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DeCode-Led Team IDs Ovarian Cancer Risk Gene

NEW YORK (GenomeWeb News) – Researchers from DeCode Genetics and elsewhere have identified mutations in the gene BRIP1 that appear to significantly increase ovarian cancer risk in Icelandic and Spanish populations.

As they reported online in Nature Genetics yesterday, the team tracked down the risk gene using a genome-wide association study informed by whole-genome sequence data for 457 individuals from Iceland. The GWAS, which involved hundreds of Icelandic women with ovarian cancer and more than 40,000 unaffected controls from the same population, unearthed a rare BRIP1 frameshift mutation that not only increased ovarian cancer risk by roughly eight times compared to rates in the general population, but also bumped up overall cancer risk.

In follow-up studies in ovarian cancer cases and controls from Spain, the Netherlands, and Finland, meanwhile, the researchers detected a distinct frameshift mutation in BRIP1 that coincided with elevated ovarian and breast cancer risk in the Spanish group.

"[W]e are committed to working with our collaborators, as we did in this case, to identify the spectrum of mutations occurring in other populations," senior author Kari Stefansson, DeCode CEO, who is also affiliated with the University of Reykjavik, said in statement. "This allows us to use the Icelandic resource as a unique discovery cohort, and then quickly elucidate the broader utility."

Ovarian cancer is notoriously difficult to detect at an early stage and just 19 percent of cases are diagnosed when the disease is localized to the ovary. Beyond mutations to BRCA1, BRCA2, and other hereditary breast/ovarian cancer syndrome genes or DNA mismatch repair gene mutations contributing to Lynch syndrome, researchers explained, not much is known about the genetic patterns that predispose some women to ovarian cancer.

Past GWAS of common variants turned up some leads on chromosomes 2, 8, 9, and 19, they added, but the team suspected that they might some find some rarer genetic variants contributing to the ovarian cancer by leveraging information from hundreds of Icelandic whole-genome sequences in combination with array data for tens of thousands of individuals from the same population.

"In order to search for rare and low-frequency variants with a greater impact on the disease than the common variants measured by DNA chips," they explained, "the whole genomes of a large number of Icelanders are currently being sequenced."

"The SNPs identified through sequencing are then imputed to 41,675 Icelanders who were genotyped with chips of 300,000-1,000,000 SNPs by using long-range phasing information," they added. "The nationwide Icelandic genealogical database then allows the propagation of this genotype information and the creation of in silico genotypes for the close relatives of the chip-genotyped individuals."

The researchers, who have used a similar approach to study other conditions, focused on nearly 16 million autosomal SNPs that had been genotyped and/or imputed from whole-genome data for the ovarian cancer study.

Along with 68 individuals with ovarian cancer who were genotyped using the Illumina HumanHap300 or CNV370 arrays and 41,607 control individuals genotyped with chips, the team had in silico genotype information for 572 ovarian cancer patients.

The search for ovarian cancer-associated loci led the researchers to nine SNPs on chromosome 17 that appeared to correlate with one another. The mostly strongly associated SNP, rs34289250, fell in intronic sequence of the BRIP1 gene.

BRIP1 codes for a protein that interacts with BRCA1 and plays a critical role in BRCA1's double-strand DNA break repair functions, the study authors noted, and mutations in BRIP1 have been linked to genome instability and a somewhat increased risk of breast cancer.

By sifting through genome sequence data for 10 sequenced Icelanders who carried the same rs34289250 allele detected in the discovery phase of the study, the team found that four of these individuals had insertions in an exon of BRIP1 that caused a frameshift that truncates the gene's protein product — findings that they verified using genotype data for thousands more Icelandic individuals with or without cancer.

In the Icelandic population, the BRIP1 insertion corresponded to an elevated ovarian cancer risk of roughly eight times compared to the rate in the broader population.

The frameshift was associated with several other cancers as well, researchers reported, increasing cancer risk by 36 percent and lowering life expectancy by an average of 3.6 years in the Icelandic population.

The same insertion was not found in 144 cases and 896 controls from Spain, 307 cases and 921 controls from the Netherlands, and 55 cases and 1,000 controls from Finland.

But when researchers sequenced the BRIP1 gene in pooled samples from individuals with or without ovarian cancer in those populations, they did detect a different frameshift mutation in BRIP1 in the Spanish ovarian cancer samples. The deletion, while rare in that population, was associated with a much higher risk of both ovarian and breast cancer, they found during their follow-up genotyping studies.

"[We]e have discovered frameshift mutations in the BRIP1 gene that greatly affect the risk of invasive ovarian cancer," the study authors concluded.

"Ovarian tumors form BRIP1 mutation carriers show loss of the wild-type allele," they added, "suggesting that the BRIP1 gene behaves like a classical tumor suppressor gene in ovarian cancer and that tumors with bi-allelic loss of BRIP1 may be good targets for therapeutic agents that affect DNA repair pathways."

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