TY - JOUR
T1 - Genetic modifiers of CHEK2∗1100delC-associated breast cancer risk
AU - Breast Cancer Association Consortium
AU - KConFab,AOCS Investigators
AU - Muranen, Taru A.
AU - Greco, Dario
AU - Blomqvist, Carl
AU - Aittomäki, Kristiina
AU - Khan, Sofia
AU - Hogervorst, Frans
AU - Verhoef, Senno
AU - Pharoah, Paul D.P.
AU - Dunning, Alison M.
AU - Shah, Mitul
AU - Luben, Robert
AU - Bojesen, Stig E.
AU - Nordestgaard, Børge G.
AU - Schoemaker, Minouk
AU - Swerdlow, Anthony
AU - García-Closas, Montserrat
AU - Figueroa, Jonine
AU - Dörk, Thilo
AU - Bogdanova, Natalia V.
AU - Hall, Per
AU - Li, Jingmei
AU - Khusnutdinova, Elza
AU - Bermisheva, Marina
AU - Kristensen, Vessela
AU - Borresen-Dale, Anne Lise
AU - Investigators, Nbcs
AU - Peto, Julian
AU - Dos Santos Silva, Isabel
AU - Couch, Fergus J.
AU - Olson, Janet E.
AU - Hillemans, Peter
AU - Park-Simon, Tjoung Won
AU - Brauch, Hiltrud
AU - Hamann, Ute
AU - Burwinkel, Barbara
AU - Marme, Frederik
AU - Meindl, Alfons
AU - Schmutzler, Rita K.
AU - Cox, Angela
AU - Cross, Simon S.
AU - Sawyer, Elinor J.
AU - Tomlinson, Ian
AU - Lambrechts, Diether
AU - Moisse, Matthieu
AU - Lindblom, Annika
AU - Margolin, Sara
AU - Hollestelle, Antoinette
AU - Martens, John W.M.
AU - Fasching, Peter A.
AU - Beckmann, Matthias W.
N1 - Publisher Copyright:
© American College of Medical Genetics and Genomics.
PY - 2017/5/1
Y1 - 2017/5/1
N2 - Purpose:CHEK2∗1100delC is a founder variant in European populations that confers a two- to threefold increased risk of breast cancer (BC). Epidemiologic and family studies have suggested that the risk associated with CHEK2∗1100delC is modified by other genetic factors in a multiplicative fashion. We have investigated this empirically using data from the Breast Cancer Association Consortium (BCAC).Methods:Using genotype data from 39,139 (624 1100delC carriers) BC patients and 40,063 (224) healthy controls from 32 BCAC studies, we analyzed the combined risk effects of CHEK2∗1100delC and 77 common variants in terms of a polygenic risk score (PRS) and pairwise interaction.Results:The PRS conferred odds ratios (OR) of 1.59 (95% CI: 1.21-2.09) per standard deviation for BC for CHEK2∗1100delC carriers and 1.58 (1.55-1.62) for noncarriers. No evidence of deviation from the multiplicative model was found. The OR for the highest quintile of the PRS was 2.03 (0.86-4.78) for CHEK2∗1100delC carriers, placing them in the high risk category according to UK NICE guidelines. The OR for the lowest quintile was 0.52 (0.16-1.74), indicating a lifetime risk close to the population average.Conclusion:Our results confirm the multiplicative nature of risk effects conferred by CHEK2∗1100delC and the common susceptibility variants. Furthermore, the PRS could identify carriers at a high lifetime risk for clinical actions.
AB - Purpose:CHEK2∗1100delC is a founder variant in European populations that confers a two- to threefold increased risk of breast cancer (BC). Epidemiologic and family studies have suggested that the risk associated with CHEK2∗1100delC is modified by other genetic factors in a multiplicative fashion. We have investigated this empirically using data from the Breast Cancer Association Consortium (BCAC).Methods:Using genotype data from 39,139 (624 1100delC carriers) BC patients and 40,063 (224) healthy controls from 32 BCAC studies, we analyzed the combined risk effects of CHEK2∗1100delC and 77 common variants in terms of a polygenic risk score (PRS) and pairwise interaction.Results:The PRS conferred odds ratios (OR) of 1.59 (95% CI: 1.21-2.09) per standard deviation for BC for CHEK2∗1100delC carriers and 1.58 (1.55-1.62) for noncarriers. No evidence of deviation from the multiplicative model was found. The OR for the highest quintile of the PRS was 2.03 (0.86-4.78) for CHEK2∗1100delC carriers, placing them in the high risk category according to UK NICE guidelines. The OR for the lowest quintile was 0.52 (0.16-1.74), indicating a lifetime risk close to the population average.Conclusion:Our results confirm the multiplicative nature of risk effects conferred by CHEK2∗1100delC and the common susceptibility variants. Furthermore, the PRS could identify carriers at a high lifetime risk for clinical actions.
KW - 1100delC
KW - Breast Cancer Association Consortium
KW - CHEK2
KW - breast cancer
KW - common variants
KW - polygenic risk score
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U2 - 10.1038/gim.2016.147
DO - 10.1038/gim.2016.147
M3 - Article
C2 - 27711073
AN - SCOPUS:85021757649
SN - 1098-3600
VL - 19
SP - 599
EP - 603
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 5
ER -