A genome-wide association study of contralateral breast cancer in the Women's Environmental Cancer and Radiation Epidemiology Study

Xiaohui Sun; Anne S Reiner; Anh Phong Tran; Gordon P Watt; Jung Hun Oh; Lene Mellemkjær; Charles F Lynch; Julia A Knight; Esther M John; Kathleen E Malone; Xiaolin Liang; Meghan Woods; Andriy Derkach; Patrick Concannon; Jonine L Bernstein; Xiang Shu

doi:10.1186/s13058-024-01765-1

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A genome-wide association study of contralateral breast cancer in the Women's Environmental Cancer and Radiation Epidemiology Study

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A genome-wide association study of contralateral breast cancer in the Women's Environmental Cancer and Radiation Epidemiology Study

Xiaohui Sun, Anne S Reiner, Anh Phong Tran, Gordon P Watt, Jung Hun Oh, Lene Mellemkjær, Charles F Lynch, Julia A Knight, Esther M John, Kathleen E Malone, …

Breast cancer research : BCR, Vol.26(1), 16

01/23/2024

DOI: 10.1186/s13058-024-01765-1

PMCID: PMC10807183

PMID: 38263039

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Abstract

Contralateral breast cancer (CBC) is the most common second primary cancer diagnosed in breast cancer survivors, yet the understanding of the genetic susceptibility of CBC, particularly with respect to common variants, remains incomplete. This study aimed to investigate the genetic basis of CBC to better understand this malignancy. We performed a genome-wide association analysis in the Women's Environmental Cancer and Radiation Epidemiology (WECARE) Study of women with first breast cancer diagnosed at age < 55 years including 1161 with CBC who served as cases and 1668 with unilateral breast cancer (UBC) who served as controls. We observed two loci (rs59657211, 9q32, SLC31A2/FAM225A and rs3815096, 6p22.1, TRIM31) with suggestive genome-wide significant associations (P < 1 × 10 ). We also found an increased risk of CBC associated with a breast cancer-specific polygenic risk score (PRS) comprised of 239 known breast cancer susceptibility single nucleotide polymorphisms (SNPs) (rate ratio per 1-SD change: 1.25; 95% confidence interval 1.14-1.36, P < 0.0001). The protective effect of chemotherapy on CBC risk was statistically significant only among patients with an elevated PRS (P = 0.04). The AUC that included the PRS and known breast cancer risk factors was significantly elevated. The present GWAS identified two previously unreported loci with suggestive genome-wide significance. We also confirm that an elevated risk of CBC is associated with a comprehensive breast cancer susceptibility PRS that is independent of known breast cancer risk factors. These findings advance our understanding of genetic risk factors involved in CBC etiology.

Breast

Breast Neoplasms

Cancer Survivors

Female

Genetic Predisposition to Disease

Genetic Risk Score

Genome-Wide Association Study

Humans

Middle Aged

Tripartite Motif Proteins

Ubiquitin-Protein Ligases

Details

Title: Subtitle: A genome-wide association study of contralateral breast cancer in the Women's Environmental Cancer and Radiation Epidemiology Study
Creators: Xiaohui Sun - Memorial Sloan Kettering Cancer Center
Anne S Reiner - Memorial Sloan Kettering Cancer Center
Anh Phong Tran - Memorial Sloan Kettering Cancer Center
Gordon P Watt - Memorial Sloan Kettering Cancer Center
Jung Hun Oh - Memorial Sloan Kettering Cancer Center
Lene Mellemkjær - Danish Cancer Society
Charles F Lynch - University of Iowa
Julia A Knight - Lunenfeld-Tanenbaum Research Institute
Esther M John - Stanford University
Kathleen E Malone - Fred Hutch Cancer Center
Xiaolin Liang - Memorial Sloan Kettering Cancer Center
Meghan Woods - Memorial Sloan Kettering Cancer Center
Andriy Derkach - Memorial Sloan Kettering Cancer Center
Patrick Concannon - University of Florida
Jonine L Bernstein - Memorial Sloan Kettering Cancer Center
Xiang Shu - Memorial Sloan Kettering Cancer Center
Resource Type: Journal article
Publication Details: Breast cancer research : BCR, Vol.26(1), 16
DOI: 10.1186/s13058-024-01765-1
PMID: 38263039
PMCID: PMC10807183
NLM abbreviation: Breast Cancer Res
ISSN: 1465-542X
eISSN: 1465-542X
Grant note: R00CA230205 / U.S. National Cancer Institute U01CA083178 / U.S. National Cancer Institute R21CA234752 / U.S. National Cancer Institute 202108330197 / China Scholarship Council P30CA008748 / MSK Cancer Center Support Grant
Language: English
Date published: 01/23/2024
Academic Unit: Epidemiology
Record Identifier: 9984548665202771

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