HOXB13 and other high penetrant genes for prostate cancer

prostate cancer has been shown to increase prostate cancer risk whereby the risk is influenced by: (1) the number of affected family members, (2) first degree affected relatives compared to those who are more distantly related, (3) the presence of early onset cancers in a pedigree (typically men diagnosed at or before age 55).5,6 Despite this recognized familial component, identification of highly penetrant genes in hereditary prostate cancer has proven challenging. However, it is becoming increasingly important to identify these individuals with germline mutations at higher risk for prostate cancer, given that there are no uniformly recommended prostate cancer screening practices for the general population of men in the United States.7 Early genome-wide linkage studies focusing on families with a history of hereditary prostate cancer resulted in the identification of a number of potential candidate loci, many of which were not confirmed in replication studies. The University of Michigan Prostate Cancer Genetics Project (PCGP) conducted a genome-wide linkage scan on 175 prostate cancer pedigrees and identified a novel linkage on chromosome 17q near BRCA1.8–10 BRCA1 was excluded as the cause of this linkage signal through mutation screening in families with linkage evidence to chromosome 17q markers.11 Chromosome 17q remained a candidate linkage region when linkage studies were combined including research conducted by the International Consortium for Prostate Cancer Genetics of ICPCG.9 The candidate region was subsequently narrowed by fine-mapping to an approximately 10 cM region and notably the 147 families with >4 cases of prostate cancer, and evidence of early-onset prostate cancer diagnosis provided the strongest evidence for linkage to this region (LOD = 5.49 near D17S1820).12 With the advent of next generation sequencing C initiation and progression is the result of an accumulation of mutations in key tumor suppressor genes, mismatch repair genes, or oncogenes, which impact cancer cell growth, death, and differentiation. Mutations occurring in cancer tissue are termed somatic; whereas, heritable mutations that may be passed onto subsequent generations occur in germline DNA. It is these germline mutations that can lead to cancer family syndromes whereby family members carrying a deleterious germline mutation have an increased susceptibility to certain cancer phenotypes. Common features of hereditary cancer syndromes include early age‐of‐onset, multiple affected generations, rare tumor types, and/or multiple primary malignancies. Approximately, 5%–10% of all common cancers, including prostate cancer, have a hereditary component and are attributable to highly penetrant germline mutations.1 Across all cancer types, known cancer susceptibility syndromes number >100; however, it is important to note that mutations in high‐penetrance genes explain only a fraction of heritable cancers.2 Well‐known examples of hereditary cancer syndromes include Lynch (HNPCC), Cowden (PHTS), Li‐Fraumeni, and Hereditary Breast and Ovarian Cancer (HBOC) syndromes, which are attributable to mutations in mismatch repair genes, PTEN, p53, and BRCA1/2, respectively.3 Prostate cancer has been shown to cluster within families and exhibit Mendelian inheritance patterns.4 Family history of INVITED RESEARCH HIGHLIGHT