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

O. Obazee; L. Archibugi; A. Andriulli; P. Soucek; E. Małecka-Panas; A. Ivanauskas; T. Johnson; M. Gazouli; T. Pausch; R. T. Lawlor; G. M. Cavestro; A. C. Milanetto; M. Di Leo; C. Pasquali; P. Hegyi; A. Szentesi; C. E. Radu; C. Gheorghe; G. E. Theodoropoulos; F. Bergmann; H. Brenner; L. Vodickova; V. Katzke; D. Campa; O. Strobel; J. Kaiser; R. Pezzilli; F. Federici; B. Mohelnikova-Duchonova; U. Boggi; R. Lemstrova; J. S. Johansen; S. E. Bojesen; I. Chen; B. V. Jensen; G. Capurso; V. Pazienza; C. Dervenis; C. Sperti; A. Mambrini; T. Hackert; R. Kaaks; D. Basso; R. Talar-Wojnarowska; E. Maiello; J. R. Izbicki; K. Cuk; K. U. Saum; M. Cantore; J. Kupcinskas; O. Palmieri; G. Delle Fave; S. Landi; R. Salvia; P. Fogar; Y. K. Vashist; A. Scarpa; P. Vodicka; C. Tjaden; E. Iskierka-Jazdzewska; F. Canzian

doi:10.1002/ijc.32127

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

O. Obazee, L. Archibugi, A. Andriulli, P. Soucek, E. Małecka-Panas, A. Ivanauskas, T. Johnson, M. Gazouli, T. Pausch, R. T. Lawlor, G. M. Cavestro, A. C. Milanetto, M. Di Leo, C. Pasquali, P. Hegyi, A. Szentesi, C. E. Radu, C. Gheorghe, G. E. Theodoropoulos, F. BergmannH. Brenner, L. Vodickova, V. Katzke, D. Campa, O. Strobel, J. Kaiser, R. Pezzilli, F. Federici, B. Mohelnikova-Duchonova, U. Boggi, R. Lemstrova, J. S. Johansen, S. E. Bojesen, I. Chen, B. V. Jensen, G. Capurso, V. Pazienza, C. Dervenis, C. Sperti, A. Mambrini, T. Hackert, R. Kaaks, D. Basso, R. Talar-Wojnarowska, E. Maiello, J. R. Izbicki, K. Cuk, K. U. Saum, M. Cantore, J. Kupcinskas, O. Palmieri, G. Delle Fave, S. Landi, R. Salvia, P. Fogar, Y. K. Vashist, A. Scarpa, P. Vodicka, C. Tjaden, E. Iskierka-Jazdzewska, F. Canzian

Research output: Contribution to journal › Article › peer-review

Abstract

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 (OR _dom ) = 1.78, 95% confidence interval (CI) = 1.26–2.52, p = 1.19 × 10 ⁻³ and OR _dom = 1.74, 95% CI = 1.15–2.63, p = 8.57 × 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.

Original language	English
Journal	International Journal of Cancer
DOIs	https://doi.org/10.1002/ijc.32127
Publication status	Published - Jan 1 2019

Keywords

I157T
K3326X
pancreatic cancer
PANDoRA consortium
rs11571833
rs17879961

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1002/ijc.32127

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Obazee, O., Archibugi, L., Andriulli, A., Soucek, P., Małecka-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., ... Canzian, F. (2019). Germline BRCA2 K3326X and CHEK2 I157T mutations increase risk for sporadic pancreatic ductal adenocarcinoma. International Journal of Cancer. https://doi.org/10.1002/ijc.32127

Obazee, O, Archibugi, L, Andriulli, A, Soucek, P, Małecka-Panas, E, Ivanauskas, A, Johnson, T, Gazouli, M, Pausch, T, Lawlor, RT, Cavestro, GM, Milanetto, AC, Di Leo, M, Pasquali, C, Hegyi, P, Szentesi, A, Radu, CE, Gheorghe, C, Theodoropoulos, GE, Bergmann, F, Brenner, H, Vodickova, L, Katzke, V, Campa, D, Strobel, O, Kaiser, J, Pezzilli, R, Federici, F, Mohelnikova-Duchonova, B, Boggi, U, Lemstrova, R, Johansen, JS, Bojesen, SE, Chen, I, Jensen, BV, Capurso, G, Pazienza, V, Dervenis, C, Sperti, C, Mambrini, A, Hackert, T, Kaaks, R, Basso, D, Talar-Wojnarowska, R, Maiello, E, Izbicki, JR, Cuk, K, Saum, KU, Cantore, M, Kupcinskas, J, Palmieri, O, Delle Fave, G, Landi, S, Salvia, R, Fogar, P, Vashist, YK, Scarpa, A, Vodicka, P, Tjaden, C, Iskierka-Jazdzewska, E & Canzian, F 2019, 'Germline BRCA2 K3326X and CHEK2 I157T mutations increase risk for sporadic pancreatic ductal adenocarcinoma', International Journal of Cancer. https://doi.org/10.1002/ijc.32127

