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Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers

Karoline B Kuchenbaecker, Lesley McGuffog, Daniel Barrowdale, Andrew Lee, Penny Soucy, Sue Healey, Joe Dennis, Michael Lush, Mark Robson, Amanda B Spurdle, et al. (2017) JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE. 109(7).
abstract
Background: 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 x 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 x 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.
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author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
EARLY BILATERAL OOPHORECTOMY, WIDE ASSOCIATION ANALYSIS, SUSCEPTIBILITY ALLELES, FUNCTIONAL VARIANTS, LOCUS, WOMEN, IDENTIFICATION, MORTALITY, MODIFIERS, COHORT
journal title
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE
JNCI-J. Natl. Cancer Inst.
volume
109
issue
7
article number
djw302
pages
15 pages
Web of Science type
Article
Web of Science id
000405496200004
ISSN
0027-8874
1460-2105
DOI
10.1093/jnci/djw302
language
English
UGent publication?
yes
classification
A1
copyright statement
Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
id
8525301
handle
http://hdl.handle.net/1854/LU-8525301
date created
2017-06-27 09:15:29
date last changed
2018-03-15 10:58:23
@article{8525301,
  abstract     = {Background: 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 x 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 x 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.},
  articleno    = {djw302},
  author       = {Kuchenbaecker, Karoline B and McGuffog, Lesley and Barrowdale, Daniel and Lee, Andrew and Soucy, Penny and Healey, Sue and Dennis, Joe and Lush, Michael and Robson, Mark and Spurdle, Amanda B and Ramus, Susan J and Mavaddat, Nasim and Terry, Mary Beth and Neuhausen, Susan L and Hamann, Ute and Southey, Melissa and John, Esther M and Chung, Wendy K and Daly, Mary B and Buys, Saundra S and Goldgar, David E and Dorfling, Cecilia M and van Rensburg, Elizabeth J and Ding, Yuan Chun and Ejlertsen, Bent and Gerdes, Anne-Marie and Hansen, Thomas VO and Slager, Susan and Hallberg, Emily and Benitez, Javier and Osorio, Ana and Cohen, Nancy and Lawler, William and Weitzel, Jeffrey N and Peterlongo, Paolo and Pensotti, Valeria and Dolcetti, Riccardo and Barile, Monica and Bonanni, Bernardo and Azzollini, Jacopo and Manoukian, Siranoush and Peissel, Bernard and Radice, Paolo and Savarese, Antonella and Papi, Laura and Giannini, Giuseppe and Fostira, Florentia and Konstantopoulou, Irene and Adlard, Julian and Brewer, Carole and Cook, Jackie and Davidson, Rosemarie and Eccles, Diana and Eeles, Ros and Ellis, Steve and Frost, Debra and Hodgson, Shirley and Izatt, Louise and Lalloo, Fiona and Ong, Kai-ren and Godwin, Andrew K and Arnold, Norbert and Dworniczak, Bernd and Engel, Christoph and Gehrig, Andrea and Hahnen, Eric and Hauke, Jan and Kast, Karin and Meindl, Alfons and Niederacher, Dieter and Schmutzler, Rita Katharina and Varon-Mateeva, Raymonda and Wang-Gohrke, Shan and Wappenschmidt, Barbara and Barjhoux, Laure and Collonge-Rame, Marie-Agn{\`e}s and Elan, Camille and Golmard, Lisa and Barouk-Simonet, Emmanuelle and Lesueur, Fabienne and Mazoyer, Sylvie and Sokolowska, Joanna and Stoppa-Lyonnet, Dominique and Isaacs, Claudine and Claes, Kathleen and Poppe, Bruce and de la Hoya, Miguel