A candidate prostate cancer susceptibility gene at chromosome 17p

Abstract

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 from Utah has provided evidence for linkage to a locus on chromosome 17p. We carried out positional cloning and mutation screening within the refined interval, identifying a gene, ELAC2, harboring mutations (including a frameshift and a nonconservative missense change) that segregate with prostate cancer in two pedigrees. In addition, two common missense variants in the gene are associated with the occurrence of prostate cancer. ELAC2 is a member of an uncharacterized gene family predicted to encode a metal-dependent hydrolase domain that is conserved among eukaryotes, archaebacteria and eubacteria. The gene product bears amino acid sequence similarity to two better understood protein families, namely the PSO2 (SNM1) DNA interstrand crosslink repair proteins and the 73-kD subunit of mRNA 3' end cleavage and polyadenylation specificity factor (CPSF73).

ELAC2, a putative prostate cancer susceptibility gene product, potentiates TGF-β/Smad-induced growth arrest of prostate cells

“…Further investigations are needed to determine whether ELAC2 can function as a general nuclear cofactor or scaffold protein in the TGF-b/Smad pathway. Using a genomewide screen together with positional cloning, ELAC2 was identified as a candidate prostate cancer susceptibility gene (Tavtigian et al, 2001). However, the association of ELAC2 with prostate cancer has been questioned in several publications (Wang et al, 2001;Shea et al, 2002).…”

“…However, it cannot be excluded that missense variants are more easily degraded than the wild type, resulting in a decreased TGF-b/Smad signaling. Furthermore, it remains possible that loss or decreased ELAC2 expression or functional inactivation through mutations in N-terminal half of ELAC2 gene might be found in other tumors because ELAC2 is ubiquitously expressed (Tavtigian et al, 2001). Recently, FAST-1 was reported to block the transactivation of androgen receptor (Chen et al, 2005a).…”

“…One of the TGF-b resistant NRP-154 clones expressed an antisense transcript for ELAC2. Linkage analysis by Tavtigian et al (2001) showed that ELAC2 is a candidate prostate cancer susceptibility gene. Recently it has been reported that ELAC2 at its C-terminal region possesses tRNA 3 0 processing endoribonuclease (3 0 -tRNase) activity in yeast and mammals (Takaku et al, 2003;Chen et al, 2005b;Minagawa et al, 2005), and that ELAC2 interacts with g-tubulin to cause a delay in G2-M progression in Hela cells (Korver et al, 2003).…”

Role of genetic polymorphisms of the RNASEL gene on familial prostate cancer risk in a Japanese population

“…Six prostate cancer susceptibility loci (HPC1 at 1q24-25 (Smith et al, 1996), PCAP at 1q42-43 (Berthon et al, 1998), HPCX at Xq27-28 (Xu et al, 1998), CAPB at 1p36 (Gibbs et al, 1999), HPC20 at 20q13 (Berry et al, 2000) and HPC2 at 17p12 (Tavtigian et al, 2001)) and two candidate susceptibility genes (HPC2/ELAC2 at 17q (Tavtigian et al, 2001) and RNASEL at 1q24-25 ) have been reported.…”

Simple methods for assessing haplotype‐environment interactions in case‐only and case‐control studies

“…While some studies have debated the merit of haplotype analysis over single-SNP analysis [Chapman et al, 2003;Tzeng and Roeder, 2006], simulation studies [Akey et al, 2001;Morris and Kaplan, 2002;Rosenberg et al, 2006] have demonstrated haplotype procedures are more powerful than single-SNP procedures when either the causal polymorphism is not genotyped (which is highly likely) or when multiple causal polymorphisms act in cis fashion in the haplotype region. Studies provide empirical evidence of this latter event occurring in many genetic diseases, such as prostate cancer [Tavtigian et al, 2001].…”