Case-Case Genome-Wide Analyses Identify Subtype-Informative Variants That Confer Risk for Breast Cancer
Xiaohui Sun1,2, Shiv P Verma1, Guochong Jia3
1Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
Cancer Research
|June 4, 2024
Summary
This study identified new genetic risk variants for breast cancer subtypes, particularly triple-negative breast cancer (TNBC). These findings improve understanding of breast cancer
Area of Science:
- Genetics
- Oncology
- Epidemiology
Background:
- Breast cancer comprises heterogeneous subtypes with distinct clinical and biological features.
- Understanding subtype-specific genetic etiology is crucial for targeted prevention and treatment strategies.
- Previous research has identified some breast cancer susceptibility loci, but subtype-specific insights remain limited.
Purpose of the Study:
- To elucidate the subtype-specific genetic etiology of breast cancer using a case-case genome-wide association study (CC-GWAS) approach.
- To identify novel genetic loci associated with specific breast cancer subtypes, especially triple-negative breast cancer (TNBC).
- To develop and validate subtype-informative polygenic risk scores (PRS) for breast cancer risk and survival.
Main Methods:
- Applied a pairwise case-case genome-wide association study (CC-GWAS) approach to summary statistics from the Breast Cancer Association Consortium.
- Conducted pairwise comparisons among five breast cancer subtypes.
- Performed fine mapping to identify putative functional variants and risk genes, and conducted functional investigation of a specific SNP (rs16867605).
- Derived and validated subtype-informative polygenic risk scores (PRS) using CC-GWAS data and external cohorts.
Main Results:
- Identified 13 statistically significant and eight suggestive genetic loci, predominantly from comparisons between triple-negative breast cancer (TNBC) and luminal A breast cancer.
- Confirmed associations of lead variants in 12 loci, including two genome-wide significant loci, after accounting for known susceptibility variants.
- Fine mapping implicated specific genes (e.g., TNFSF10, NACAP1/GRHL2, LINC00536/TRPS1) for TNBC.
- Demonstrated that a high subtype-informative PRS increased the risk of TNBC by up to two-fold compared to luminal cancers.
- CC-GWAS PRS showed statistical significance independent of traditional TNBC PRS and was associated with overall and disease-specific survival.
Conclusions:
- The study advanced the understanding of breast cancer subtype-specific genetic etiology, particularly for TNBC.
- Discovery of subtype-informative genetic risk variants highlights the etiologic heterogeneity of breast cancer.
- These findings could accelerate the identification of therapeutic targets and personalized prevention/treatment strategies for breast cancer.
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