A candidate prostate cancer susceptibility gene at chromosome 17p

It is difficult to identify genes that predispose to prostate cancer due to late age at diagnosis, presence of phenocopies within high-risk pedigrees and genetic complexity. A genome-wide scan of large, high-risk pedigrees fr om Utah has provided evidence for linkage to a locus on chromosome 17p. We carried out positional cloning and mutation screening within the refined in terval, identifying a gene, ELAC2, harboring mutations (including a framesh ift and a nonconservative missense change) that segregate with prostate can cer in two pedigrees. In addition, two common missense variants in the gene are associated with the occurrence of prostate cancer. ELAC2 is a member o f an uncharacterized gene family predicted to encode a metal-dependent hydr olase domain that is conserved among eukaryotes, archaebacteria and eubacte ria. The gene product bears amino acid sequence similarity to two better un derstood protein families, namely the PSO2 (SNM1) DNA interstrand crosslink repair proteins and the 73-kD subunit of mRNA 3' end cleavage and polyaden ylation specificity factor (CPSF73).