Editors' ChoiceCancer Genetics

An Oncogene Arises

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Science Translational Medicine  09 Nov 2011:
Vol. 3, Issue 108, pp. 108ec179
DOI: 10.1126/scitranslmed.3003402

Ovarian cancer is the most deadly gynecologic malignancy in the world and, unfortunately, is not usually detected until the disease is in advanced stages. The mutations in breast cancer (BRCA1 and BRCA2) and DNA mismatch repair (MMR) genes account for a small portion of ovarian cancer cases, yet the genetic basis of most cases remains elusive. Now, Rafnar et al. use a new approach to help decode the genetic architecture of ovarian cancer, with hopes that new predictive biomarkers might emerge.

The authors first identified nearly 16 million common and rare single-nucleotide polymorphisms (SNPs) in 457 Icelandic individuals. These SNPs were then assessed in a genome-wide association study (GWAS) of 640 ovarian cancer cases and 3000 controls. The most significantly associated SNP, rs34289250, was present in 1% of the Icelandic population and conferred a remarkable eightfold increase in risk for ovarian cancer. rs34289250 resides in an intronic region of the gene BRIP1 (BRCA1-interacting protein C-terminal helicase 1), whose protein product is required for double-strand DNA break repair by BRCA1. Rafnar and colleagues then identified a 2–base-pair insertion in the protein-coding portion of BRIP1 that was present in 4 out of the 10 rs34289250 carriers but was absent in all 447 noncarriers. Tumor sequencing in several individual carriers of this susceptibility SNP demonstrated a loss of the normal allele in tumor specimens. This phenomenon—known as “loss of heterozygosity”— is commonly seen with many oncogenes, such as BRCA1/2.

Despite the statistical significance of the at-risk SNP in Icelandic populations, these findings were not replicated in three independent populations from Europe. As such, two important aspects of this study become apparent. First, rare variants may indeed represent a large portion of the heritability missed by the recent GWAS of common variants. Second, rare SNPs such as rs34289250 are more likely to be ancestry-specific, requiring validation in several independent populations. Nonetheless, as DNA sequencing costs continue to drop and whole-genome sequencing becomes common in both research and clinical settings, we can expect many more candidate oncogenes to emerge, hopefully enhancing our ability to both understand and treat cancers.

T. Rafnar et al., Mutations in BRIP1 confer high risk of ovarian cancer. Nat. Genet. 43, 1104–1107 (2011). [PubMed]

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