Case-case genome-wide analyses identify subtype-informative variants that confer risk for breast cancer Journal Article


Authors: Sun, X.; Verma, S. P.; Jia, G.; Wang, X.; Ping, J.; Guo, X.; Shu, X. O.; Chen, J.; Derkach, A.; Cai, Q.; Liang, X.; Long, J.; Offit, K.; Oh, J. H.; Reiner, A. S.; Watt, G. P.; Woods, M.; Yang, Y.; Ambrosone, C. B.; Ambs, S.; Chen, Y.; Concannon, P.; Garcia-Closas, M.; Gu, J.; Haiman, C. A.; Hu, J. J.; Huo, D.; John, E. M.; Knight, J. A.; Li, C. I.; Lynch, C. F.; Mellemkjær, L.; Nathanson, K. L.; Nemesure, B.; Olopade, O. I.; Olshan, A. F.; Pal, T.; Palmer, J. R.; Press, M. F.; Sanderson, M.; Sandler, D. P.; Troester, M. A.; Zheng, W.; Bernstein, J. L.; Buas, M. F.; Shu, X.
Article Title: Case-case genome-wide analyses identify subtype-informative variants that confer risk for breast cancer
Abstract: Breast cancer includes several subtypes with distinct characteristic biological, pathologic, and clinical features. Elucidating subtype-specific genetic etiology could provide insights into the heterogeneity of breast cancer to facilitate the development of improved prevention and treatment approaches. In this study, we conducted pairwise case–case comparisons among five breast cancer subtypes by applying a case–case genome-wide association study (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 with luminal cancer. Functional investigation further identified rs16867605 at 8q22.3 as a SNP that modulates the enhancer activity of GRHL2. Subtype-informative polygenic risk scores (PRS) were derived, and patients with a high subtype-informative PRS had an up to two-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 patients with breast cancer. Overall, these findings have advanced our understanding of the genetic etiology of breast cancer subtypes, particularly for TNBC. Significance: The discovery of subtype-informative genetic risk variants for breast cancer advances our understanding of the etiologic heterogeneity of breast cancer, which could accelerate the identification of targets and personalized strategies for prevention and treatment. ©2024 American Association for Cancer Research.
Keywords: controlled study; unclassified drug; human cell; overall survival; single nucleotide polymorphism; case control study; genetics; case-control studies; polymorphism, single nucleotide; clinical feature; cancer risk; cancer staging; molecular genetics; cancer susceptibility; genetic predisposition to disease; breast cancer; genetic variability; gene frequency; genome-wide association study; risk factors; transcription factor; pathology; breast neoplasms; risk factor; gene mapping; genome analysis; genetic transfection; cell culture; breast tumor; plasmid; regression analysis; computer model; genetic predisposition; genetic correlation; enhancer region; cloning; genotyping; short tandem repeat; triple negative breast cancer; luminal a breast cancer; humans; human; female; article; luciferase assay; triple negative breast neoplasms; breast cancer molecular subtype; mcf-7 cell line; genetic risk score; grainyhead like transcription factor 2; gene set analysis
Journal Title: Cancer Research
Volume: 84
Issue: 15
ISSN: 0008-5472
Publisher: American Association for Cancer Research  
Date Published: 2024-08-01
Start Page: 2533
End Page: 2548
Language: English
DOI: 10.1158/0008-5472.Can-23-3854
PUBMED: 38832928
PROVIDER: scopus
PMCID: PMC11293972
DOI/URL:
Notes: Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Xiang Shu -- Source: Scopus
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MSK Authors
  1. Anne S Reiner
    252 Reiner
  2. Kenneth Offit
    791 Offit
  3. Jonine L Bernstein
    142 Bernstein
  4. Jung Hun Oh
    189 Oh
  5. Xiaolin Liang
    62 Liang
  6. Meghan   Woods
    30 Woods
  7. Gordon Patrick Watt
    16 Watt
  8. Andriy Derkach
    170 Derkach
  9. Xiang Shu
    22 Shu
  10. Xiaohui Sun
    6 Sun
  11. Xinjun Wang
    14 Wang
  12. Shiv Prakash Verma
    2 Verma
  13. Matthew Frank Buas
    2 Buas