Prostate cancer is more hereditary than any other common cancer where there are known mutations. In fact, the heritability has been estimated at 57% compared to 39% for ovarian, 38% for kidney, and 31% for breast cancers. Starting with work from 1960-1980 in the Utah Mormon population, a 3-fold increased risk of prostate cancer death was noted for relatives of men with prostate cancer. Furthermore, the relative risk for brothers of men with prostate cancer was found to be elevated at 2.4 in this population; and if that brother was younger than 62 years old, the relative risk rose to 4. Confirming this finding, data from Johns Hopkins noted a 2.2 and 4.9 relative risk of prostate cancer when either one or two first degree relatives were affected, respectively.
The short-comings of these early analyses were that family history does not distinguish inherited genetic risk factors from the influence of a shared environment. This required segregation analysis. One hundred six families were analyzed and the risk of prostate cancer inheritance was 3-fold higher if prostate cancer was diagnosed before age 53 in the proband compared to when prostate cancer was diagnosed after 65 years of age. This allowed for the initial definition of hereditary prostate cancer which was 3 or more first degree relatives or 3 or more generations, or 2 first degree relatives if both were younger than 55 years at prostate cancer diagnosis.
The next development was genome wide association studies (GWAS) which allowed for large population analysis. Millions of common variants (e.g. single nucleotide polymorphisms, SNPs) could be looked at this way. GWAS demonstrated that a large number of variants existed (over 100), each of which have a very small effect. Even still, these SNPs only explain about 25% of the hereditability associated with prostate cancer.
Next generation sequencing helped to identify linkages at chromosome 17q21. High throughput sequencing was able to distill 6 individuals with the same mutation in HOXB13. Fascinatingly, 100% (18/18) men in four families with this mutation had the G84E HOXB13 mutation identified in the prior linkage analysis (NEJM 2012; 366:141). This appears to be a founder gene originating in Nordic countries, and it has 60% penetrance by age 80. Other candidate genes identified are BRCA 1/2, DNA repair mutations (e.g. ATM), and genes associated with Lynch Syndrome (e.g. MSH2). Taken together, these genetic aberrations were present in over 12% of the total number of castration-resistant prostate cancer (NEJM 2016;375:5).
The clinical implications of these findings loom large. Family history is a major risk factor for the development of prostate cancer. A proper family history should include age at diagnosis of prostate cancer for all relatives, any history of BRCA 1/2 associated cancers, and a complete list of other family cancers. Factors suggesting a genetic contribution are multiple affected first degree relatives with prostate cancer, early onset (age < 55 years) disease, and prostate cancer with a family history of BRCA 1/2 or associated cancers. Patients of Nordic descent, BRCA 1/2 family history, and men with CRPC who may be preferentially selected for PARP inhibitors or platinum instead of taxanes if they harbor mismatch repair mutations.
Speaker(s): P. Walsh, Baltimore, MD, USA
Written By: Benjamin T. Ristau, MD, SUO Fellow, Fox Chase Cancer Center, Philadelphia, PA
at the #EAU17 - March 24-28, 2017- London, England