Preventing familial breast and ovarian cancer: major research advances with little implication
Primary prevention of hereditary breast–ovarian cancer syndrome, which accounts for 5–10% of all breast cancer diagnosis, represents a prime paradigm of excellence of personalized medicine [1,2]. However, genetic testing can reveal that BRCA mutation carriers account for less than 25% of the familial risk. There has been little progress in explaining the missing heritability of the remaining 75% of women with family history who test negative for BRCA mutations. Neither recently identified common low-penetrance variants alone, nor their interactions with established environmental risk factors, are able to explain missing heritability. But even among BRCA mutation carriers, the decision by an expert scientific team for the optimal preventive strategy, choosing between prophylactic surgery and intensive surveillance, is very difficult and should be individualized for each woman. Here we discuss the latest advances in breast cancer genetics, their potential to impact prevention strategies and practices, and the future perspectives for a true personalized preventive medicine...........
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Previous work has suggested the polygenic model to help understand the 75% of breast cancer familial risk [6]. According to this model, the missing heritability could be explained by the accumulation of low to moderate genetic risk variants other than BRCA1/2 genes, namely BRCA3 or BRCA4 high-penetrance genes. Indeed, more than 15 years after the discovery of BRCA1/2 genes, the ‘classical’ linkage studies in high-risk families have identified no other high-penetrance genes. The completion of the HapMap 3 project with a database of common and rare variants [7] and high-throughput screening technology has allowed a new generation of association studies to provide improved understanding of the genetics of familial cancer.
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