Credit: Neil Smith

Over the past few years, genome-wide association studies (GWAS) have been useful in identifying genetic variations that are associated with risk for several types of cancer. Three GWAS recently reported in the same issue of Nature Genetics identify several new susceptibility loci for breast and ovarian cancer.

Gayther, Pharoah, Easton and collaborators re-analysed the data from a previous GWAS that had allowed them to identify an ovarian cancer susceptibility locus. This time they stratified cases by histological subtype and specifically considered risks associated with the serous subtype of ovarian cancer. They identified single nucleotide polymorphisms (SNPs) in four different loci that were associated with ovarian cancer risk, one with decreased risk (at 8q24) and three with an increased risk (at 2q31, 3q25 and 7q21). The authors examined the expression of the candidate genes in these loci: MYC, TIPARP (which encodes a poly(ADP-ribose) polymerase (PARP)), HOXD1 and HOXD3 (which are involved in embryogenesis and organogenesis) and SKAP1 (which encodes a Src-related phosphoprotein). There were significant differences in the patterns of expression of all of these candidate genes between normal and ovarian cancer cells, suggesting that they may have functional roles in the development of ovarian cancer.

Three genome-wide association studies recently reported in the same issue of Nature Genetics identify several new susceptibility loci for breast and ovarian cancer.

These authors also led an independent three-phase GWAS to identify genes associated with ovarian cancer survival. In the first two phases of this study, they identified two SNPs that were associated with survival and located at 19p13. Data from the third phase, however, revealed that these SNPs were more significantly associated with susceptibility to ovarian cancer than survival, especially when the analysis was restricted to patients with the serous subtype of ovarian cancer. One SNP is located in C19orf62 (also known as MERIT40), which encodes a protein that regulates the stability of BRCA1 at sites of DNA damage, and the other SNP lies in ANKLE1. Although MERIT40 was significantly overexpressed in ovarian cancer cell lines, there was no difference in the expression of ANKLE1 between normal and ovarian cancer cells.

In a separate study, Easton, Couch and collaborators also identified an association between 19p13 and breast cancer risk in women carrying mutations in the well-known breast cancer susceptibility gene BRCA1. The authors identified a cluster of five SNPs on chromosome 19. Two of these SNPs were located in coding regions that contained the genes ABHD8, ANKLE1 and MERIT40. Further studies of the SNPs in the general population identified associations with risk of oestrogen receptor-negative breast cancer and triple-negative (oestrogen receptor-negative, progesterone receptor-negative and ERBB2-negative) breast cancer. The authors speculate that genetic variations that affect MERIT40 expression could modify BRCA1-dependent DNA repair. These three studies indicate that focusing on particular subtypes ofcancer can allow the identification of genetic variations that might contribute to different types of cancer, such as the associations of ANKLE1 and MERIT40 with both ovarian and breast cancer.