Abstract 3411: Rare BRCA2 K3326X increases susceptibility to sporadic pancreatic ductal adenocarcinoma: a PANDoRA study
Authors: Obazee Ofure M. , Capurso Gabriele , Andriulli Angelo , Soucek Pavel , Panas Ewa Małecka- , Kupcinskas Juozas , Kaaks Rudolf , Gazouli Maria , Hackert Thilo , Scarpa Aldo , Cavestro Giulia M. , Pasquali Claudio , Brenner Hermann , Campa Daniele , Pezzilli Raffaele , Mambrini Andrea , Duchonova Beatrice Mohelnikova- , Boggi Ugo , Izbicki Jakob , Vodicka Pavel , Iskierka-Jazdzewska Elzbieta , Canzian Federico 
Published: July 2017

Abstract
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 &lt;10% of sporadic cases. Germline variants in breast cancer tumor suppressor BRCA2 have been reported to increase predisposition to several cancers including pancreatic tumors. Rare K3326X (rs11571833, c.9976A&gt;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, Andrea Mambrini, Beatrice Mohelnikova- Duchonova, Ugo Boggi, Jakob Izbicki, Pavel Vodicka, Elzbieta Iskierka-Jazdzewska, Federico Canzian. Rare BRCA2 K3326X increases susceptibility to sporadic pancreatic ductal adenocarcinoma: a PANDoRA study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3411. doi:10.1158/1538-7445.AM2017-3411