New Breast Cancer Susceptibility Genes Identified

May 30, 2007 — Four novel breast cancer genes have been added to the list of known susceptibility genes such as BRCA1 and BRCA2. "This is an outstanding discovery," Harpal Kumar, chief executive of Cancer Research UK, in London, said in a news release about the findings. "Thanks to the international collaboration of more than 15 research teams, this is the first study in the world to demonstrate that by searching the whole genome it's possible to discover new genes that can increase breast cancer risk." The large, genomewide association study, published online May 27 in Nature, also points to many more genetic markers that should be pursued for their link to disease. Together with 2 related papers published online May 27 in Nature Genetics, these results help elucidate the genetic component of breast cancer risk.

"We're very excited by these results because the regions we identified don't contain previously known inherited cancer genes," lead author of the study, Douglas Easton, PhD, director of Cancer Research UK's Genetic Epidemiology Unit, in Cambridge, told reporters. "This opens the door to new research directions. Only very recent advances in technology have allowed us to carry out such a large comparison study."

Senior author Bruce Ponder, PhD, director of Cancer Research UK's Cambridge Research Institute at the University of Cambridge, said he agrees. "Previously, scientists have had to search for new cancer genes 1 at a time, but we have been able to search two thirds of the genome in 1 go," he noted. "Rather than fish for new genes 1 at a time with a rod and line, we have trawled the pool. This is not only a more efficient approach, but it gets round the bias of previous studies in which scientists examined only genes they already knew something about."

The investigators point out that BRCA1 and BRCA2 account for less than 25% of the familial risk of breast cancer. It has been suggested that a combination of many additional genetic factors, each playing a smaller role, also contribute to the disease. To identify additional susceptibility alleles, the research team conducted a 2-stage association study in 4398 breast cancer cases and 4316 controls. This was followed by a third stage where the group tested 30 single nucleotide polymorphisms (SNPs) for confirmation in 21,860 cases and 22,578 controls from 22 studies.

More Information Needed on How Genes Interact With Each Other

The researchers identified 4 genes positively associated with genetic susceptibility to breast cancer. They are FGFR2, TNRC9, MAP3K1, and LSP1. Most previously identified breast cancer susceptibility genes are involved in DNA repair, but the associations identified by this group appear to relate more to the control of cell growth or to cell signaling. Only 1 of the genes — FGFR2 — had a clear prior relevance to breast cancer.

"At the moment, we don't know how these genes interact with each other or with lifestyle factors, each of which might increase the risk," Dr. Ponder pointed out to reporters. "We'll continue to search for more genes, but we'll also focus on unraveling this information so that we're ready to offer advice to women who may carry 1 or more of these faulty genes in the future." The researchers suggest that it may be possible to identify many additional susceptibility alleles of more modest effect using this approach.

In a second study, published in Nature Genetics, lead author David Hunter, ScD, from Brigham and Women’s Hospital and Harvard Medical School, in Boston, Massachusetts, and his team identified alleles for the gene FGFR2 as being particularly associated with the risk of sporadic postmenopausal breast cancer.

The research team conducted a genomewide association study of breast cancer by genotyping 528,173 SNPs in 1145 postmenopausal women of European ancestry with invasive breast cancer and 1142 controls.

"We identified 4 single nucleotide polymorphisms in intron 2 of FGFR2," they write. "The association with all 4 single nucleotide polymorphisms was highly statistically significant (Ptrend for the most strongly associated SNP [rs1219648] = 1.1 × 10?10; population attributable risk = 16%)."

In a third study evaluating breast cancer risk, also published in Nature Genetics, lead author Simon Stacey, PhD, from deCODE Genetics, in Reykjavik, Iceland, and his team genotyped approximately 300,000 SNPs in 1600 breast cancer patients and 11,563 controls. They then tested selected polymorphisms in 5 replication sample sets. They found genetic variants each on chromosomes 2 and 16, which both increase the risk of estrogen-receptor–positive breast cancer. One of these variants is located near gene TNRC9, which was also identified in the study from Dr. Easton and colleagues.

"These findings will open doors for cancer researchers across the globe to unearth even more genes linked to cancer, and ultimately this will benefit patients," Mr. Kumar said. "Understanding more about what causes breast cancer will help doctors in the future identify and better manage more women at increased risk for the disease."

Nature. 2007. Published online May 27, 2007.
Nat Genet. 2007. Published online May 27, 2007.

Source: http://www.medscape.com/viewarticle/557462?src=mp