Prediction of Breast Cancer Risk Based on Profiling With Common Genetic Variants

N Mavaddat; PDP Pharoah; K Michailidou; J Tyrer; MN Brook; MK Bolla; Q (Qing) Wang; J Dennis; AM Dunning; M Shah; R Luben; J Brown; SE Bojesen; BG Nordestgaard; SF Nielsen; H Flyger; K Czene; H Darabi; M Eriksson; J Peto; I dos-Santos-Silva; F Dudbridge; N Johnson; MK (Marjanka) Schmidt; A Broeks; S Verhoef; EJ Rutgers; A Swerdlow; A Ashworth; N Orr; MJ Schoemaker; J Figueroa; SJ Chanock; L Brinton; J Lissowska; FJ Couch; JE Olson; C Vachon; VS Pankratz; D Lambrechts; H Wildiers; C Van Ongeval; E van Limbergen; V Kristensen; GG Alnaes; S Nord; AL Borresen-Dale; H Nevanlinna; TA Muranen; K Aittomaki; C Blomqvist; J Chang-Claude; A Rudolph; P Seibold; D Flesch-Janys; PA Fasching; L Haeberle; AB Ekici; MW Beckmann; B Burwinkel; F Marme; A Schneeweiss; C Sohn; A Trentham-Dietz; P Newcomb; L Titus; KM Egan; DJ Hunter; S Lindstrom; RM Tamimi; P Kraft; N Rahman; C Turnbull; A Renwick; S Seal; JM Li; JJ Liu; K Humphreys; J Benitez; MP Zamora; JIA Perez; P Menendez; A Jakubowska; J Lubinski; K Jaworska-Bieniek; K Durda; NV Bogdanova; NN Antonenkova; T Dork; H Anton-Culver; SL Neuhausen; A Ziogas; L Bernstein; P Devilee; RAEM Tollenaar; Caroline Seynaeve; CJ van Asperen; A Cox; SS Cross; MWR Reed; E Khusnutdinova; M Bermisheva; D Prokofyeva; Z Takhirova; A Meindl; RK Schmutzler; C Sutter; RX Yang; P Schurmann; M Bremer; H Christiansen; TW Park-Simon; P Hillemanns; P Guenel; T Truong; F Menegaux; M Sanchez; P Radice; P Peterlongo; S Manoukian; V Pensotti; JL Hopper; H Tsimiklis; C Apicella; MC Southey; H Brauch; T Bruning; YD Ko; AJ Sigurdson; MM Doody; U Hamann; D Torres; HU Ulmer; A Forsti; EJ Sawyer; I Tomlinson; MJ Kerin; N Miller; IL Andrulis; JA Knight; G Glendon; AM Mulligan; G Chenevix-Trench; R Balleine; GG Giles; RL Milne; C McLean; A Lindblom; S Margolin; CA Haiman; BE Henderson; F Schumacher; L Le Marchand; U Eilber; S Wang-Gohrke; Maartje Hooning; Antoinette Hollestelle; Ans van den Ouweland; Linetta Koppert; J Carpenter; C Clarke; R Scott; A Mannermaa; V Kataja; VM Kosma; JM Hartikainen; H Brenner; V Arndt; C Stegmaier; AK Dieffenbach; R Winqvist; K Pylkas; A Jukkola-Vuorinen; M Grip; K Offit; J Vijai; M Robson; R Rau-Murthy; M Dwek; R Swann; KA Perkins; MS Goldberg; F Labreche; M Dumont; DM Eccles; WJ Tapper; S Rafiq; EM John; AS Whittemore; S Slager; D Yannoukakos; AE Toland; S Yao; W Zheng; SL Halverson; A Gonzalez-Neira; G Pita; MR Alonso; N Alvarez; D Herrero; DC Tessier; D Vincent; F Bacot; C Luccarini; C Baynes; S (Shahana) Ahmed; M Maranian; CS Healey; J Simard; P Hall; DF Easton; M Garcia-Closas

