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Multi-stage GWAS Uncovers Loci Linked to Breast Cancer in East Asians

NEW YORK (GenomeWeb) – A new Nature Genetics study is pointing to a trio of loci that appear to be linked to breast cancer risk in individuals of East Asian ancestry.

Through a three-stage, genome-wide association study involving tens of thousands of East Asian women with or without breast cancer, a Vanderbilt University-led team tracked down apparent breast cancer risk loci on chromosomes 1, 5, and 15. A fourth site on chromosome 18 showed more tenuous ties to the disease.

The team's initial efforts to identify related functions for genes and regulatory regions near the risk loci turned up several promising ties to breast cancer biology, supporting the notion that the sites may prove useful for not only assessing breast cancer risk in this population, but also understanding new biological features of the disease.

"Further studies of possible mechanisms through which these loci and genes are involved in breast tumorigenesis are warranted," senior author Wei Zheng, an epidemiology researcher at the Vanderbilt-Ingram Cancer Center, and colleagues wrote. "Results from this study provide additional insights into the genetics and biology of breast cancer."

As part of an ongoing effort to find breast cancer risk loci, the Asian Breast Cancer Consortium (ABCC) brought together data for women enrolled in more than a dozen past research efforts in countries across Asia. Together, the team considered information on almost 23,000 breast cancer cases from East Asia and more than 24,000 population-matched controls.

For the discovery stage of the three-part study, researchers compared directly measured and imputed SNP profiles in the genomes of 2,867 Chinese women with breast cancer and 2,285 Chinese women without the disease who'd been genotyped using Affymetrix's SNP 6.0 array. They also assessed 2,246 breast cancer cases from Korea that had been analyzed with the same Affymetrix SNP, along with 2,052 Korean controls.

Using Illumina Infinium arrays, the team successfully genotyped some 4,000 suspicious SNPs selected from the first phase of the study in another 3,944 breast cancer cases and 3,980 controls from Shanghai, further whittling down the set of possible susceptibility SNPs.

When researchers took a few dozen variants that stood out in that testing round forward for additional replication in samples from 14,195 more breast cancer cases and 16,249 controls, they saw 11 SNPs that remained associated with breast cancer.

Of those, variants at just three loci showed genome-wide significance in their analysis of the complete case and control set: SNPs in and around the chromosome 1 gene ZC3H11A, the chromosome 5 arrestin gene ARRDC3, and the protein regulator of the cytokinesis 1 (PRC1) gene on chromosome 15.

Variants at the same loci tracked with breast cancer risk in the group's follow-up analysis of 16,003 European ancestry breast cancer cases and 41,335 controls, albeit with weaker associations, suggesting the sites may contribute to breast cancer susceptibility in other populations as well.

When they folded in information from the ENCODE project — an effort to identify regulatory regions in human and animal model genomes — the researchers got hints that at least two of the newly detected SNPs may fall in genome sequences contributing to gene enhancer or transcription factor binding activity.

Other expression patterns and reported roles for genes at the three sites seemed to fit with possible breast cancer risk contributions, too. In particular, the team's analysis highlighted possible involvement by pathways related to cell growth, migration, and metastasis.