PALB2, CHEK2 and ATM rare variants and cancer risk: Data from COGS

Melissa C. Southey, University of Melbourne
David E. Goldgar, Huntsman Cancer Institute
Robert Winqvist, University of Oulu
Katri Pylkäs, University of Oulu
Fergus Couch, Mayo Clinic
Marc Tischkowitz, University of Cambridge
William D. Foulkes, Lady Davis Institute for Medical Research
Joe Dennis, Strangeways Research Laboratory
Kyriaki Michailidou, Strangeways Research Laboratory
Elizabeth J. van Rensburg, University of Pretoria
Tuomas Heikkinen, Helsinki University Hospital
Heli Nevanlinna, Helsinki University Hospital
John L. Hopper, University of Melbourne
Thilo Dörk, Medizinische Hochschule Hannover (MHH)
Kathleen B.M. Claes, Universitair Ziekenhuis Gent
Jorge Reis-Filho, Memorial Sloan-Kettering Cancer Center
Zhi Ling Teo, University of Melbourne
Paolo Radice, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan
Irene Catucci, Fondazione IFOM Istituto Firc di Oncologia Molecolare
Paolo Peterlongo, Fondazione IFOM Istituto Firc di Oncologia Molecolare
Helen Tsimiklis, University of Melbourne


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.