Screening for familial and hereditary prostate cancer

Abstract

Prostate cancer (PC) has the highest degree of genetic transmission of any form of malignancy. In some families, the hereditary pattern is so strong as to mimic an autosomal dominance trait. We reviewed the known predisposing genetic markers to assess possible strategies for screening of families at risk. We carried out a systematic literature search using the Pubmed service of the National Center for Biotechnology Information (NCBI) and several gene libraries, including the NCBI SNP Library, the Online Mendelian Inheritance in ManV R Catalog of Human Genes and Genetic Disorders (OMIM) and SNPedia to obtain known gene loci, SNPs and satellite markers associated with PC. We further cross referenced information on identified loci comparing data from different articles and gene reference sites. Whenever possible, we recorded the odds ratio (OR) for the allele associated with PC. In multiple different linkage studies, many independent PC associated loci have been identified on separate chromosomes. Genome-wide association studies have added many more markers to the set derived from linkage investigations. A subset of the alleles is associated with early onset and aggressive cancer. Due to the great heterogeneity, the OR for any one allele predicting future development of this malignancy is low. The strongest predictors are the BRCA2 mutations, and the highly penetrant G84E mutation in HOXB13. The presence of multiple risk alleles is more highly predictive than a single allele. Technical limitations on screening large panels of alleles are being overcome. It is appropriate to begin supplementing prostate specific antigen testing with alleles, such as BRCA2 and HOXB13, disclosed by targeted genomic analysis in families with an unfavorable family cancer history. Future population studies of PC should include genomic sequencing protocols, particularly in families with a history of PC and other malignancies.

Somatic molecular subtyping of prostate tumors from HOXB13 G84E carriers

“…A significant proportion of prostate cancer risk is inherited and the genetic variations modulating this risk are increasingly well known [1, 2]. A rare mutation in the HOXB13 gene, G84E, is reproducibly associated with a 4- to 8-fold increased risk of prostate cancer [3–12].…”

Rare ADAR and RNASEH2B variants and a type I interferon signature in glioma and prostate carcinoma risk and tumorigenesis

“…Similarly, familial prostate cancer has been described and tumor syndromes exist that are associated with prostate cancer susceptibility, e.g. Lynch syndrome and hereditary breast and ovarian cancer caused by mutations in DNA-repair genes (reviewed in [41]).…”

“…the mismatch repair genes MSH2, MSH6, MLH1, and PMS2) or chromosomal regions (e.g. the 8q24 locus) confer increased risk for different tumor entities including gliomas [35,36] and prostate cancer [4,41]. Therefore in some families, gliomas and prostate cancer may both be part of a tumor spectrum associated with a common genetic basis.…”

Commentary on Almassalha et al., “The Greater Genomic Landscape: The Heterogeneous Evolution of Cancer”

“…Structural genetic modifications have been demonstrated in these breast-ovarian malignancy families (14). Familial prostate cancer is the epitome of a multigenic malignancy phenotype (15). We have called attention to the phenotypic heterogeneity of hereditary cancer syndromes.…”