and Garcia-Barberan, Vanesa and Aittom{\"a}ki, Kristiina and Nevanlinna, Heli and Ausems, Margreet GEM and de Lange, JL and G{\'o}mez Garcia, Encarna B and Hogervorst, Frans BL and Kets, Carolien M and Meijers-Heijboer, Hanne EJ and Oosterwijk, Jan C and Rookus, Matti A and van Asperen, Christi J and van den Ouweland, Ans MW and van Doorn, Helena C and van Os, Theo AM and Kwong, Ava and Olah, Edith and Diez, Orland and Brunet, Joan and Lazaro, Conxi and Teul{\'e}, Alex and Gronwald, Jacek and Jakubowska, Anna and Kaczmarek, Katarzyna and Lubinski, Jan and Sukiennicki, Grzegorz and Barkardottir, Rosa B and Chiquette, Jocelyne and Agata, Simona and Montagna, Marco and Teixeira, Manuel R and Park, Sue Kyung and Olswold, Curtis and Tischkowitz, Marc and Foretova, Lenka and Gaddam, Pragna and Vijai, Joseph and Pfeiler, Georg and Rappaport-Fuerhauser, Christine and Singer, Christian F and Tea, Muy-Kheng M and Greene, Mark H and Loud, Jennifer T and Rennert, Gad and Imyanitov, Evgeny N and Hulick, Peter J and Hays, John L and Piedmonte, Marion and Rodriguez, Gustavo C and Martyn, Julie and Glendon, Gord and Mulligan, Anna Marie and Andrulis, Irene L and Toland, Amanda Ewart and Jensen, Uffe Birk and Kruse, Torben A and Pedersen, Inge Sokilde and Thomassen, Mads and Caligo, Maria A and Teo, Soo-Hwang and Berger, Raanan and Friedman, Eitan and Laitman, Yael and Arver, Brita and Borg, Ake and Ehrencrona, Hans and Rantala, Johanna and Olopade, Olufunmilayo I and Ganz, Patricia A and Nussbaum, Robert L and Bradbury, Angela R and Domchek, Susan M and Nathanson, Katherine L and Arun, Banu K and James, Paul and Karlan, Beth Y and Lester, Jenny and Simard, Jacques and Pharoah, Paul DP and Offit, Kenneth and Couch, Fergus J and Chenevix-Trench, Georgia and Easton, Douglas F and Antoniou, Antonis C},
  issn         = {0027-8874},
  journal      = {JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE},
  keyword      = {EARLY BILATERAL OOPHORECTOMY,WIDE ASSOCIATION ANALYSIS,SUSCEPTIBILITY ALLELES,FUNCTIONAL VARIANTS,LOCUS,WOMEN,IDENTIFICATION,MORTALITY,MODIFIERS,COHORT},
  language     = {eng},
  number       = {7},
  pages        = {15},
  title        = {Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers},
  url          = {http://dx.doi.org/10.1093/jnci/djw302},
  volume       = {109},
  year         = {2017},
}

Chicago
Kuchenbaecker, Karoline B, Lesley McGuffog, Daniel Barrowdale, Andrew Lee, Penny Soucy, Sue Healey, Joe Dennis, et al. 2017. “Evaluation of Polygenic Risk Scores for Breast and Ovarian Cancer Risk Prediction in BRCA1 and BRCA2 Mutation Carriers.” Jnci-journal of the National Cancer Institute 109 (7).
APA
Kuchenbaecker, K. B., McGuffog, L., Barrowdale, D., Lee, A., Soucy, P., Healey, S., Dennis, J., et al. (2017). Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers. JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE, 109(7).
Vancouver
1.
Kuchenbaecker KB, McGuffog L, Barrowdale D, Lee A, Soucy P, Healey S, et al. Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers. JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE. 2017;109(7).
MLA
Kuchenbaecker, Karoline B, Lesley McGuffog, Daniel Barrowdale, et al. “Evaluation of Polygenic Risk Scores for Breast and Ovarian Cancer Risk Prediction in BRCA1 and BRCA2 Mutation Carriers.” JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE 109.7 (2017): n. pag. Print.