An apparent quandary: adoption of polygenics and gene panels for personalised breast cancer risk stratification

Abstract

AbstractOver the past 30 years, genetic and epidemiological advances have revolutionised the prediction of breast cancer risk in women with significant family history. By screening these women for high- and intermediate-risk pathogenic variants and by interrogating their genomes for multiple lower-risk single-nucleotide polymorphisms (SNPs), we can provide individually tailored risk profiles in carriers of Mendelian breast cancer risk variants and in non-carriers, but clinical implementation of this approach is suboptimal. Risk mitigation may involve enhanced surveillance, preventive medications or risk-reducing surgery but barriers exist to the adoption of polygenic risk score (PRS)-based models in the clinic. PRS development has suffered from both systematic biases resulting from development and validation in those of European ancestry and from the consequences of unanticipated evolutionary differences particularly with regard to those of African ancestry. PRS approaches which take into account underlying genetic diversity offer a practical solution to the misapplication of European-derived PRS to other population groups including women of multiple ancestries. All ancestry PRS technology offers net benefit regardless of potency differences. While the new science of polygenics has surged ahead and its stratification insights have been incorporated into risk modelling, training of providers and genetic counsellors lags far behind and an educational revolution is also necessary to provide optimal patient care.