Unlocking the Genetic Complexity of Breast Cancer: Focus on Rare Haplotypes

By: Amanda E. Ruffino, BA
Posted: Monday, September 25, 2023

William Letsou, PhD, of the New York Institute of Technology, Old Westbury, and colleagues have pioneered an innovative approach to deciphering the genetic underpinnings of breast cancer risk. Although previous studies have identified numerous common genetic variants linked to marginal increases in breast cancer susceptibility, Dr. Letsou’s team has delved deeper into the genetic landscape, suggesting a certain, rare combination of common variants may increase breast cancer risk. Their findings were published in Life Science Alliance.

In contrast to the conventional polygenic model, which primarily emphasizes common genetic variants, this study highlights the role of rare haplotypes in amplifying the connection between breast cancer risk and common germline alleles. Employing the Chromosome Overlap algorithm, the researchers iteratively paired chromosomes from affected individuals, pinpointing noncontiguous patterns of shared alleles.

To validate their findings, the team examined genotyped single nucleotide polymorphisms (SNPs) in female breast cancer cases from the UK Biobank, specifically scrutinizing four loci harboring common breast cancer–risk SNPs. Of note, they identified two rare haplotypes at the 11q13 locus, with frequencies below 0.1%, displaying substantial hazard ratios of 4.21 and 16.7. These findings replicated those observed in an independent European ancestry population, signifying the haplotypes’ robustness (P < .05). Moreover, the study uncovered another rare haplotype at the 22q12 locus, with a frequency below 0.2% and a hazard ratio of 2.58. This haplotype extended the risk pool to individuals lacking a Genome-Wide Association Study (GWAS) hit.

Overall, this study’s results suggest that rare haplotypes, potentially even mutations, may underlie the observed “synthetic association” between breast cancer risk and certain common genetic variants.

Disclosure: The study authors reported no conflicts of interest.

Life Science Alliance

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