by ecancer reporter Clare Sansom

Breast cancer is a complex and heterogeneous disease, and many genetic variants have been associated with an increased risk of its development.

With the exception of the “breast cancer susceptibility” genes BRCA1 and BRCA2, the extra risk associated with each of these variants is small.

Incidence of breast cancer is very much lower in East Asian women than in those of Caucasian origin, although it is increasing rapidly, probably due to lifestyle factors.

Many genome-wide association studies (GWAS) of breast cancer susceptibility have been conducted, but almost all have been in Caucasian women.

Furthermore, only about 10% of the familial difference in breast cancer susceptibility in East Asians can currently be explained by known genetic variation.

A large group of researchers headed by Qiuyin Cai of Vanderbilt University, Nashville, Tennessee, USA have now conducted an extensive GWAS study of East Asian women in order to discover novel breast cancer susceptibility loci.

The study was conducted through the Asia Breast Cancer Consortium (ABCC).

A total of 22,780 breast cancer cases and 24,181 control subjects without the disease were recruited from 14 centres located throughout East Asia.

The first, or discovery, stage of analysis included validated data from 5,152 women of Chinese origin (2,867 cases and 2,285 controls) and 4,298 of Korean origin (2,246 cases and 2,052 controls).

The genomes of these women were scanned using Affymetrix technology against an array consisting of 906,602 single nucleotide polymorphisms (SNPs).

Variants that appeared to be significantly associated with an increased risk of breast cancer (P < 0.05) in both populations and that were not in linkage disequilibrium (LD) with any known or suspected breast cancer susceptibility loci were selected for inclusion in the second stage of the analysis.

Only one of each set of two or more SNPs that met these criteria but were in linkage disequilibrium with each other was included in this stage.

These criteria led to the selection of a total of 4,598 SNPs, and 3,850 of these were successfully genotyped in an independent set of 3,944 cases and 3,980 controls from China.

The 50 SNPs with the most significant associations with breast cancer in both of these study populations were selected for the final stage of the analysis.

After testing in a third independent set of 14,195 cases and 16,249 controls, eleven of these 50 SNPs remained associated with breast cancer risk with P-values less than 0.05, and three remained associated at the genome-wide significance level (P < 5x10-8) after the study populations had been combined.

The association between these genetic loci and breast cancer risk was consistent across populations of Chinese, Japanese and Korean women.

Two of these SNPs, rs10474352 and rs2290203, appeared to be more strongly associated with oestrogen receptor positive (ER ) than for oestrogen receptor negative (ER-) breast cancer; the association of the third, rs4951011, with breast cancer risk was independent of the oestrogen receptor status of the disease.

These three SNPs were further evaluated in women of European origin using 16,003 cases and 41,335 controls obtained from previous GWAS conducted through the GAME-ON initiative.

Each of the SNPs was found to be significantly associated with breast cancer in these Caucasian women, although the associations were weaker than those in East Asians.

The researchers then evaluated candidate genes and functional variants in the regions of DNA close to each SNP.

One of these, rs10474352, is located on chromosomal region 5q14.3 and was found to be close to a member of the arrestin gene family, ARRDC3, which has already been linked to breast cancer.

The SNP rs2290203 is located on region 15q26.1 in an intron of the gene PRC2; this gene encodes a protein that is involved in the last stages of cell division and is a substrate for several of the kinases that regulate the cell cycle; however, no association could be detected between this SNP and expression levels of the PRC2 protein.

Finally, SNP rs4951011 is located on chromosome 1 region q32.1, in an intron of the gene ZC3H11A and close to the gene ZBED6.

Both these genes encode proteins with DNA-binding zinc finger domains; the function of the protein ZC3H11A is unknown, whereas ZBED6 encodes a transcription factor.

Further analysis suggested that this SNP might lie in an enhancer region of DNA, and thus be involved in activating gene transcription.

This study suggests several mechanisms through which these genetic variants might be involved in breast cancer development, and therefore provides new insights into breast the genetics of the disease, particularly in East Asian women.

Reference

Cai, Q., Zhang, B., Sung, H. and 48 others, and the DRIVE GAME-ON consortium (2014). Genome-wide association analysis in East Asians identifies breast cancer susceptibility loci at 1q32.1, 5q14.3 and 15q26.1. Nature Genetics, published online ahead of print 20 July 2014.