Genome-Wide Analysis of Rare Haplotypes Associated with Breast Cancer Risk
Fan Wang1, Wonjong Moon1, William Letsou1
1Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, Tennessee.
Cancer Research
|November 10, 2022
Summary
Rare genetic variations, specifically rare haplotypes, significantly increase breast cancer risk. This study identified 13 such loci, highlighting their importance in understanding breast cancer heritability.
Area of Science:
- Genetics
- Cancer Research
- Genomic Epidemiology
Background:
- Common genetic variants explain only a fraction of breast cancer heritability.
- Rare, high-risk genetic loci are inferred to be major determinants of breast cancer risk.
Purpose of the Study:
- To identify rare high-risk genetic loci for breast cancer using haplotypes.
- To investigate the role of rare haplotypes in breast cancer susceptibility.
Main Methods:
- Genome-wide haplotype association analysis in 181,034 UK Biobank participants.
- Two-stage analysis including discovery and replication cohorts (totaling 5,487 and 3,524 cases, respectively).
- Cox regression for estimating hazard ratios (HR) of haplotypic effects and functional annotation.
Main Results:
- Identified 13 rare loci (frequency <1%) significantly associated with increased breast cancer risk (discovery HRs=2.84-6.10, replication HRs=2.08-5.61).
- Individual variants within these haplotypes showed smaller effects.
- Six loci were generalizable in an independent OncoArray study (ORs=1.48-7.67).
- Functional annotation revealed cis-regulatory elements in relevant cells.
Conclusions:
- Rare haplotypes are effective in capturing novel breast cancer risk loci.
- These findings highlight the importance of rare genetic variants in breast cancer heritability.
- Future whole-genome sequencing studies may uncover additional genetic elements contributing to cancer risk.
