The predictive ability of the 313 variant-based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant.

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ICR Authors

Eeles, Rosalind

Authors

Lakeman, IMM
van den Broek, AJ
Vos, JAM
Barnes, DR
Adlard, J
Andrulis, IL
Arason, A
Arnold, N
Arun, BK
Balmaña, J
Barrowdale, D
Benitez, J
Borg, A
Caldés, T
Caligo, MA
Chung, WK
Claes, KBM
GEMO Study Collaborators,
EMBRACE Collaborators,
Collée, JM
Couch, FJ
Daly, MB
Dennis, J
Dhawan, M
Domchek, SM
Eeles, R
Engel, C
Evans, DG
Feliubadaló, L
Foretova, L
Friedman, E
Frost, D
Ganz, PA
Garber, J
Gayther, SA
Gerdes, A-M
Godwin, AK
Goldgar, DE
Hahnen, E
Hake, CR
Hamann, U
Hogervorst, FBL
Hooning, MJ
Hopper, JL
Hulick, PJ
Imyanitov, EN
OCGN Investigators,
HEBON Investigators,
KconFab Investigators,
Isaacs, C
Izatt, L
Jakubowska, A
James, PA
Janavicius, R
Jensen, UB
Jiao, Y
John, EM
Joseph, V
Karlan, BY
Kets, CM
Konstantopoulou, I
Kwong, A
Legrand, C
Leslie, G
Lesueur, F
Loud, JT
Lubiński, J
Manoukian, S
McGuffog, L
Miller, A
Gomes, DM
Montagna, M
Mouret-Fourme, E
Nathanson, KL
Neuhausen, SL
Nevanlinna, H
Yie, JNY
Olah, E
Olopade, OI
Park, SK
Parsons, MT
Peterlongo, P
Piedmonte, M
Radice, P
Rantala, J
Rennert, G
Risch, HA
Schmutzler, RK
Sharma, P
Simard, J
Singer, CF
Stadler, Z
Stoppa-Lyonnet, D
Sutter, C
Tan, YY
Teixeira, MR
Teo, SH
Teulé, A
Thomassen, M
Thull, DL
Tischkowitz, M
Toland, AE
Tung, N
van Rensburg, EJ
Vega, A
Wappenschmidt, B
Devilee, P
van Asperen, CJ
Bernstein, JL
Offit, K
Easton, DF
Rookus, MA
Chenevix-Trench, G
Antoniou, AC
Robson, M
Schmidt, MK

Document Type

Journal Article

Date

2021-06-10

Date Accepted

2021-04-26

Abstract

PURPOSE: To evaluate the association between a previously published 313 variant-based breast cancer (BC) polygenic risk score (PRS313) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes. METHODS: We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS313 and CBC risk. RESULTS: For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS313 showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06-1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS313, HR = 1.15, 95% CI (1.07-1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC < age 40 years, the cumulative PRS313 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes, respectively. CONCLUSION: The PRS313 can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the PRS313 needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decision-making.

Citation

Genetics in medicine : official journal of the American College of Medical Genetics, 2021

DOI

10.1038/s41436-021-01198-7

URI

https://repository.icr.ac.uk/handle/internal/4753

Rights

https://creativecommons.org/licenses/by/4.0

Source Title

Publisher

ELSEVIER SCIENCE INC

ISSN

1098-3600

eISSN

1530-0366

Collections

Genetics and Epidemiology
Radiotherapy and Imaging

Research Team

Oncogenetics
Oncogenetics

Notes