doi:10.1093/jnci/djv036

Prediction of Breast Cancer Risk Based on Profiling With Common Genetic Variants

N Mavaddat, PDP Pharoah, K Michailidou, J Tyrer, MN Brook, MK Bolla, Q (Qing) Wang, J Dennis, AM Dunning, M Shah, R Luben, J Brown, SE Bojesen, BG Nordestgaard, SF Nielsen, H Flyger, K Czene, H Darabi, M Eriksson, J PetoI dos-Santos-Silva, F Dudbridge, N Johnson, MK (Marjanka) Schmidt, A Broeks, S Verhoef, EJ Rutgers, A Swerdlow, A Ashworth, N Orr, MJ Schoemaker, J Figueroa, SJ Chanock, L Brinton, J Lissowska, FJ Couch, JE Olson, C Vachon, VS Pankratz, D Lambrechts, H Wildiers, C Van Ongeval, E van Limbergen, V Kristensen, GG Alnaes, S Nord, AL Borresen-Dale, H Nevanlinna, TA Muranen, K Aittomaki, C Blomqvist, J Chang-Claude, A Rudolph, P Seibold, D Flesch-Janys, PA Fasching, L Haeberle, AB Ekici, MW Beckmann, B Burwinkel, F Marme, A Schneeweiss, C Sohn, A Trentham-Dietz, P Newcomb, L Titus, KM Egan, DJ Hunter, S Lindstrom, RM Tamimi, P Kraft, N Rahman, C Turnbull, A Renwick, S Seal, JM Li, JJ Liu, K Humphreys, J Benitez, MP Zamora, JIA Perez, P Menendez, A Jakubowska, J Lubinski, K Jaworska-Bieniek, K Durda, NV Bogdanova, NN Antonenkova, T Dork, H Anton-Culver, SL Neuhausen, A Ziogas, L Bernstein, P Devilee, RAEM Tollenaar, Caroline Seynaeve, CJ van Asperen, A Cox, SS Cross, MWR Reed, E Khusnutdinova, M Bermisheva, D Prokofyeva, Z Takhirova, A Meindl, RK Schmutzler, C Sutter, RX Yang, P Schurmann, M Bremer, H Christiansen, TW Park-Simon, P Hillemanns, P Guenel, T Truong, F Menegaux, M Sanchez, P Radice, P Peterlongo, S Manoukian, V Pensotti, JL Hopper, H Tsimiklis, C Apicella, MC Southey, H Brauch, T Bruning, YD Ko, AJ Sigurdson, MM Doody, U Hamann, D Torres, HU Ulmer, A Forsti, EJ Sawyer, I Tomlinson, MJ Kerin, N Miller, IL Andrulis, JA Knight, G Glendon, AM Mulligan, G Chenevix-Trench, R Balleine, GG Giles, RL Milne, C McLean, A Lindblom, S Margolin, CA Haiman, BE Henderson, F Schumacher, L Le Marchand, U Eilber, S Wang-Gohrke, Maartje Hooning, Antoinette Hollestelle, Ans van den Ouweland, Linetta Koppert, J Carpenter, C Clarke, R Scott, A Mannermaa, V Kataja, VM Kosma, JM Hartikainen, H Brenner, V Arndt, C Stegmaier, AK Dieffenbach, R Winqvist, K Pylkas, A Jukkola-Vuorinen, M Grip, K Offit, J Vijai, M Robson, R Rau-Murthy, M Dwek, R Swann, KA Perkins, MS Goldberg, F Labreche, M Dumont, DM Eccles, WJ Tapper, S Rafiq, EM John, AS Whittemore, S Slager, D Yannoukakos, AE Toland, S Yao, W Zheng, SL Halverson, A Gonzalez-Neira, G Pita, MR Alonso, N Alvarez, D Herrero, DC Tessier, D Vincent, F Bacot, C Luccarini, C Baynes, S (Shahana) Ahmed, M Maranian, CS Healey, J Simard, P Hall, DF Easton, M Garcia-Closas

Research output: Contribution to journal › Article › Academic › peer-review

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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.

