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Studies Spell Out Common, Rare Variants Contributing to Breast Cancer Susceptibility

NEW YORK (GenomeWeb) – Several new studies are pointing out the sites in the genome marked by variants that contribute to breast cancer susceptibility.

For the first of the studies, appearing online today in Nature, an international team led by investigators in the UK, the US, and Canada reported on findings from a genome-wide association study involving hundreds of thousands of individuals of European or East Asian ancestry with or without breast cancer.

When they compared array-genotyped and imputed SNP patterns for 122,977 individuals with breast cancer and 105,974 unaffected controls, the researchers found potential associations at known and new risk loci. Their follow-up analyses in 14,068 East Asian individuals with and without breast cancer validated dozens of loci that had previously been linked to breast cancer, and highlighted significant associations at 65 loci.

Using a new computational pipeline called INQUISIT, the team tapped into existing chromatin immunoprecipitation sequence, RNA sequence, and other breast cell genomic data to get a glimpse at functional variants at the risk loci — an analysis that led to apparent regulatory regions and candidate genes prone to somatic mutation in breast cancer.

"The majority of credible risk single nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumors" co-senior author Douglas Easton, a cancer genetic epidemiology researcher at the University of Cambridge, and his colleagues wrote.

For a related study in Nature Genetics, investigators described variants with specific ties to estrogen receptor-negative breast cancer. That effort — also led by Easton as well as other researchers from the UK, Canada, the US, Australia, and the Netherlands — relied on a GWAS encompassing genotyping profiles for nearly 21,500 ER-negative breast cancer cases, more than 18,900 BRCA1 mutation carriers (with or without breast cancer), and almost 100,600 unaffected control individuals.

Their risk variant search validated all but one of the 11 SNPs previously implicated in ER-negative breast cancer cases or already found in BRCA1 mutation carriers. But they also identified nine loci not linked to the condition in the past, including 10 variants in and around the cell cycle gene CCNE1, the cadherin-coding CDH2 gene, and other genes.

Across the broader set of variants linked to breast cancer in general, including those at new loci identified in the new Nature study, the researchers saw overlap with ER-negative breast cancer susceptibility at 105 SNP sites. Together, they reported, roughly 16 percent of ER-negative breast cancer risk could be gleaned from variants associated with ER-negative breast cancer alone or with breast cancer risk in general.

A co-author on the latter study, Peter MacCallum Cancer Centre and University of Melbourne researcher Ian Campbell, led another study focused on rare variant contributions to breast cancer risk — work that was scheduled to be presented by PhD student Na Li at the American Society of Human Genetics annual meeting in Orlando, Florida late last week.

As they reported in an accompanying ASHG abstract, that team focused on thousands of high risk breast cancer patients from families frequently affected by cancer, comparing targeted candidate gene sequences in roughly 6,000 individuals with familial breast cancer and about as many unaffected control individuals.

Based on these sequences, combined with insights from prior studies, the researchers narrowed in on nearly four dozen genes in which mutations were over-represented in the breast cancer cases. And using that set, they have started to put together a polygenic breast cancer prediction score that encompasses not only common risk variants, but also rarer variants implicated in medium or higher breast cancer risk.