Inherited Predisposition to Prostate Cancer: From Gene Discovery to Clinical Impact.

Family history of prostate cancer is one of the three most important risk factors for the disease in addition to age and race. Yet despite the recognition of this significant heritable component, it has been challenging to identify the genes associated with prostate cancer predisposition. Initial approaches focused on the collection of multiplex prostate cancer families. However, despite more than 20 years of linkage studies, few genes have been identified that account for a significant number of hereditary prostate cancer families. Our research team studied a large number of families with linkage evidence to chromosome 17q21-22 and ultimately identified a recurrent mutation in the HOXB13 gene. The HOXB13 G84E mutation occurs on a common haplotype consistent with a founder allele and worldwide, this allele accounts for ~5% of hereditary prostate cancer families. Current research from us and others focuses on the use of whole exome sequencing to identify rare cancer-causing alleles in early-onset and/or metastatic prostate cancer cases. The recent recognition of both germline and somatic alterations in DNA repair genes is important because mutation carriers appear to have a significant likelihood of developing aggressive/metastatic cancer.