Original language	Undefined/Unknown
Journal	Journal of the National Cancer Institute
Volume	107
Issue number	5
DOIs	https://doi.org/10.1093/jnci/djv036
Publication status	Published - 2015

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Mavaddat, N., Pharoah, PDP., 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., ... Garcia-Closas, M. (2015). Prediction of Breast Cancer Risk Based on Profiling With Common Genetic Variants. Journal of the National Cancer Institute, 107(5). https://doi.org/10.1093/jnci/djv036

@article{06ef77b47b2d4c8eb16820435cc03397,

title = "Prediction of Breast Cancer Risk Based on Profiling With Common Genetic Variants",

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.",

author = "N Mavaddat and PDP Pharoah and K Michailidou and J Tyrer and MN Brook and MK Bolla and Wang, {Q (Qing)} and J Dennis and AM Dunning and M Shah and R Luben and J Brown and SE Bojesen and BG Nordestgaard and SF Nielsen and H Flyger and K Czene and H Darabi and M Eriksson and J Peto and I dos-Santos-Silva and F Dudbridge and N Johnson and Schmidt, {MK (Marjanka)} and A Broeks and S Verhoef and EJ Rutgers and A Swerdlow and A Ashworth and N Orr and MJ Schoemaker and J Figueroa and SJ Chanock and L Brinton and J Lissowska and FJ Couch and JE Olson and C Vachon and VS Pankratz and D Lambrechts and H Wildiers and {Van Ongeval}, C and {van Limbergen}, E and V Kristensen and GG Alnaes and S Nord and AL Borresen-Dale and H Nevanlinna and TA Muranen and K Aittomaki and C Blomqvist and J Chang-Claude and A Rudolph and P Seibold and D Flesch-Janys and PA Fasching and L Haeberle and AB Ekici and MW Beckmann and B Burwinkel and F Marme and A Schneeweiss and C Sohn and A Trentham-Dietz and P Newcomb and L Titus and KM Egan and DJ Hunter and S Lindstrom and RM Tamimi and P Kraft and N Rahman and C Turnbull and A Renwick and S Seal and JM Li and JJ Liu and K Humphreys and J Benitez and MP Zamora and JIA Perez and P Menendez and A Jakubowska and J Lubinski and K Jaworska-Bieniek and K Durda and NV Bogdanova and NN Antonenkova and T Dork and H Anton-Culver and SL Neuhausen and A Ziogas and L Bernstein and P Devilee and RAEM Tollenaar and Caroline Seynaeve and {van Asperen}, CJ and A Cox and SS Cross and MWR Reed and E Khusnutdinova and M Bermisheva and D Prokofyeva and Z Takhirova and A Meindl and RK Schmutzler and C Sutter and RX Yang and P Schurmann and M Bremer and H Christiansen and TW Park-Simon and P Hillemanns and P Guenel and T Truong and F Menegaux and M Sanchez and P Radice and P Peterlongo and S Manoukian and V Pensotti and JL Hopper and H Tsimiklis and C Apicella and MC Southey and H Brauch and T Bruning and YD Ko and AJ Sigurdson and MM Doody and U Hamann and D Torres and HU Ulmer and A Forsti and EJ Sawyer and I Tomlinson and MJ Kerin and N Miller and IL Andrulis and JA Knight and G Glendon and AM Mulligan and G Chenevix-Trench and R Balleine and GG Giles and RL Milne and C McLean and A Lindblom and S Margolin and CA Haiman and BE Henderson and F Schumacher and {Le Marchand}, L and U Eilber and S Wang-Gohrke and Maartje Hooning and Antoinette Hollestelle and {van den Ouweland}, Ans and Linetta Koppert and J Carpenter and C Clarke and R Scott and A Mannermaa and V Kataja and VM Kosma and JM Hartikainen and H Brenner and V Arndt and C Stegmaier and AK Dieffenbach and R Winqvist and K Pylkas and A Jukkola-Vuorinen and M Grip and K Offit and J Vijai and M Robson and R Rau-Murthy and M Dwek and R Swann and KA Perkins and MS Goldberg and F Labreche and M Dumont and DM Eccles and WJ Tapper and S Rafiq and EM John and AS Whittemore and S Slager and D Yannoukakos and AE Toland and S Yao and W Zheng and SL Halverson and A Gonzalez-Neira and G Pita and MR Alonso and N Alvarez and D Herrero and DC Tessier and D Vincent and F Bacot and C Luccarini and C Baynes and Ahmed, {S (Shahana)} and M Maranian and CS Healey and J Simard and P Hall and DF Easton and M Garcia-Closas",

