Abstract 3411: Rare BRCA2 K3326X increases susceptibility to sporadic pancreatic ductal adenocarcinoma: a PANDoRA study

Background: The incredibly poor outlook of pancreatic cancer patients underscores an urgent need for early diagnostic markers. Pancreatic cancer ranks third most-frequent among BRCA1/2-deficient cancers with germline mutations detected in T) which introduces a premature stop codon thus truncating the protein, has previously been implicated in familial PDAC, but not in sporadic cases. A frameshift pathogenic mutation c.6503delTT (rs11571658, p.Leu2092Profs) reported to occur in tandem with K3326X in breast and ovarian cancer families, has also been speculated to influence risk associations due to linkage disequilibrium between both variants. Method and results: K3326X was genotyped in 2,969 sporadic cases and 4,700 controls using Taqman chemistry and fidelity of genotypes assessed based on concordance of internal replicates and negative controls. K3326X was observed in 1.2% of cases and 0.8% of controls. Odds ratios (ORs) and associated 95% confidence intervals (CIs) were estimated by multivariate unconditional logistic regression with adjustment for age, sex and region of origin. We also performed a stratified analysis based on age at diagnosis to estimate the risk association between K3326X and early-onset pancreatic cancer. To rule out the likely shared effect of the c.6503delTT mutation on sporadic PDAC risk, we also sequenced DNA from carriers of K3326X in this study. We found K3326X to be associated with increased risk of developing sporadic PDAC ((OR = 1.71, 95% CI = 1.18 - 2.49), P = 0.005). This risk was considerably higher among cases aged 50 years and younger (OR = 2.13, 95% CI = 1.10 - 4.11, P = 0.03). Furthermore, carriers of K3326X did not bear the c.6503delTT mutation thus confirming that the observed risk effect was not influenced by the latter. Conclusion: These robust associations implicate K3326X in the etiology of sporadic and early-onset PDAC, and therefore warrant replication as well as functional studies to elucidate the role of K3326X in DNA repair mechanisms. Citation Format: Ofure M. Obazee, Gabriele Capurso, Angelo Andriulli, Pavel Soucek, Ewa Małecka- Panas, Juozas Kupcinskas, Rudolf Kaaks, Maria Gazouli, Thilo Hackert, Aldo Scarpa, Giulia M. Cavestro, Claudio Pasquali, Hermann Brenner, Daniele Campa, Raffaele Pezzilli, Andr