Breast cancer susceptibility genes identified

Four novel breast cancer susceptibility genes have been identified in a huge genome-wide association study led by Cambridge University

The study, led by Douglas Easton and involving researchers from throughout the world, including the University of Melbourne, the Cancer Council Victoria and the KConFab consortium, was published today in Nature. (DOI: 10.1038/nature05887)

Known susceptibility genes such as BRCA1 and BRCA2 account for less than 25 per cent of the familial risk of cancer and it has long been suspected that there must be additional genetic factors contributing to the disease.

The researchers conducted a two-stage genome-wide association study in 4398 breast cancer cases and 4316 controls, followed by a third stage in which 30 single nucleotide polymorphisms (SNPs) were tested for confirmation in 21,860 cases and 22,578 controls from 22 studies.

"We used 227,876 SNPs that were estimated to correlate with 77 per cent of known common SNPs in Europeans," the paper states.

"SNPs in five novel independent loci exhibited strong and consistent evidence of association with breast cancer. Four of these contain plausible causative genes."

These four genes are FGFR2, TNRC9, MAP3K1 and LSP1.

Most previously identified breast cancer susceptibility genes are involved in DNA repair, but this study showed associations that appear to relate more to the control of cell growth or to cell signalling. Only one of the genes - FGFR2 - had a clear prior relevance to breast cancer.

According to the Cambridge researchers, the increased risks associated with the common faulty low-risk genes found in this study are relatively small and would not be suitable for genetic testing. But as more of these low risk genes are found, it may be possible to design tests for a combination of genes.

Two other studies published this week in Nature Genetics provide further evidence of the risk for breast cancer.

One paper, by David J Hunter et al from the Harvard School of Public Health, identifies alleles for the gene FGFR2 as being particularly associated with the risk of sporadic postmenopausal breast cancer (DOI: 10.1038/ng2075).

The other, by Simon Stacey, Kari Stefansson and colleagues from deCODE in Iceland, reports genetic variants on each of chromosomes 2 and 16, which both increase the risk of oestrogen-receptor-positive breast cancer.

One of these variants is located in close proximity to the gene TNRC9, which was also identified in the study from Easton and colleagues (DOI: 10.1038/ng2064).