Genetic modifiers of CHEK2*1100delC-associated breast cancer risk.
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Authors
Muranen, TA
Greco, D
Blomqvist, C
Aittomäki, K
Khan, S
Hogervorst, F
Verhoef, S
Pharoah, PDP
Dunning, AM
Shah, M
Luben, R
Bojesen, SE
Nordestgaard, BG
Schoemaker, M
Swerdlow, A
García-Closas, M
Figueroa, J
Dörk, T
Bogdanova, NV
Hall, P
Li, J
Khusnutdinova, E
Bermisheva, M
Kristensen, V
Borresen-Dale, A-L
NBCS Investigators,
Peto, J
Dos Santos Silva, I
Couch, FJ
Olson, JE
Hillemans, P
Park-Simon, T-W
Brauch, H
Hamann, U
Burwinkel, B
Marme, F
Meindl, A
Schmutzler, RK
Cox, A
Cross, SS
Sawyer, EJ
Tomlinson, I
Lambrechts, D
Moisse, M
Lindblom, A
Margolin, S
Hollestelle, A
Martens, JWM
Fasching, PA
Beckmann, MW
Andrulis, IL
Knight, JA
kConFab/AOCS Investigators,
Anton-Culver, H
Ziogas, A
Giles, GG
Milne, RL
Brenner, H
Arndt, V
Mannermaa, A
Kosma, V-M
Chang-Claude, J
Rudolph, A
Devilee, P
Seynaeve, C
Hopper, JL
Southey, MC
John, EM
Whittemore, AS
Bolla, MK
Wang, Q
Michailidou, K
Dennis, J
Easton, DF
Schmidt, MK
Nevanlinna, H
Greco, D
Blomqvist, C
Aittomäki, K
Khan, S
Hogervorst, F
Verhoef, S
Pharoah, PDP
Dunning, AM
Shah, M
Luben, R
Bojesen, SE
Nordestgaard, BG
Schoemaker, M
Swerdlow, A
García-Closas, M
Figueroa, J
Dörk, T
Bogdanova, NV
Hall, P
Li, J
Khusnutdinova, E
Bermisheva, M
Kristensen, V
Borresen-Dale, A-L
NBCS Investigators,
Peto, J
Dos Santos Silva, I
Couch, FJ
Olson, JE
Hillemans, P
Park-Simon, T-W
Brauch, H
Hamann, U
Burwinkel, B
Marme, F
Meindl, A
Schmutzler, RK
Cox, A
Cross, SS
Sawyer, EJ
Tomlinson, I
Lambrechts, D
Moisse, M
Lindblom, A
Margolin, S
Hollestelle, A
Martens, JWM
Fasching, PA
Beckmann, MW
Andrulis, IL
Knight, JA
kConFab/AOCS Investigators,
Anton-Culver, H
Ziogas, A
Giles, GG
Milne, RL
Brenner, H
Arndt, V
Mannermaa, A
Kosma, V-M
Chang-Claude, J
Rudolph, A
Devilee, P
Seynaeve, C
Hopper, JL
Southey, MC
John, EM
Whittemore, AS
Bolla, MK
Wang, Q
Michailidou, K
Dennis, J
Easton, DF
Schmidt, MK
Nevanlinna, H
Document Type
Journal Article
Date
2017-05-01
Date Accepted
2016-07-27
Abstract
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.Genet Med advance online publication 06 October 2016.
Citation
Genetics in medicine : official journal of the American College of Medical Genetics, 2017, 19 (5), pp. 599 - 603
Rights
Source Title
Publisher
NATURE PUBLISHING GROUP
ISSN
1098-3600
eISSN
1530-0366
Research Team
Aetiological Epidemiology