Genetic modifiers of CHEK2*1100delC-associated breast cancer risk

被引：69

作者：

Muranen, Taru A. ^{[1
]}

Greco, Dario ^{[2
]}

Blomqvist, Carl ^{[3
]}

Aittomaki, Kristiina ^{[4
]}

Khan, Sofia ^{[1
]}

Hogervorst, Frans ^{[5
]}

Verhoef, Senno ^{[5
]}

Pharoah, Paul D. P. ^{[6
,7
]}

Dunning, Alison M. ^{[6
]}

Shah, Mitul ^{[6
]}

Luben, Robert ^{[8
]}

Bojesen, Stig E. ^{[9
,10
,11
]}

Nordestgaard, Borge G. ^{[9
,10
,11
]}

Schoemaker, Minouk ^{[12
]}

Swerdlow, Anthony ^{[12
,13
]}

Garcia-Closas, Montserrat ^{[12
,14
]}

Figueroa, Jonine ^{[14
]}

Doerk, Thilo ^{[15
]}

Bogdanova, Natalia V. ^{[16
]}

Hall, Per ^{[17
]}

Li, Jingmei ^{[17
]}

Khusnutdinova, Elza ^{[18
,19
]}

Bermisheva, Marina ^{[15
,19
]}

Kristensen, Vessela ^{[20
,21
,22
]}

Borresen-Dale, Anne-Lise ^{[20
,22
]}

Peto, Julian ^{[24
]}

Silva, Isabel dos Santos ^{[24
]}

Couch, Fergus J. ^{[25
]}

Olson, Janet E. ^{[26
]}

Hillemans, Peter ^{[15
]}

Park-Simon, Tjoung-Won ^{[15
]}

Brauch, Hiltrud ^{[27
,28
,29
]}

Hamann, Ute ^{[30
]}

Burwinkel, Barbara ^{[31
,32
]}

Marme, Frederik ^{[32
,33
]}

Meindl, Alfons ^{[34
]}

Schmutzler, Rita K. ^{[35
,36
,37
]}

Cox, Angela ^{[38
]}

Cross, Simon S. ^{[39
]}

Sawyer, Elinor J. ^{[40
]}

Tomlinson, Ian ^{[41
,42
]}

Lambrechts, Diether ^{[43
,44
]}

Moisse, Matthieu ^{[43
]}

Lindblom, Annika ^{[45
]}

Margolin, Sara ^{[46
]}

Hollestelle, Antoinette ^{[47
]}

Martens, John W. M. ^{[47
]}

Fasching, Peter A. ^{[48
,49
]}

Beckmann, Matthias W. ^{[48
]}

Andrulis, Irene L. ^{[50
,51
]}

机构：

[1] Univ Helsinki, Helsinki Univ Hosp, Dept Obstet & Gynecol, Helsinki, Finland

[2] Finnish Inst Occupat Hlth, Unit Syst Toxicol, Helsinki, Finland

[3] Univ Helsinki, Helsinki Univ Hosp, Dept Oncol, Helsinki, Finland

[4] Univ Helsinki, Helsinki Univ Hosp, Dept Clin Genet, Helsinki, Finland

[5] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Amsterdam, Netherlands

[6] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England

[7] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England

[8] Univ Cambridge, Dept Publ Hlth & Primary Care, Clin Gerontol, Cambridge, England

[9] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark

[10] Copenhagen Univ Hosp, Herlev Hosp, Copenhagen Gen Populat Study, Herlev, Denmark

[11] Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, Herlev, Denmark

[12] Inst Canc Res, Div Genet & Epidemiol, London, England

[13] Inst Canc Res, Div Breast Canc Res, London, England

[14] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA

[15] Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany

[16] Hannover Med Sch, Dept Radiat Oncol, Hannover, Germany

[17] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden

[18] Bashkir State Univ, Dept Genet & Fundamental Med, Ufa, Russia

[19] Russian Acad Sci, Ufa Sci Ctr, Inst Biochem & Genet, Ufa, Russia

[20] Univ Oslo, Oslo Univ Hosp, Radiumhosp, Department Genet,Inst Canc Res, Oslo, Norway

[21] Oslo Univ Hosp, Dept Clin Mol Biol, Oslo, Norway

[22] Univ Oslo, Fac Med, Inst Clin Med, KG Jebsen Ctr Breast Canc Res, Oslo, Norway

[23] Arctic Univ Norway, Univ Tromso, Fac Hlth Sci, Dept Community Med, Tromso, Norway

[24] London Sch Hyg & Trop Med, Dept Noncommunicable Dis Epidemiol, London, England

[25] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA

[26] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA

[27] German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany

[28] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany

[29] Univ Tubingen, Tubingen, Germany

[30] German Canc Res Ctr, Mol Genet Breast Canc, Heidelberg, Germany

[31] German Canc Res Ctr, Mol Epidemiol Grp, Heidelberg, Germany

[32] Heidelberg Univ, Dept Obstet & Gynecol, Heidelberg, Germany

[33] Heidelberg Univ, Natl Ctr Tumor Dis, Heidelberg, Germany

[34] Tech Univ Munich, Div Gynaecol & Obstet, Munich, Germany

[35] Univ Cologne, CMMC, Cologne, Germany

[36] Univ Hosp Cologne, Ctr Hereditary Breast & Ovarian Canc, Cologne, Germany

[37] Univ Hosp Cologne, CIO, Cologne, Germany

[38] Univ Sheffield, Dept Oncol, Sheffield Canc Res, Sheffield, S Yorkshire, England

[39] Univ Sheffield, Dept Neurosci, Acad Unit Pathol, Sheffield, S Yorkshire, England

[40] Kings Coll London, Guys Hosp, Res Oncol, London, England

[41] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England

[42] Univ Oxford, Oxford NIHR Biomed Res Ctr, Oxford, England

[43] Univ Leuven, Dept Oncol, Lab Translat Genet, Leuven, Belgium

[44] VIB, Vesalius Res Ctr, Leuven, Belgium

[45] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden

[46] Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden

[47] Erasmus MC Canc Inst, Family Canc Clin, Dept Med Oncol, Rotterdam, Netherlands

[48] Friedrich Alexander Univ Erlangen Nuremberg, Comprehens Canc Ctr Erlangen EMN, Univ Hosp Erlangen, Dept Gynaecol & Obstet, Erlangen, Germany

[49] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA

[50] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada

来源：

GENETICS IN MEDICINE | 2017年 / 19卷 / 05期

基金：

英国惠康基金;

关键词：

breast cancer; Breast Cancer Association Consortium; CHEK2*1100delC; common variants; polygenic risk score; FAMILY-HISTORY; MUTATION; BRCA2; WOMEN;

D O I：

10.1038/gim.2016.147

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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: 1.212.09) 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.

引用

页码：599 / 603

页数：5

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