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J Natl Cancer Inst. 2015 Apr 8;107(5). pii: djv036. doi: 10.1093/jnci/djv036. Print 2015 May.

Prediction of breast cancer risk based on profiling with common genetic variants.

Mavaddat N1, Pharoah PD1, Michailidou K1, Tyrer J1, Brook MN1, Bolla MK1, Wang Q1, Dennis J1, Dunning AM1, Shah M1, Luben R1, Brown J1, Bojesen SE1, Nordestgaard BG1, Nielsen SF1, Flyger H1, Czene K1, Darabi H1, Eriksson M1, Peto J1, Dos-Santos-Silva I1, Dudbridge F1, Johnson N1, Schmidt MK1, Broeks A1, Verhoef S1, Rutgers EJ1, Swerdlow A1, Ashworth A1, Orr N1, Schoemaker MJ1, Figueroa J1, Chanock SJ1, Brinton L1, Lissowska J1, Couch FJ1, Olson JE1, Vachon C1, Pankratz VS1, Lambrechts D1, Wildiers H1, Van Ongeval C1, van Limbergen E1, Kristensen V1, Grenaker Alnæs G1, Nord S1, Borresen-Dale AL1, Nevanlinna H1, Muranen TA1, Aittomäki K1, Blomqvist C1, Chang-Claude J1, Rudolph A1, Seibold P1, Flesch-Janys D1, Fasching PA1, Haeberle L1, Ekici AB1, Beckmann MW1, Burwinkel B1, Marme F1, Schneeweiss A1, Sohn C1, Trentham-Dietz A1, Newcomb P1, Titus L1, Egan KM1, Hunter DJ1, Lindstrom S1, Tamimi RM1, Kraft P1, Rahman N1, Turnbull C1, Renwick A1, Seal S1, Li J1, Liu J1, Humphreys K1, Benitez J1, Pilar Zamora M1, Arias Perez JI1, Menéndez P1, Jakubowska A1, Lubinski J1, Jaworska-Bieniek K1, Durda K1, Bogdanova NV1, Antonenkova NN1, Dörk T1, Anton-Culver H1, Neuhausen SL1, Ziogas A1, Bernstein L1, Devilee P1, Tollenaar RA1, Seynaeve C1, van Asperen CJ1, Cox A1, Cross SS1, Reed MW1, Khusnutdinova E1, Bermisheva M1, Prokofyeva D1, Takhirova Z1, Meindl A1, Schmutzler RK1, Sutter C1, Yang R1, Schürmann P1, Bremer M1, Christiansen H1, Park-Simon TW1, Hillemanns P1, Guénel P1, Truong T1, Menegaux F1, Sanchez M1, Radice P1, Peterlongo P1, Manoukian S1, Pensotti V1, Hopper JL1, Tsimiklis H1, Apicella C1, Southey MC1, Brauch H1, Brüning T1, Ko YD1, Sigurdson AJ1, Doody MM1, Hamann U1, Torres D1, Ulmer HU1, Försti A1, Sawyer EJ1, Tomlinson I1, Kerin MJ1, Miller N1, Andrulis IL1, Knight JA1, Glendon G1, Marie Mulligan A1, Chenevix-Trench G1, Balleine R1, Giles GG1, Milne RL1, McLean C1, Lindblom A1, Margolin S1, Haiman CA1, Henderson BE1, Schumacher F1, Le Marchand L1, Eilber U1, Wang-Gohrke S1, Hooning MJ1, Hollestelle A1, van den Ouweland AM1, Koppert LB1, Carpenter J1, Clarke C1, Scott R1, Mannermaa A1, Kataja V1, Kosma VM1, Hartikainen JM1, Brenner H1, Arndt V1, Stegmaier C1, Karina Dieffenbach A1, Winqvist R1, Pylkäs K1, Jukkola-Vuorinen A1, Grip M1, Offit K1, Vijai J1, Robson M1, Rau-Murthy R1, Dwek M1, Swann R1, Annie Perkins K1, Goldberg MS1, Labrèche F1, Dumont M1, Eccles DM1, Tapper WJ1, Rafiq S1, John EM1, Whittemore AS1, Slager S1, Yannoukakos D1, Toland AE1, Yao S1, Zheng W1, Halverson SL1, González-Neira A1, Pita G1, Rosario Alonso M1, Álvarez N1, Herrero D1, Tessier DC1, Vincent D1, Bacot F1, Luccarini C1, Baynes C1, Ahmed S1, Maranian M1, Healey CS1, Simard J1, Hall P1, Easton DF1, Garcia-Closas M1.

Author information

1
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK (NM, PDPP, KM, MKB, QW, JD, RL, JBr, DFE); Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK (PDPP, JT, AMD, MS, CL, CB, SA, MM, CSH, DFE); Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK (MNB, ASw, MJS); Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark (SEB, BGN, SFN); Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Herlev, Denmark (SEB, BGN, SFN); Faculty of Health and Medical Sciences, Copenhagen University Hospital, Copenhagen, Herlev, Denmark (SEB, BGN); Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Herlev, Denmark (HF); Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (KC, HD, ME, KH, PHa); Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK (JP, IdSS, FD); Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK (NJ, AA, NO, MGC); Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam, the Netherlands (MKS, AB, SV, EJR); Division of Breast Cancer Research, Institute of Cancer Research, London, UK (ASw); Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD (JF, SJC, LB, ASi, MD); Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland (JLis); Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN (FJC); Department of Health Sciences Research, Mayo Clinic, Rochester, MN (JEO, CV, VSP, SS); Vesalius Research Center, VIB, Leuven, Belgium (DL); Laboratory for Translational Genetics, Department of Oncology, University of

Abstract

BACKGROUND:

Data for multiple common susceptibility alleles for breast cancer may be combined to identify women at different levels of breast cancer risk. Such stratification could guide preventive and screening strategies. However, empirical evidence for genetic risk stratification is lacking.

METHODS:

We investigated the value of using 77 breast cancer-associated single nucleotide polymorphisms (SNPs) for risk stratification, in a study of 33 673 breast cancer cases and 33 381 control women of European origin. We tested all possible pair-wise multiplicative interactions and constructed a 77-SNP polygenic risk score (PRS) for breast cancer overall and by estrogen receptor (ER) status. Absolute risks of breast cancer by PRS were derived from relative risk estimates and UK incidence and mortality rates.

RESULTS:

There was no strong evidence for departure from a multiplicative model for any SNP pair. Women in the highest 1% of the PRS had a three-fold increased risk of developing breast cancer compared with women in the middle quintile (odds ratio [OR] = 3.36, 95% confidence interval [CI] = 2.95 to 3.83). The ORs for ER-positive and ER-negative disease were 3.73 (95% CI = 3.24 to 4.30) and 2.80 (95% CI = 2.26 to 3.46), respectively. Lifetime risk of breast cancer for women in the lowest and highest quintiles of the PRS were 5.2% and 16.6% for a woman without family history, and 8.6% and 24.4% for a woman with a first-degree family history of breast cancer.

CONCLUSIONS:

The PRS stratifies breast cancer risk in women both with and without a family history of breast cancer. The observed level of risk discrimination could inform targeted screening and prevention strategies. Further discrimination may be achievable through combining the PRS with lifestyle/environmental factors, although these were not considered in this report.

PMID:
25855707
PMCID:
PMC4754625
DOI:
10.1093/jnci/djv036
[Indexed for MEDLINE]
Free PMC Article

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