year = "2015",

doi = "10.1093/jnci/djv036",

language = "Undefined/Unknown",

volume = "107",

journal = "Journal of the National Cancer Institute",

issn = "0027-8874",

publisher = "Oxford University Press",

number = "5",

}

Mavaddat, N, Pharoah, PDP, 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, Alnaes, GG, Nord, S, Borresen-Dale, AL, Nevanlinna, H, Muranen, TA, Aittomaki, 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, JM, Liu, JJ, Humphreys, K, Benitez, J, Zamora, MP, Perez, JIA, Menendez, P, Jakubowska, A, Lubinski, J, Jaworska-Bieniek, K, Durda, K, Bogdanova, NV, Antonenkova, NN, Dork, T, Anton-Culver, H, Neuhausen, SL, Ziogas, A, Bernstein, L, Devilee, P, Tollenaar, RAEM, Seynaeve, C, van Asperen, CJ, Cox, A, Cross, SS, Reed, MWR, Khusnutdinova, E, Bermisheva, M, Prokofyeva, D, Takhirova, Z, Meindl, A, Schmutzler, RK, Sutter, C, Yang, RX, Schurmann, P, Bremer, M, Christiansen, H, Park-Simon, TW, Hillemanns, P, Guenel, 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, Bruning, T, Ko, YD, Sigurdson, AJ, Doody, MM, Hamann, U, Torres, D, Ulmer, HU, Forsti, A, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, Andrulis, IL, Knight, JA, Glendon, G, Mulligan, AM, 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, M , Hollestelle, A, van den Ouweland, A, Koppert, L, Carpenter, J, Clarke, C, Scott, R, Mannermaa, A, Kataja, V, Kosma, VM, Hartikainen, JM, Brenner, H, Arndt, V, Stegmaier, C, Dieffenbach, AK, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Grip, M, Offit, K, Vijai, J, Robson, M, Rau-Murthy, R, Dwek, M, Swann, R, Perkins, KA, Goldberg, MS, Labreche, 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, Gonzalez-Neira, A, Pita, G, Alonso, MR, Alvarez, 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 2015, 'Prediction of Breast Cancer Risk Based on Profiling With Common Genetic Variants', Journal of the National Cancer Institute, vol. 107, no. 5. https://doi.org/10.1093/jnci/djv036

TY - JOUR

T1 - Prediction of Breast Cancer Risk Based on Profiling With Common Genetic Variants

AU - Mavaddat, N

AU - Pharoah, PDP

AU - Michailidou, K

AU - Tyrer, J

AU - Brook, MN

AU - Bolla, MK

AU - Wang, Q (Qing)

AU - Dennis, J

AU - Dunning, AM

AU - Shah, M

AU - Luben, R

AU - Brown, J

AU - Bojesen, SE

AU - Nordestgaard, BG

AU - Nielsen, SF

AU - Flyger, H

AU - Czene, K

AU - Darabi, H

AU - Eriksson, M

AU - Peto, J

AU - dos-Santos-Silva, I

AU - Dudbridge, F

AU - Johnson, N

AU - Schmidt, MK (Marjanka)

