TY - JOUR
T1 - PALB2, CHEK2 and ATM rare variants and cancer risk
T2 - Data from COGS
AU - kConFab Investigators66
AU - Australian Ovarian Cancer Study Group65,66
AU - Southey, Melissa C.
AU - Goldgar, David E.
AU - Winqvist, Robert
AU - Pylkäs, Katri
AU - Couch, Fergus
AU - Tischkowitz, Marc
AU - Foulkes, William D.
AU - Dennis, Joe
AU - Michailidou, Kyriaki
AU - van Rensburg, Elizabeth J.
AU - Heikkinen, Tuomas
AU - Nevanlinna, Heli
AU - Hopper, John L.
AU - Dörk, Thilo
AU - Claes, Kathleen B.M.
AU - Reis-Filho, Jorge
AU - Teo, Zhi Ling
AU - Radice, Paolo
AU - Catucci, Irene
AU - Peterlongo, Paolo
AU - Tsimiklis, Helen
AU - Odefrey, Fabrice A.
AU - Dowty, James G.
AU - Schmidt, Marjanka K.
AU - Broeks, Annegien
AU - Hogervorst, Frans B.
AU - Verhoef, Senno
AU - Carpenter, Jane
AU - Clarke, Christine
AU - Scott, Rodney J.
AU - Fasching, Peter A.
AU - Haeberle, Lothar
AU - Ekici, Arif B.
AU - Beckmann, Matthias W.
AU - Peto, Julian
AU - dos-Santos-Silva, Isabel
AU - Fletcher, Olivia
AU - Johnson, Nichola
AU - Bolla, Manjeet K.
AU - Sawyer, Elinor J.
AU - Tomlinson, Ian
AU - Kerin, Michael J.
AU - Miller, Nicola
AU - Marme, Federik
AU - Burwinkel, Barbara
AU - Yang, Rongxi
AU - Guénel, Pascal
AU - Truong, Thérèse
AU - Menegaux, Florence
AU - Sanchez, Marie
PY - 2016/12/1
Y1 - 2016/12/1
N2 - Background The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. Methods We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T > G and c.3113G > A, CHEK2 c.349A > G, c.538C > T, c.715G > A, c.1036C > T, c.1312G > T, and c.1343T > G and ATM c.7271T > G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. Results For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10-5), PALB2 c.3113G > A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10-8) and ATM c.7271T > G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A > G OR 2.26 (95% CI 1.29 to 3.95), c.1036C > T OR 5.06 (95% CI 1.09 to 23.5) and c.538C > T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T > G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G > T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. Conclusions This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.
AB - Background The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. Methods We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T > G and c.3113G > A, CHEK2 c.349A > G, c.538C > T, c.715G > A, c.1036C > T, c.1312G > T, and c.1343T > G and ATM c.7271T > G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. Results For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10-5), PALB2 c.3113G > A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10-8) and ATM c.7271T > G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A > G OR 2.26 (95% CI 1.29 to 3.95), c.1036C > T OR 5.06 (95% CI 1.09 to 23.5) and c.538C > T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T > G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G > T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. Conclusions This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.
UR - http://www.scopus.com/inward/record.url?scp=84986246968&partnerID=8YFLogxK
U2 - 10.1136/jmedgenet-2016-103839
DO - 10.1136/jmedgenet-2016-103839
M3 - Article
C2 - 27595995
AN - SCOPUS:84986246968
SN - 0022-2593
VL - 53
SP - 800
EP - 811
JO - Journal of Medical Genetics
JF - Journal of Medical Genetics
IS - 12
ER -
