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Genomic Analysis of Breast Cancer Risk

Harry Ostrer, MD, Albert Einstein College of Medicine, Bronx, New York
Study abstract

Genome wide association studies (GWAS) of breast cancer risk have provided clues for the identification of other risk genes. Single nucleotide polymorphisms (SNPs) in or near the FGFR2, TNRC9, MAP3K1, LSP1 and CASP genes, in addition to a presumed regulatory region upstream from the C-MYC gene on chromosome 8q24 and on 2q have been studied in several populations. An alternative approach would be to identify the rare but high-penetrant alleles that are not captured by GWAS. This approach has been successful when applied to studying the tails of the risk distribution for blood pressure and cardiac phenotypes. Recognizing the importance of this approach, the National Heart, Lung and Blood Institute established the Exome Sequencing Project (ESP) to study the tails of the distributions for diseases that fall within their mission. Exome sequencing offers the advantage of surveying key regions of the expressed regions, rather than the entire, genome, thus reducing complexity and cost. The ESP strategy can be applied by analyzing DNA for a well-defined high-risk phenotype (≥3 women affected with premenopausal breast cancer – likely to have a heritable mutation, or early onset breast cancer with no family history – likely to have a de novo mutation) and by studying well-defined populations that are likely to have common founder alleles.

Study review

The purpose of this study was to identify new inherited genetic mutations that increase breast cancer risk. The research team analyzed blood samples from two groups of survivors: women with a strong family history of breast and/or ovarian cancer and women who had early onset breast cancer but no family history. The researchers wanted to enroll up to 400 volunteers from the Army of Women (AOW) from anywhere in the U.S. The Call to Action for this study was sent to AOW members on October 1, 2014. The researchers closed enrollment on July 28, 2016, after the AOW provided them with 339 women who were interested in enrolling in the study.

Resulting Publications:
Differential analysis of mutations in the Jewish population and their implications for diseases.