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Breast Cancer GWAS Leads to New Risk Loci in Japanese Population

NEW YORK – A team from Japan has tracked down and validated two new breast cancer risk loci in that population, folding these variants into pathway, functional, and risk score analyses aimed at better understanding risk of the disease in this population.

"To the best of our knowledge, [the study] is the largest and most well-powered GWAS to date that aims to investigate the genetic architecture as well as to assess the common genetic risk model of breast cancer in the Japanese population," corresponding and co-first author Siew-Kee Low, a researcher affiliated with the Japanese Foundation for Cancer Research's Cancer Precision Medicine Center and the Riken Center for Integrative Medical Sciences, and her colleagues wrote. 

Through a genome-wide association study involving almost 7,700 Japanese individuals with breast cancer and more than 23,300 unaffected female controls from the same population, the researchers narrowed in on nine known risk loci as well as two previously unappreciated risk variants near the ALCAM and CLIC6-RUNX1 genes on chromosome 3, along with a broader over-representation of variants in and around genes in dopamine receptor signaling and protein amino acid deacetylation pathways. Their findings appeared online today in Scientific Reports.

Dozens of prior GWAS have unearthed common variants contributing to breast cancer risk at 70 sites in the genome in European, East Asian, and other populations, the team explained, though the suite of risk variants at play seems to vary from one population to the next due to differences in allele frequency, linkage disequilibrium patterns, environmental interactions, and so on.

More generally, the authors suggested, "studies have indicated the importance of carrying out regional GWAS to identify specific genetic risk factors that are associated with complex disease, which could facilitate better risk assessment in the regional clinical settings."

By tapping into samples from Biobank Japan, the researchers generated Illumina array-based genotypes for 6,669 breast cancer cases and 21,930 female controls, which they fleshed out further through imputation with available genome sequences for East Asian individuals.

In addition to known risk variants with non-significant associations with breast cancer in those cases and controls, the team identified a dozen variants with independent, genome-wide significant ties to multiple breast cancer subtypes at 11 loci on chromosomes 2, 3, 5, 6, 10, 12, 16, and 21.

The loci had comparable effect sizes in another 981 Japanese individuals with breast cancer and 1,394 without and remained associated with breast cancer in a meta-analysis that included the discovery cohort, the investigators noted, though risk variants at the sites did not reach statistical significance in the validation group alone.

Along with pathway analyses that highlighted an apparent role for dopamine receptor and amino acid deacetylation pathways in breast cancer, the team went on to find an expression quantitative trait loci for one of the risk SNPs, which appears to dial down expression of genes such as CASP8 and ALS2CR12 in mammary tissue, based on information in a GTEx database.

Moreover, by bringing together all 12 breast cancer-associated SNPs found in the study, the researchers showed that it may be possible to distinguish between Japanese individuals at particularly high or low risk of breast cancer using a weighted polygenic risk score. In particular, they estimated that individuals from a group carrying the greatest number of breast cancer-related alleles had nearly four times the risk of developing the disease compared to those with the fewest risk SNPs in their genome.

Based on five groups defined by the weighted risk score, the authors suggested that "individuals who were categorized in the highest risk group are approximately 3.7 times more likely to develop breast cancer compared to individuals in the lowest risk group."