Abstract
After reconnaissance of a troublesome chromosome 9 region identified a novel breast cancer risk factor, rs865686, scientists based at The Institute of Cancer Research, London, swooped down for a closer look. Using fine-mapping analysis, which is the genomic equivalent of a low-altitude pass, the scientists found two additional risk factors—single-nucleotide polymorphisms (SNPs) designated rs10816625 and rs13294895. The two new risk factors appear to be specifically linked to the most common form of breast cancer, namely, estrogen-receptor-positive breast cancer.
The finding emerged from a study of the DNA of 100,000 women. Contributing to the total were about 86,000 women of European, 12,000 of Asian, and 2,000 or African ancestries. About half of the women had breast cancer; the rest were controls.
Women with rs10816625 were 12% more likely to develop breast cancer than women without, and those with rs13294895 had an increased risk of 9%. The increases in risk were slightly higher—14% and 11%, respectively—for estrogen-receptor-positive breast cancer, but there was no association with estrogen-receptor-negative forms of the disease.
Both SNPs were associated with increased risk in European women; only one of them, rs10816625, was associated with increased risk in women of Asian ancestry.
These results appeared February 4 in the journal Human Molecular Genetics, in an article entitled, “Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2.” The article emphasized that the newly identified genetic risk factors provide important clues about the causes of breast cancer. In particular, the one-letter aberrations in DNA code appear to implicate a gene called KLF4, which is thought to help control the way cells grow and divide.
“Functional genomic annotation using data derived from breast cancer cell-line models indicates that [the SNPs rs10816625 and rs13294895] localize to putative enhancer elements that bind known drivers of hormone dependent breast cancer, including ER-α, FOXA1, and GATA-3,” wrote the article's authors. “In vitro analyses indicate that rs10816625 and rs13294895 have allele-specific effects on enhancer activity and suggest chromatin interactions with the KLF4 gene locus.”
The authors noted that the newly discovered genetic variants are thought to help control the activity of KLF4, despite lying a long distance away from that gene. More generally, the authors added that the analysis of associations using subjects with different ancestry, combined with bioinformatic and genomic characterization, can provide strong evidence for the likely causative alleles and their functional basis.
“The two new variants uncovered by this study could be factored into potential future screening tools for breast cancer that incorporate all known genetic risk factors for the disease,” said Paul Workman, Ph.D., chief executive of The Institute of Cancer Research. “They also provide important clues to the genetic causes of the most common form of breast cancer and potential leads for the discovery of new treatments.”
“The more genetic risk factors for breast cancer we discover, of which there are currently more than 80, the more accurately we will be able predict who is at risk of getting the disease,” added Nick Orr, Ph.D., team leader in Complex Trait Genetics at The Institute of Cancer Research. “Ultimately this will be vital for designing preventative strategies against breast cancer.”