Germline BRCA2 K3326X and CHEK2 I157T mutations increase risk for sporadic pancreatic ductal adenocarcinoma

0518023 - ÚEM 2020 RIV DE eng J - Journal Article
Obazee, O. - Archibugi, L. - Andriulli, A. - Souček, P. - Malecká-Panas, E. - Ivanauskas, A. - Johnson, T. - Gazouli, M. - Pausch, T. - Lawlor, R.T. - Cavestro, G.M. - Milanetto, A.C. - Di Leo, M. - Pasquali, C. - Hegyi, P. - Szentesi, A. - Radu, C.E. - Gheorghe, C. - Theodoropoulos, G.E. - Bergmann, F. - Brenner, H. - Vodičková, Ludmila - Katzke, V. - Campa, D. - Strobel, O. - Kaiser, J. - Pezzilli, R. - Federici, F. - Mohelníková-Duchoňová, B. - Boggi, U. - Lemstrová, R. - Johansen, J.S. - Bojesen, S.E. - Chen, I. - Jensen, B.V. - Capurso, G. - Pazienza, V. - Dervenis, C. - Sperti, C. - Mambrini, A. - Hackert, T. - Kaaks, R. - Basso, D. - Talar-Wojnarowska, R. - Maiello, E. - Izbicki, J. - Cuk, K. - Saum, K.U. - Cantore, M. - Kupcinskas, J. - Palmieri, O. - Delle Fave, G. - Landi, S. - Salvia, R. - Fogar, P. - Vashist, Y.K. - Scarpa, A. - Vodička, Pavel - Tjaden, C. - Iskierka-Jazdzewska, E. - Canzian, F.
Germline BRCA2 K3326X and CHEK2 I157T mutations increase risk for sporadic pancreatic ductal adenocarcinoma.
International Journal of Cancer. Roč. 145, č. 3 (2019), s. 686-693. ISSN 0020-7136. E-ISSN 1097-0215
R&D Projects: GA ČR(CZ) GAP301/12/1734
Institutional support: RVO:68378041
Keywords : pancreatic cancer * rs11571833 * I157T * K3326X
OECD category: Human genetics
Impact factor: 5.145, year: 2019
Method of publishing: Open access with time embargo
https://onlinelibrary.wiley.com/doi/abs/10.1002/ijc.32127

Rare truncating BRCA2 K3326X (rs11571833) and pathogenic CHEK2 I157T (rs17879961) variants have previously been implicated in familial pancreatic ductal adenocarcinoma (PDAC), but not in sporadic cases. The effect of both mutations in important DNA repair genes on sporadic PDAC risk may shed light on the genetic architecture of this disease. Both mutations were genotyped in germline DNA from 2,935 sporadic PDAC cases and 5,626 control subjects within the PANcreatic Disease ReseArch (PANDoRA) consortium. Risk estimates were evaluated using multivariate unconditional logistic regression with adjustment for possible confounders such as sex, age and country of origin. Statistical analyses were two-sided with p values <0.05 considered significant. K3326X and I157T were associated with increased risk of developing sporadic PDAC (odds ratio (ORdom) = 1.78, 95% confidence interval (CI) = 1.26-2.52, p = 1.19 x 10(-3) and ORdom = 1.74, 95% CI = 1.15-2.63, p = 8.57 x 10(-3), respectively). Neither mutation was significantly associated with risk of developing early-onset PDAC. This retrospective study demonstrates novel risk estimates of K3326X and I157T in sporadic PDAC which suggest that upon validation and in combination with other established genetic and non-genetic risk factors, these mutations may be used to improve pancreatic cancer risk assessment in European populations. Identification of carriers of these risk alleles as high-risk groups may also facilitate screening or prevention strategies for such individuals, regardless of family history.
Permanent Link: http://hdl.handle.net/11104/0303231