Journal article
Case-Case Genome-Wide Analyses Identify Subtype-Informative Variants that Confer Risk for Breast Cancer
Cancer research (Chicago, Ill.), Vol.84(15), pp.2533-2548
06/04/2024
DOI: 10.1158/0008-5472.CAN-23-3854
PMCID: PMC11293972
PMID: 38832928
Abstract
Breast cancer includes several subtypes with distinct characteristic biological, pathological, and clinical features. Elucidating subtype-specific genetic etiology could provide insights into the heterogeneity of breast cancer to facilitate development of improved prevention and treatment approaches. Here, we conducted pairwise case-case comparisons among five breast cancer subtypes by applying a case-case GWAS (CC-GWAS) approach to summary statistics data of the Breast Cancer Association Consortium. The approach identified 13 statistically significant loci and eight suggestive loci, the majority of which were identified from comparisons between triple-negative breast cancer (TNBC) and luminal A breast cancer. Associations of lead variants in 12 loci remained statistically significant after accounting for previously reported breast cancer susceptibility variants, among which two were genome-wide significant. Fine mapping implicated putative functional/causal variants and risk genes at several loci, e.g., 3q26.31/TNFSF10, 8q22.3/NACAP1/GRHL2, and 8q23.3/LINC00536/TRPS1, for TNBC as compared to luminal cancer. Functional investigation further identified rs16867605 at 8q22.3 as a SNP that modulates enhancer activity of GRHL2. Subtype-informative polygenic risk scores (PRS) were derived, and patients with a high subtype-informative PRS had an up to 2-fold increased risk of being diagnosed with TNBC instead of luminal cancers. The CC-GWAS PRS remained statistically significant after adjusting for TNBC PRS derived from traditional case-control GWAS in The Cancer Genome Atlas and the African Ancestry Breast Cancer Genetic Consortium. The CC-GWAS PRS was also associated with overall survival and disease-specific survival among breast cancer patients. Overall, these findings have advanced our understanding of the genetic etiology of breast cancer subtypes, particularly for TNBC.
Details
- Title: Subtitle
- Case-Case Genome-Wide Analyses Identify Subtype-Informative Variants that Confer Risk for Breast Cancer
- Creators
- Xiaohui Sun - Memorial Sloan Kettering Cancer CenterShiv Prakash Verma - Memorial Sloan Kettering Cancer CenterGuochong Jia - Vanderbilt University Medical CenterXinjun Wang - Memorial Sloan Kettering Cancer CenterJie Ping - Vanderbilt University Medical CenterXingyi Guo - Vanderbilt University Medical CenterXiao-Ou ShuJianhong Chen - Roswell Park Comprehensive Cancer CenterAndriy DerkachQiuyin Cai - Vanderbilt University Medical CenterXiaolin LiangJirong Long - Vanderbilt University Medical CenterKenneth Offit - Memorial Sloan Kettering Cancer CenterJung Hun Oh - Memorial Sloan Kettering Cancer CenterAnne S Reiner - Memorial Sloan Kettering Cancer CenterGordon P Watt - The Netherlands Cancer InstituteMeghan Woods - Memorial Sloan Kettering Cancer CenterYaohua Yang - University of VirginiaChristine B Ambrosone - Roswell Park Comprehensive Cancer CenterStefan Ambs - National Cancer InstituteYu Chen - New York UniversityPatrick Concannon - University of FloridaMontserrat Garcia-Closas - National Cancer InstituteJian Gu - The University of Texas MD Anderson Cancer CenterChristopher A Haiman - University of Southern CaliforniaJennifer J Hu - University of MiamiDezheng Huo - University of ChicagoEsther M John - Palo Alto UniversityJulia A Knight - Sinai Health SystemChristopher I Li - Fred Hutch Cancer CenterCharles F Lynch - University of IowaLene MellemkjaerKatherine L Nathanson - University of PennsylvaniaBarbara Nemesure - Stony Brook UniversityOlufunmilayo I Olopade - University of ChicagoAndrew F Olshan - University of North Carolina at Chapel HillTuya Pal - Vanderbilt University Medical CenterJulie R Palmer - Boston UniversityMichael F Press - University of Southern CaliforniaMaureen Sanderson - Meharry Medical CollegeDale P Sandler - National Institute of Environmental Health SciencesMelissa A Troester - University of North Carolina at Chapel HillWei ZhengJonine L Bernstein - Memorial Sloan Kettering Cancer CenterMatthew F Buas - Memorial Sloan Kettering Cancer CenterXiang Shu - Memorial Sloan Kettering Cancer Center
- Resource Type
- Journal article
- Publication Details
- Cancer research (Chicago, Ill.), Vol.84(15), pp.2533-2548
- DOI
- 10.1158/0008-5472.CAN-23-3854
- PMID
- 38832928
- PMCID
- PMC11293972
- NLM abbreviation
- Cancer Res
- ISSN
- 0008-5472
- eISSN
- 1538-7445
- Publisher
- AMER ASSOC CANCER RESEARCH
- Grant note
This work was partly supported by R00CA230205, R01CA235553 and R01DK128615. The WECARE Study was supported by U01CA083178, R01CA097397, R01CA129639, and R21CA234752 and MSK Cancer Center Support Grant P30CA008748. The AABCG was supported by R01CA202981. The funder did not play a role in the design of the study; the collection, analysis, and interpretation of the data; the writing of the manuscript; and the decision to submit the manuscript for publication.
- Language
- English
- Electronic publication date
- 06/04/2024
- Academic Unit
- Epidemiology
- Record Identifier
- 9984632118502771
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