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Title: Prediction of breast cancer risk based on profiling with common genetic variants.
Authors: Mavaddat N,  Pharoah PD,  Michailidou K,  Tyrer J,  Brook MN,  Bolla MK,  Wang Q,  Dennis J,  Dunning AM,  Shah M,  Luben R,  Brown J,  Bojesen SE,  Nordestgaard BG,  Nielsen SF,  Flyger H,  Czene K,  Darabi H,  Eriksson M,  Peto J,  Dos-Santos-Silva I,  Dudbridge F,  Johnson N,  Schmidt MK,  Broeks A,  Verhoef S,  Rutgers EJ,  Swerdlow A,  Ashworth A,  Orr N,  Schoemaker MJ,  Figueroa J,  Chanock SJ,  Brinton L,  Lissowska J,  Couch FJ,  Olson JE,  Vachon C,  Pankratz VS,  Lambrechts D,  Wildiers H,  Van Ongeval C,  van Limbergen E,  Kristensen V,  Grenaker Alnćs G,  Nord S,  Borresen-Dale AL,  Nevanlinna H,  Muranen TA,  Aittomäki K,  Blomqvist C,  Chang-Claude J,  Rudolph A,  Seibold P,  Flesch-Janys D,  Fasching PA,  Haeberle L,  Ekici AB,  Beckmann MW,  Burwinkel B,  Marme F,  Schneeweiss A,  Sohn C,  Trentham-Dietz A,  Newcomb P,  Titus L,  Egan KM,  Hunter DJ,  Lindstrom S,  Tamimi RM,  Kraft P,  Rahman N,  Turnbull C,  Renwick A,  Seal S,  Li J,  Liu J,  Humphreys K,  Benitez J,  Pilar Zamora M,  Arias Perez JI,  Menéndez P,  Jakubowska A,  Lubinski J,  Jaworska-Bieniek K,  Durda K,  Bogdanova NV,  Antonenkova NN,  Dörk T,  Anton-Culver H,  Neuhausen SL,  Ziogas A,  Bernstein L,  Devilee P,  Tollenaar RA,  Seynaeve C,  van Asperen CJ,  Cox A,  Cross SS,  Reed MW,  Khusnutdinova E,  Bermisheva M,  Prokofyeva D,  Takhirova Z,  Meindl A,  Schmutzler RK,  Sutter C,  Yang R,  Schürmann P,  Bremer M,  Christiansen H,  Park-Simon TW,  Hillemanns P,  Guénel P,  Truong T,  Menegaux F,  Sanchez M,  Radice P,  Peterlongo P,  Manoukian S,  Pensotti V,  Hopper JL,  Tsimiklis H,  Apicella C,  Southey MC,  Brauch H,  Brüning T,  Ko YD,  Sigurdson AJ,  Doody MM,  Hamann U,  Torres D,  Ulmer HU,  Försti A,  Sawyer EJ,  Tomlinson I,  Kerin MJ,  Miller N,  Andrulis IL,  Knight JA,  Glendon G,  Marie Mulligan A,  Chenevix-Trench G,  Balleine R,  Giles GG,  Milne RL,  McLean C,  Lindblom A,  Margolin S,  Haiman CA,  Henderson BE,  Schumacher F,  Le Marchand L,  Eilber U,  Wang-Gohrke S,  Hooning MJ,  Hollestelle A,  van den Ouweland AM,  Koppert LB,  Carpenter J,  Clarke C,  Scott R,  Mannermaa A,  Kataja V,  Kosma VM,  Hartikainen JM,  Brenner H,  Arndt V,  Stegmaier C,  Karina Dieffenbach A,  Winqvist R,  Pylkäs K,  Jukkola-Vuorinen A,  Grip M,  Offit K,  Vijai J,  Robson M,  Rau-Murthy R,  Dwek M,  Swann R,  Annie Perkins K,  Goldberg MS,  Labrčche F,  Dumont M,  Eccles DM,  Tapper WJ,  Rafiq S,  John EM,  Whittemore AS,  Slager S,  Yannoukakos D,  Toland AE,  Yao S,  Zheng W,  Halverson SL,  González-Neira A,  Pita G,  Rosario Alonso M,  Álvarez N,  Herrero D,  Tessier DC,  Vincent D,  Bacot F,  Luccarini C,  Baynes C,  Ahmed S,  Maranian M,  Healey CS,  Simard J,  Hall P,  Easton DF,  Garcia-Closas M
Journal: J Natl Cancer Inst
Date: 2015 May
Branches: HREB, LTG, OD, OEEB, REB
PubMed ID: 25855707
PMC ID: not available
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.