Contribution of known and novel DNA repair genes to pancreatic cancer susceptibility

Pancreatic adenocarcinoma (PAC) is a deadly malignancy that most commonly presents at a late stage and is ultimately refractory to systemic therapies. Even more devastating is the familial clustering of PAC (and other cancers) that is observed in 10-15% of cases. These kindreds, however, represent an opportune subset of patients for studies aimed at early detection and precision oncology strategies. While a fraction of the observed familial clustering of PAC is attributable to inherited (i.e., germline) genetic mutations in known PAC susceptibility genes (e.g., BRCA1 and BRCA2), the genetic causes for the overwhelming majority of familial PAC (~85%) remain undefined. The rapid lethality of PAC has hindered the collection of DNA, tumour specimens, and high-quality clinical and epidemiologic data that are critical for genetic studies of PAC. Herein, we demonstrate that a rapid ascertainment methodology, as used by the Quebec Pancreas Cancer Study (QPCS), a prospective clinic-based PAC research registry that was established in our lab in 2012, leads to high participation rates and allows for the collection of rare "high-risk" kindreds for studies of PAC heredity. Motivated by recent studies by our group and others suggesting that PAC associated with germline mutations in homology-directed DNA repair (HDR) genes have increased sensitivities to DNA damaging agents (e.g., platinums) and poly(ADP-ribose) polymerase inhibitors, we combined the resources of the QPCS and the Ontario Pancreas Cancer Study to define the prevalence of germline mutations in 4 known HDR-implicated PAC susceptibility genes (BRCA1, BRCA2, PALB2 and ATM) among 150 consecutive PAC cases with French-Canadian ancestry – a population known to harbour founder (i.e., recurrent) mutations in these genes – and 236 cases unselected for ancestry. Using clinical data collected by these registries, we provide supporting evidence for the role of precision therapy in this PAC subtype, and make recommendations for reflex genetic testing that can be easily applied in the routine management of PAC. To elucidate the unexplained majority of familial PAC, we used next-generation sequencing to interrogate the germline exomes of 109 PAC cases from 93 "high-risk" kindreds and used a filter-based approach to identify several candidate PAC susceptibility genes involved in DNA repair. Most notable are FAN1, NEK1 and RHNO1, which each harboured pathogenic mutations in 3 kindreds (3.2%) and demonstrated segregation with PAC in 2 kindreds. The identification of several low prevalence candidate genes, rather than a single major gene in our large case series highlights the likely heterogeneity of PAC heredity. Adverse survival was observed in early stage PAC cases with germline mutations in DNA repair genes, pointing to a hypothesis that these cases may represent a distinct clinical subtype with selective drug sensitivities. Overall, this thesis aims to characterize the contribution of both known and novel germline genetic causes of PAC and supports the notion that distinct genetic subtypes of PAC may benefit from targeted therapies, highlighting the limitations of the current "one-size-fits-all" approach to PAC treatment.

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