (VUS) in genes of this pathway. Concordance between PDAC and PDX was found in 94% of cases.Conclusion: The finding of a significant PDAC subgroup (13%) with germ-line HR gene mutations identifies a group of patients that could profit from existing and novel target therapies as well as screening programs for family members. This study also identifies VUS that may be tested for potential response to therapy availing of the in vivo PDX avatars developed herein. PDX in fact, represent a valuable model that faithfully recapitulates the main genetic feature of primary diseases that may be used for novel diagnostics to predict drug responses as well as enable identification of effective therapeutic schemes.