AU - Broeks, A

AU - Verhoef, S

AU - Rutgers, EJ

AU - Swerdlow, A

AU - Ashworth, A

AU - Orr, N

AU - Schoemaker, MJ

AU - Figueroa, J

AU - Chanock, SJ

AU - Brinton, L

AU - Lissowska, J

AU - Couch, FJ

AU - Olson, JE

AU - Vachon, C

AU - Pankratz, VS

AU - Lambrechts, D

AU - Wildiers, H

AU - Van Ongeval, C

AU - van Limbergen, E

AU - Kristensen, V

AU - Alnaes, GG

AU - Nord, S

AU - Borresen-Dale, AL

AU - Nevanlinna, H

AU - Muranen, TA

AU - Aittomaki, K

AU - Blomqvist, C

AU - Chang-Claude, J

AU - Rudolph, A

AU - Seibold, P

AU - Flesch-Janys, D

AU - Fasching, PA

AU - Haeberle, L

AU - Ekici, AB

AU - Beckmann, MW

AU - Burwinkel, B

AU - Marme, F

AU - Schneeweiss, A

AU - Sohn, C

AU - Trentham-Dietz, A

AU - Newcomb, P

AU - Titus, L

AU - Egan, KM

AU - Hunter, DJ

AU - Lindstrom, S

AU - Tamimi, RM

AU - Kraft, P

AU - Rahman, N

AU - Turnbull, C

AU - Renwick, A

AU - Seal, S

AU - Li, JM

AU - Liu, JJ

AU - Humphreys, K

AU - Benitez, J

AU - Zamora, MP

AU - Perez, JIA

AU - Menendez, P

AU - Jakubowska, A

AU - Lubinski, J

AU - Jaworska-Bieniek, K

AU - Durda, K

AU - Bogdanova, NV

AU - Antonenkova, NN

AU - Dork, T

AU - Anton-Culver, H

AU - Neuhausen, SL

AU - Ziogas, A

AU - Bernstein, L

AU - Devilee, P

AU - Tollenaar, RAEM

AU - Seynaeve, Caroline

AU - van Asperen, CJ

AU - Cox, A

AU - Cross, SS

AU - Reed, MWR

AU - Khusnutdinova, E

AU - Bermisheva, M

AU - Prokofyeva, D

AU - Takhirova, Z

AU - Meindl, A

AU - Schmutzler, RK

AU - Sutter, C

AU - Yang, RX

AU - Schurmann, P

AU - Bremer, M

AU - Christiansen, H

AU - Park-Simon, TW

AU - Hillemanns, P

AU - Guenel, P

AU - Truong, T

AU - Menegaux, F

AU - Sanchez, M

AU - Radice, P

AU - Peterlongo, P

AU - Manoukian, S

AU - Pensotti, V

AU - Hopper, JL

AU - Tsimiklis, H

AU - Apicella, C

AU - Southey, MC

AU - Brauch, H

AU - Bruning, T

AU - Ko, YD

AU - Sigurdson, AJ

AU - Doody, MM

AU - Hamann, U

AU - Torres, D

AU - Ulmer, HU

AU - Forsti, A

AU - Sawyer, EJ

AU - Tomlinson, I

AU - Kerin, MJ

AU - Miller, N

AU - Andrulis, IL

AU - Knight, JA

AU - Glendon, G

AU - Mulligan, AM

AU - Chenevix-Trench, G

AU - Balleine, R

AU - Giles, GG

AU - Milne, RL

AU - McLean, C

AU - Lindblom, A

AU - Margolin, S

AU - Haiman, CA

AU - Henderson, BE

AU - Schumacher, F

AU - Le Marchand, L

AU - Eilber, U

AU - Wang-Gohrke, S

AU - Hooning, Maartje

AU - Hollestelle, Antoinette

AU - van den Ouweland, Ans

AU - Koppert, Linetta

AU - Carpenter, J

AU - Clarke, C

AU - Scott, R

AU - Mannermaa, A

AU - Kataja, V

AU - Kosma, VM

AU - Hartikainen, JM

AU - Brenner, H

AU - Arndt, V

AU - Stegmaier, C

AU - Dieffenbach, AK

AU - Winqvist, R

AU - Pylkas, K

AU - Jukkola-Vuorinen, A

AU - Grip, M

AU - Offit, K

AU - Vijai, J

AU - Robson, M

AU - Rau-Murthy, R

AU - Dwek, M

AU - Swann, R

AU - Perkins, KA

AU - Goldberg, MS

AU - Labreche, F

AU - Dumont, M

AU - Eccles, DM

AU - Tapper, WJ

AU - Rafiq, S

AU - John, EM

AU - Whittemore, AS

AU - Slager, S

AU - Yannoukakos, D

AU - Toland, AE

AU - Yao, S

AU - Zheng, W

AU - Halverson, SL

AU - Gonzalez-Neira, A

AU - Pita, G

AU - Alonso, MR

AU - Alvarez, N

AU - Herrero, D

AU - Tessier, DC

AU - Vincent, D

AU - Bacot, F

AU - Luccarini, C

AU - Baynes, C

AU - Ahmed, S (Shahana)

AU - Maranian, M

AU - Healey, CS

AU - Simard, J

AU - Hall, P

AU - Easton, DF

AU - Garcia-Closas, M

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

U2 - 10.1093/jnci/djv036

DO - 10.1093/jnci/djv036

M3 - Article

SN - 0027-8874

VL - 107

JO - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

IS - 5

ER -