NEW YORK (GenomeWeb News) – Using genetic data on up to 70,000 women with breast cancer and roughly the same number of controls, an international team of researchers has identified three previously undetected variants influencing risk of the disease.
As they reported in the online version of Nature Genetics yesterday, the researchers did an association study focusing on dozens of variants suspected of having a role in breast cancer based on findings from two past genome-wide association studies.
When they tested these SNPs in tens of thousands of cases or controls using data collected for nine previous GWAS and dozens of case-control studies, the investigators found three sites that were significantly associated with breast cancer, ratcheting up the extent of estimated breast cancer heritability that can be explained by common variants.
"The three susceptibility variants newly identified in this study are relatively common … and together explain [approximately 0.7 percent] of the familial risk of breast cancer," University of Cambridge researcher Douglas Easton, the study's corresponding author, and colleagues wrote, "and bring the total contribution of common low-penetrance breast cancer susceptibility loci to [approximately nine percent]."
Although past association and candidate gene studies have unearthed 22 common loci that can ramp up breast cancer susceptibility, the team explained, variants at these sites are estimated to explain just eight percent or so of inherited breast cancer risk within affected families.
In an attempt to add to the familial risk that can be explained by common variants, the researchers turned their attention to 72 variants that had been somewhat associated with breast cancer — either through the University of Cambridge-led UK2 Breast Cancer GWAS or the British Breast Cancer Study — but not conclusively linked to the disease.
The team looked at how each of the 72 variants related to breast cancer risk in up to 69,564 cases and 68,150 unaffected controls, using data from nine breast cancer GWAS and 41 case-control studies. Data from the GWAS represented women of European ancestry, while the case-control studies involved women from other populations as well.
For the European women tested, the researchers' search led them to three verified breast cancer loci. Two of the loci were on chromosome 12: one near the TBX3 gene, believed to influence mammary gland development, and another near a gene called PTHLH that has been implicated in breast cancer metastasis to bone. A third locus fell on chromosome 21 in the vicinity of the NRIP1 gene, which codes for an estrogen receptor interacting protein with a potential role in breast cancer cell growth.
Just one of the three sites — a chromosome 12 variant known as rs10771399 — showed significant ties to breast cancer among the Asian women tested. The chromosome 21 locus, on the other hand, appeared to have modest effects, but in the opposite direction of those detected in women of European ancestry.
When they compared the patterns in estrogen receptor-positive and –negative breast cancer cases, meanwhile, the team found that one of the chromosome 12 variants was associated with both forms of the disease, while the remaining chromosome 12 locus and the chromosome 21 locus only showed links to ER-positive breast cancer cases.
"The present work highlights the importance of combining GWAS and large-scale replication studies with tumor sub-typing in the identification and characterization of breast cancer susceptibility loci," researchers wrote.