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Article: Evaluation of Polygenic Risk Scores for Breast and Ovarian Cancer Risk Prediction in BRCA1 and BRCA2 Mutation Carriers

TitleEvaluation of Polygenic Risk Scores for Breast and Ovarian Cancer Risk Prediction in BRCA1 and BRCA2 Mutation Carriers
Authors
Kuchenbaecker, KBMcGuffog, LBarrowdale, DLee, ASoucy, PDennis, JDomchek, SMRobson, MSpurdle, ABRamus, SJMavaddat, NTerry, MBNeuhausen, SLSchmutzler, RKSimard, JPharoah, PDPOffit, KCouch, FChenevix-Trench, GEaston, DFAntoniou, ACLush, MHamann, USouthey, MJohn, EMChung, WKDaly, MBBuys, SSGoldgar, DEDorfling, CMvan Rensburg, EJChun Ding, YEjlertsen, BGerdes, AMHansen, TVSlager, SHallberg, EBenitez, JOsorio, ACohen, NLawler, WWeitzel, JNPeterlongo, PPensotti, VDolcetti, RBarile, MBonanni, BAzzollini, JManoukian, SPeissel, BRadice, PSavarese, APapi, LGiannini, GFostira, FKonstantopoulou, IAdlard, JBrewer, CCook, JDavidson, REccles, DEeles, REllis, SFrost, DHodgson, SIzatt, LLalloo, FOng, KRGodwin, AKArnold, NDworniczak, BEngel, CGehrig, AHahnen, EHauke, JKast, KMeindl, ANiederacher, DSchmutzler, RKVaron-Mateeva, RWang-Gohrke, SWappenschmidt, BBarjhoux, LCollonge-Rame, MAElan, CGolmard, LGEMO, SCEMBRAC, EBarouk-Simonet, ELesueur, FMazoyer, SSokolowska, JStoppa-Lyonnet, DIsaacs, CClaes, KBMPoppe, Bde la Hoya, MGarcia-Barberan, VAittomaki, KNevanlinna, HAusems, MGEMde Lange, JLGomez Garcia, EBHogervorst, FBHEBO, NKets, CMMeijers-Heijboer, HEOosterwijk, JCRookus, MAvan Asperen, CJvan den Ouweland, AMWvan Doorn, HCvan Os, TAMKwong, AOlah, EDiez, OBrunet, JLazaro, CTeule, AGronwald, JJakubowska, AKaczmarek, KLubinski, JSukiennicki, GBarkardottir, RBChiquette, JAgata, SMontagna, MTeixeira, MRKyung Park, SKConFab Investigators, KOlswold, CTischkowitz, MForetova, LGaddam, PVijai, JPfeiler, GRappaport-Fuerhauser, CSinger, CFTea, MKMGreene, MXLoud, JTRennert, GImyanitov, ENHulick, PJHays, JLPiedmonte, MRodriguez, GCMartyn, JGlendon, GMulligan, AMAndrulis, ILAndrulis, AEJenson, UBKruse, TASokilde Pedersen, IThomassen, MCaligo, MATeo, SHBerger, RFriedman, ELaitman, YArver, BBorg, AEhrancrona, HRantala, JOlopade, OIGanz, PANussbaum, RLBradbury, ARDomchek, SMNathanson, KLArun, BKJames, PKarlan, BYLester, JSimard, JPharoah, PDPOffit, KCouch, FJChenevix-Trench, GEaston, DFAntoniou, AC
Issue Date2017
PublisherOxford University Press. The Journal's web site is located at http://jncicancerspectrum.oxfordjournals.org/
Citation
JNCI: Journal of the National Cancer Institute, 2017, v. 109 How to Cite?
AbstractBackground: Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. Methods: We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]–positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS. Results: The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2×10−53). In BRCA2 carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2×10−20). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. Conclusions: BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management.
