New breast cancer susceptibility genes identified

30 May 2007

A new study published in Nature identifies four new genes associated with increased susceptibility to breast cancer. The normal lifetime risk of developing breast cancer for women in the UK is estimated to be 1 in 9 (11%). In individuals with inherited forms of increased susceptibility to breast cancer, lifetime risk can be much higher; women with inherited mutations in the BRCA1 or BRCA2 genes have a lifetime risk of as much as 85%. However, mutations in genes known to be linked with breast cancer such as the BRCA genes cannot be identified in the majority of families with a significant history of breast cancer. It has previously been presumed that these forms of familial breast cancer are the result of multiple contributory genetic susceptibility factors. Individually, each of these gene variants confers only a modestly increased risk, and hence have been impossible to identify by standard genetic association studies.

However, a new international collaborative study led by researchers at the University of Cambridge has performed a highly powered, three-stage genome-wide association study which has identified four new susceptibility genes: FGFR2, TNRC9, MAP3K1 and LSP1 [Easton DF et al. (2007) Nature Epub ahead of print, doi:10.1038/nature05887]. The researchers first analysed more than a quarter of a million single nucleotide polymorphisms (SNPs) in nearly four hundred each of breast cancer cases and controls. More than 10,000 SNPs selected because they were significantly more frequent in the breast cancer cases were then analysed in more than four thousand each of breast cancer cases and controls. Finally, the thirty SNPS most strongly associated with breast cancer were analysed for a total of around 22,000 breast cancer cases and controls, leading to selection of four genes as the most plausible candidate breast cancer susceptibility genes.

The FGFR2 gene showed the strongest association with breast cancer, increasing the risk of disease by around 60% for individuals with two copies of the variant form of the gene. The researchers also report that their analysis suggests the existence of multiple additional candidate susceptibility genes, some conferring a degree of increased risk comparable with that associated with the FGFR2 and TNRC9 genes.

Two additional papers published in Nature Genetics from US and Icelandic-led teams also link mutations in the FGFR2 gene with increased risk of sporadic post-menopausal breast cancer [Hunter DJ et al. (2007) Nat Genet. Epub ahead of print], and in the TNRC9 gene with increased risk of estrogen receptor–positive breast cancer, respectively [Stacey SN et al. (2007) Nat Genet. Epub ahead of print].

Comment: Together, these new susceptibility genes increase the proportion of familial breast cancer predisposition for which genes are known from around 25% to around 29%; although this is in many ways a relatively modest contribution to knowledge of genetic susceptibility to the disease, the findings are important because they demonstrate that using sufficiently large and highly powered genome-wide association studies can reveal the existence of multiple alleles that make individually moderate contributions to genetic risk. This suggests that the years ahead may generate significant information about the genetics of different forms of cancer, and of other polygenic diseases.

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