Scientists at deCODE Genetics and academic collaborators from Iceland, The Netherlands, Spain and Finland today report the discovery of variants in the human genome that associate with increased risk of invasive ovarian cancer, one of the deadliest forms of cancer in women. The study was done in collaboration with Illumina, Inc., and is published today in the online edition of Nature Genetics.
Using Illumina sequencing technology, deCODE scientists determined the sequences of the entire genomes of 457 Icelanders, and identified 16 million single nucleotide polymorphisms (SNPs). Through a combination of SNP genotyping and computational techniques utilizing the extensive Icelandic genealogy, they were able to propagate those 16 million variants into over 40,000 Icelanders, including over 600 patients with ovarian cancer.
The researchers observed a rare sequence variant in a gene named BRIP1 that confers more than eightfold increase in the risk of ovarian cancer in the Icelandic population. BRIP1 plays an important role in maintaining the stability of the genome and interacting directly with the DNA repair protein encoded by the known breast cancer gene BRCA1. Interestingly, the mutation also associates with increased risk of being diagnosed with cancer in general, and individuals carrying the variant live 3.6 years fewer on average.
The researchers also searched for mutations in the BRIP1 gene in ovarian cancer patients in other populations. A rare variant in BRIP1 was found in a Spanish cohort of 144 patients and 896 controls; this mutation confers a significantly increased risk of not only ovarian cancer, but also breast cancer. Finally, examination of tumors from ovarian cancer patients that carry the mutation showed a loss of the healthy copy of the gene, further supporting the role of BRIP1 as a classical tumor suppressor.
"This study underscores the important contribution that the Icelandic population can make to the discovery of low frequency sequence variants with large effect. The potential to do this has been clear since the critical role played by Iceland in the discovery of the BRCA2 gene. Until now, however, the combination of sequencing technology and analytical techniques were insufficient to unleash the flood of discoveries that we and our collaborators are now making," said Kari Stefansson, deCODE's CEO and senior author of the study.
"Our objective is to translate our discoveries most rapidly into benefit for patients. So, we are committed to working with our collaborators, as we did in this case, to identify the spectrum of mutations occuring in other populations. This allows us to use the Icelandic resource as a unique discovery cohort, and then quickly elucidate the broader utility," Dr. Stefansson added.
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