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Fine-mapping Study Finds New Breast Cancer Risk Variants

NEW YORK (GenomeWeb) – In a study published online today in Human Molecular Genetics, an international team led by Institute of Cancer Research investigators identified two new regulatory variants that ratchet up the risk of breast cancer in individuals with European ancestry. 

Using custom array-based genotyping and fine-mapping, the researchers focused in on a chromosome 9 region uncovered through a prior genome-wide association study. Through testing on nearly 86,000 European breast cancer cases and controls and more than 12,400 cases and controls of Asian descent, they verified associations for the previously identified SNP and other variants found in linkage disequilibrium with it.

But the team also detected two new independent signals in the region: SNPs that fell in apparent enhancer sequences that seemed to mediate interactions with the KLF4 gene.

The variants were more strongly tied to estrogen receptor-positive forms of the disease and only one was significantly linked to breast cancer risk in individuals with Asian ancestry. Nevertheless, those involved in the study argued that the findings may provide insight into susceptibility factors for breast cancer in different populations, leading to refined risk models and more precise breast cancer prediction methods.

"The more genetic risk factors for breast cancer we discover, of which there are currently more than 80, the more accurately we will be able predict who is at risk of getting the disease," corresponding author Nicholas Orr, a complex trait genetics researcher at the Institute of Cancer Research, said in a statement. "Ultimately this will be vital for designing preventative strategies against breast cancer."

One of the SNPs, known as rs10816625 seemed to bump up breast cancer risk by around 12 percent in individuals with European ancestry. The other new variant, known as rs13294895, increased risk by roughly 9 percent in that population but was not significantly associated with breast cancer in those of Asian descent.

To explore functional roles for the newly detected variants, the researchers turned to bioinformatics approaches, together with regulatory, localization, and interaction data generated for the ENCODE and the Cancer Genome Atlas projects.

These analyses led them to suspect that one or more of the variants found on chromosome 9 may act as enhancer elements that not only interact with breast cancer-related players such as the estrogen receptor alpha protein and FOXA1, but also impact the expression of the KLF4 gene via long-range chromatin interactions — a notion supported by their preliminary reporter assay experiments in human breast cancer cell lines.

"Our in vitro data support the hypothesis that this locus possesses enhancer activity and indicate that the risk alleles of rs10816625 and rs1394895 can diminish its activity," Orr and colleagues wrote, "indicating that these are independent risk susceptibility variants acting through the same mechanism."