@article{f8b906e2ece04989a8518cbf115ff890,

title = "Germline BRCA2 K3326X and CHEK2 I157T mutations increase risk for sporadic pancreatic ductal adenocarcinoma",

abstract = " 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 (OR dom ) = 1.78, 95% confidence interval (CI) = 1.26–2.52, p = 1.19 × 10 −3 and OR dom = 1.74, 95% CI = 1.15–2.63, p = 8.57 × 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. ",

keywords = "I157T, K3326X, pancreatic cancer, PANDoRA consortium, rs11571833, rs17879961",

author = "O. Obazee and L. Archibugi and A. Andriulli and P. Soucek and E. Ma{\l}ecka-Panas and A. Ivanauskas and T. Johnson and M. Gazouli and T. Pausch and Lawlor, {R. T.} and Cavestro, {G. M.} and Milanetto, {A. C.} and {Di Leo}, M. and C. Pasquali and P. Hegyi and A. Szentesi and Radu, {C. E.} and C. Gheorghe and Theodoropoulos, {G. E.} and F. Bergmann and H. Brenner and L. Vodickova and V. Katzke and D. Campa and O. Strobel and J. Kaiser and R. Pezzilli and F. Federici and B. Mohelnikova-Duchonova and U. Boggi and R. Lemstrova and Johansen, {J. S.} and Bojesen, {S. E.} and I. Chen and Jensen, {B. V.} and G. Capurso and V. Pazienza and C. Dervenis and C. Sperti and A. Mambrini and T. Hackert and R. Kaaks and D. Basso and R. Talar-Wojnarowska and E. Maiello and Izbicki, {J. R.} and K. Cuk and Saum, {K. U.} and M. Cantore and J. Kupcinskas and O. Palmieri and {Delle Fave}, G. and S. Landi and R. Salvia and P. Fogar and Vashist, {Y. K.} and A. Scarpa and P. Vodicka and C. Tjaden and E. Iskierka-Jazdzewska and F. Canzian",

year = "2019",

month = jan,

day = "1",

doi = "10.1002/ijc.32127",

language = "English",

journal = "International Journal of Cancer",

issn = "0020-7136",

publisher = "Wiley-Liss Inc.",

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TY - JOUR

T1 - Germline BRCA2 K3326X and CHEK2 I157T mutations increase risk for sporadic pancreatic ductal adenocarcinoma

AU - Obazee, O.

AU - Archibugi, L.

AU - Andriulli, A.

AU - Soucek, P.

AU - Małecka-Panas, E.

AU - Ivanauskas, A.

AU - Johnson, T.

AU - Gazouli, M.

AU - Pausch, T.

AU - Lawlor, R. T.

AU - Cavestro, G. M.

AU - Milanetto, A. C.

AU - Di Leo, M.

AU - Pasquali, C.

AU - Hegyi, P.

AU - Szentesi, A.

AU - Radu, C. E.

AU - Gheorghe, C.

AU - Theodoropoulos, G. E.

AU - Bergmann, F.

AU - Brenner, H.

AU - Vodickova, L.

AU - Katzke, V.

AU - Campa, D.

AU - Strobel, O.

AU - Kaiser, J.

AU - Pezzilli, R.

AU - Federici, F.

AU - Mohelnikova-Duchonova, B.

AU - Boggi, U.

AU - Lemstrova, R.

AU - Johansen, J. S.

AU - Bojesen, S. E.

AU - Chen, I.

AU - Jensen, B. V.

AU - Capurso, G.

AU - Pazienza, V.

AU - Dervenis, C.

AU - Sperti, C.

AU - Mambrini, A.

AU - Hackert, T.

AU - Kaaks, R.

AU - Basso, D.

AU - Talar-Wojnarowska, R.

AU - Maiello, E.

AU - Izbicki, J. R.

AU - Cuk, K.

AU - Saum, K. U.

AU - Cantore, M.

AU - Kupcinskas, J.

AU - Palmieri, O.

AU - Delle Fave, G.

AU - Landi, S.

AU - Salvia, R.

AU - Fogar, P.

AU - Vashist, Y. K.

AU - Scarpa, A.

AU - Vodicka, P.

AU - Tjaden, C.

AU - Iskierka-Jazdzewska, E.

AU - Canzian, F.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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 (OR dom ) = 1.78, 95% confidence interval (CI) = 1.26–2.52, p = 1.19 × 10 −3 and OR dom = 1.74, 95% CI = 1.15–2.63, p = 8.57 × 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.

AB - 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 (OR dom ) = 1.78, 95% confidence interval (CI) = 1.26–2.52, p = 1.19 × 10 −3 and OR dom = 1.74, 95% CI = 1.15–2.63, p = 8.57 × 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.

KW - I157T

KW - K3326X

KW - pancreatic cancer

KW - PANDoRA consortium

KW - rs11571833

KW - rs17879961

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U2 - 10.1002/ijc.32127

DO - 10.1002/ijc.32127

M3 - Article

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SN - 0020-7136

JO - International Journal of Cancer

JF - International Journal of Cancer

ER -

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

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