Persistent Identifierhttp://hdl.handle.net/10722/245314
ISSN
2017 Impact Factor: 11.238
2015 SCImago Journal Rankings: 6.192
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorKuchenbaecker, KB-
dc.contributor.authorMcGuffog, L-
dc.contributor.authorBarrowdale, D-
dc.contributor.authorLee, A-
dc.contributor.authorSoucy, P-
dc.contributor.authorDennis, J-
dc.contributor.authorDomchek, SM-
dc.contributor.authorRobson, M-
dc.contributor.authorSpurdle, AB-
dc.contributor.authorRamus, SJ-
dc.contributor.authorMavaddat, N-
dc.contributor.authorTerry, MB-
dc.contributor.authorNeuhausen, SL-
dc.contributor.authorSchmutzler, RK-
dc.contributor.authorSimard, J-
dc.contributor.authorPharoah, PDP-
dc.contributor.authorOffit, K-
dc.contributor.authorCouch, F-
dc.contributor.authorChenevix-Trench, G-
dc.contributor.authorEaston, DF-
dc.contributor.authorAntoniou, AC-
dc.contributor.authorLush, M-
dc.contributor.authorHamann, U-
dc.contributor.authorSouthey, M-
dc.contributor.authorJohn, EM-
dc.contributor.authorChung, WK-
dc.contributor.authorDaly, MB-
dc.contributor.authorBuys, SS-
dc.contributor.authorGoldgar, DE-
dc.contributor.authorDorfling, CM-
dc.contributor.authorvan Rensburg, EJ-
dc.contributor.authorChun Ding, Y-
dc.contributor.authorEjlertsen, B-
dc.contributor.authorGerdes, AM-
dc.contributor.authorHansen, TV-
dc.contributor.authorSlager, S-
dc.contributor.authorHallberg, E-
dc.contributor.authorBenitez, J-
dc.contributor.authorOsorio, A-
dc.contributor.authorCohen, N-
dc.contributor.authorLawler, W-
dc.contributor.authorWeitzel, JN-
dc.contributor.authorPeterlongo, P-
dc.contributor.authorPensotti, V-
dc.contributor.authorDolcetti, R-
dc.contributor.authorBarile, M-
dc.contributor.authorBonanni, B-
dc.contributor.authorAzzollini, J-
dc.contributor.authorManoukian, S-
dc.contributor.authorPeissel, B-
dc.contributor.authorRadice, P-
dc.contributor.authorSavarese, A-
dc.contributor.authorPapi, L-
dc.contributor.authorGiannini, G-
dc.contributor.authorFostira, F-
dc.contributor.authorKonstantopoulou, I-
dc.contributor.authorAdlard, J-
dc.contributor.authorBrewer, C-
dc.contributor.authorCook, J-
dc.contributor.authorDavidson, R-
dc.contributor.authorEccles, D-
dc.contributor.authorEeles, R-
dc.contributor.authorEllis, S-
dc.contributor.authorFrost, D-
dc.contributor.authorHodgson, S-
dc.contributor.authorIzatt, L-
dc.contributor.authorLalloo, F-
dc.contributor.authorOng, KR-
dc.contributor.authorGodwin, AK-
dc.contributor.authorArnold, N-
dc.contributor.authorDworniczak, B-
dc.contributor.authorEngel, C-
dc.contributor.authorGehrig, A-
dc.contributor.authorHahnen, E-
dc.contributor.authorHauke, J-
dc.contributor.authorKast, K-
dc.contributor.authorMeindl, A-
dc.contributor.authorNiederacher, D-
dc.contributor.authorSchmutzler, RK-
dc.contributor.authorVaron-Mateeva, R-
dc.contributor.authorWang-Gohrke, S-
dc.contributor.authorWappenschmidt, B-
dc.contributor.authorBarjhoux, L-
dc.contributor.authorCollonge-Rame, MA-
dc.contributor.authorElan, C-
dc.contributor.authorGolmard, L-
dc.contributor.authorGEMO, SC-
dc.contributor.authorEMBRAC, E-
dc.contributor.authorBarouk-Simonet, E-
dc.contributor.authorLesueur, F-
dc.contributor.authorMazoyer, S-
dc.contributor.authorSokolowska, J-
dc.contributor.authorStoppa-Lyonnet, D-
dc.contributor.authorIsaacs, C-
dc.contributor.authorClaes, KBM-
dc.contributor.authorPoppe, B-
dc.contributor.authorde la Hoya, M-
dc.contributor.authorGarcia-Barberan, V-
dc.contributor.authorAittomaki, K-
dc.contributor.authorNevanlinna, H-
dc.contributor.authorAusems, MGEM-
dc.contributor.authorde Lange, JL-
dc.contributor.authorGomez Garcia, EB-
dc.contributor.authorHogervorst, FB-
dc.contributor.authorHEBO, N-
dc.contributor.authorKets, CM-
dc.contributor.authorMeijers-Heijboer, HE-
dc.contributor.authorOosterwijk, JC-
dc.contributor.authorRookus, MA-
dc.contributor.authorvan Asperen, CJ-
dc.contributor.authorvan den Ouweland, AMW-
dc.contributor.authorvan Doorn, HC-
dc.contributor.authorvan Os, TAM-
dc.contributor.authorKwong, A-
dc.contributor.authorOlah, E-
dc.contributor.authorDiez, O-
dc.contributor.authorBrunet, J-
dc.contributor.authorLazaro, C-
dc.contributor.authorTeule, A-
dc.contributor.authorGronwald, J-
dc.contributor.authorJakubowska, A-
dc.contributor.authorKaczmarek, K-
