Article Abstract

Men with a susceptibility to prostate cancer and the role of genetic based screening

Authors: Rosalind Eeles, Holly Ni Raghallaigh

Abstract

Prostate cancer is the second most common malignancy affecting men worldwide, and the commonest affecting men of African descent. Significant diagnostic and therapeutic advances have been made in the past decade. Improvements in the accuracy of prostate cancer diagnosis include the uptake of multi-parametric MRI and a shift towards targeted biopsy. We also now have more life-prolonging systemic and hormonal therapies for men with advanced disease at our disposal than ever before. However, the development of robust screening tools and targeted screening programs has not followed at the same pace. Evidence to support population-based screening remains unclear, with the use of PSA as a screening test limiting our ability to discriminate between clinically significant and insignificant disease. Prostate cancer has a large heritable component. Given that most men without risk factors have a low lifetime risk of developing lethal prostate cancer, much work is being done to further our knowledge of how we can best screen men in higher risk categories, such as those with a family history (FH) of the disease or those of African ancestry. These men have been reported to carry upwards of a two-fold increased risk of developing the disease at an earlier age, with evidence suggesting poorer survival outcomes. In men with a FH of prostate cancer, this is felt to be due to rare, high-penetrance mutations and the presence of multiple, common low penetrance alleles, with men carrying specific germline mutations in the BRCA and other DNA repair genes at particularly high risk. To date, large scale genome-wide association studies (GWAS) have led to the discovery of approximately 170 single nucleotide polymorphisms (SNPs) associated with prostate cancer risk, allowing over 30% of prostate cancer risk to be explained. Genomic tests, utilising somatic (prostate biopsy) tissue can also predict the risk of unfavourable pathology, biochemical recurrence and the likelihood of metastatic disease using gene expression. Targeted screening studies are currently under way in men with DNA repair mutations, men with a FH and those of Afro-Caribbean ethnicity which will greater inform our understanding of disease incidence and behaviour in these men, treatment outcomes and developing the most appropriate screening regime for such men. Incorporating a patient’s genetic mutation status into risk algorithms allows us an opportunity to develop targeted screening programs for men in whom early cancer detection and treatment will positively influence survival, and in the process offer male family members of affected men the chance to be counselled and screened accordingly.