Germline BRCA2 K3326X and CHEK2 I157T mutations increase risk for sporadic pancreatic ductal adenocarcinoma
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Germline BRCA2 K3326X and CHEK2 I157T mutations increase risk for sporadic pancreatic ductal adenocarcinoma. / 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; 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, 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 R; 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; Vodicka, P; Tjaden, C; Iskierka-Jazdzewska, E; Canzian, F.
In: International Journal of Cancer, Vol. 145, No. 3, 01.08.2019, p. 686-693.Research output: Contribution to journal › Journal article › peer-review
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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
N1 - © 2019 UICC.
PY - 2019/8/1
Y1 - 2019/8/1
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 (ORdom ) = 1.78, 95% confidence interval (CI) = 1.26-2.52, p = 1.19 × 10-3 and ORdom = 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 (ORdom ) = 1.78, 95% confidence interval (CI) = 1.26-2.52, p = 1.19 × 10-3 and ORdom = 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 - Aged
KW - BRCA2 Protein/genetics
KW - Carcinoma, Pancreatic Ductal/genetics
KW - Case-Control Studies
KW - Checkpoint Kinase 2/genetics
KW - Female
KW - Genes, BRCA2
KW - Genetic Predisposition to Disease
KW - Germ-Line Mutation
KW - Humans
KW - Male
KW - Middle Aged
KW - Pancreatic Neoplasms/genetics
KW - Polymorphism, Single Nucleotide
U2 - 10.1002/ijc.32127
DO - 10.1002/ijc.32127
M3 - Journal article
C2 - 30672594
VL - 145
SP - 686
EP - 693
JO - International Journal of Cancer
JF - International Journal of Cancer
SN - 0020-7136
IS - 3
ER -
ID: 234997496