dc.contributor.authorLubinski, J-
dc.contributor.authorSukiennicki, G-
dc.contributor.authorBarkardottir, RB-
dc.contributor.authorChiquette, J-
dc.contributor.authorAgata, S-
dc.contributor.authorMontagna, M-
dc.contributor.authorTeixeira, MR-
dc.contributor.authorKyung Park, S-
dc.contributor.authorKConFab Investigators, K-
dc.contributor.authorOlswold, C-
dc.contributor.authorTischkowitz, M-
dc.contributor.authorForetova, L-
dc.contributor.authorGaddam, P-
dc.contributor.authorVijai, J-
dc.contributor.authorPfeiler, G-
dc.contributor.authorRappaport-Fuerhauser, C-
dc.contributor.authorSinger, CF-
dc.contributor.authorTea, MKM-
dc.contributor.authorGreene, MX-
dc.contributor.authorLoud, JT-
dc.contributor.authorRennert, G-
dc.contributor.authorImyanitov, EN-
dc.contributor.authorHulick, PJ-
dc.contributor.authorHays, JL-
dc.contributor.authorPiedmonte, M-
dc.contributor.authorRodriguez, GC-
dc.contributor.authorMartyn, J-
dc.contributor.authorGlendon, G-
dc.contributor.authorMulligan, AM-
dc.contributor.authorAndrulis, IL-
dc.contributor.authorAndrulis, AE-
dc.contributor.authorJenson, UB-
dc.contributor.authorKruse, TA-
dc.contributor.authorSokilde Pedersen, I-
dc.contributor.authorThomassen, M-
dc.contributor.authorCaligo, MA-
dc.contributor.authorTeo, SH-
dc.contributor.authorBerger, R-
dc.contributor.authorFriedman, E-
dc.contributor.authorLaitman, Y-
dc.contributor.authorArver, B-
dc.contributor.authorBorg, A-
dc.contributor.authorEhrancrona, H-
dc.contributor.authorRantala, J-
dc.contributor.authorOlopade, OI-
dc.contributor.authorGanz, PA-
dc.contributor.authorNussbaum, RL-
dc.contributor.authorBradbury, AR-
dc.contributor.authorDomchek, SM-
dc.contributor.authorNathanson, KL-
dc.contributor.authorArun, BK-
dc.contributor.authorJames, P-
dc.contributor.authorKarlan, BY-
dc.contributor.authorLester, J-
dc.contributor.authorSimard, J-
dc.contributor.authorPharoah, PDP-
dc.contributor.authorOffit, K-
dc.contributor.authorCouch, FJ-
dc.contributor.authorChenevix-Trench, G-
dc.contributor.authorEaston, DF-
dc.contributor.authorAntoniou, AC-
dc.date.accessioned2017-09-18T02:08:25Z-
dc.date.available2017-09-18T02:08:25Z-
dc.date.issued2017-
dc.identifier.citationJNCI: Journal of the National Cancer Institute, 2017, v. 109-
dc.identifier.issn0027-8874-
dc.identifier.urihttp://hdl.handle.net/10722/245314-
dc.description.abstractBackground: Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. Methods: We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]–positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS. Results: The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2×10−53). In BRCA2 carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2×10−20). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. Conclusions: BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management.-
dc.languageeng-
dc.publisherOxford University Press. The Journal's web site is located at http://jncicancerspectrum.oxfordjournals.org/-
dc.relation.ispartofJNCI: Journal of the National Cancer Institute-
dc.rightsPre-print: Journal Title] ©: [year] [owner as specified on the article] Published by Oxford University Press [on behalf of xxxxxx]. All rights reserved. Pre-print (Once an article is published, preprint notice should be amended to): This is an electronic version of an article published in [include the complete citation information for the final version of the Article as published in the print edition of the Journal.] Post-print: This is a pre-copy-editing, author-produced PDF of an article accepted for publication in [insert journal title] following peer review. The definitive publisher-authenticated version [insert complete citation information here] is available online at: xxxxxxx [insert URL that the author will receive upon publication here]. -
dc.titleEvaluation of Polygenic Risk Scores for Breast and Ovarian Cancer Risk Prediction in BRCA1 and BRCA2 Mutation Carriers-
dc.typeArticle-
dc.identifier.emailKwong, A: avakwong@hku.hk-
dc.identifier.authorityKwong, A=rp01734-
dc.identifier.doi10.1093/jnci/djw302-
dc.identifier.pmcidPMC5408990-
dc.identifier.hkuros275878-
dc.identifier.volume109-
dc.identifier.isiWOS:000405496200004-
dc.publisher.placeUnited Kingdom-

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