Germline Alterations of the RNASEL Gene, a Candidate HPC1 Gene at 1q25, in Patients and Families with Prostate Cancer

Abstract

The RNASEL gene (2',5'-oligoisoadenylate-synthetase dependent) encodes a ribonuclease that mediates the antiviral and apoptotic activities of interferons. The RNASEL gene maps to the hereditary-prostate-cancer (HPC)-predisposition locus at 1q24-q25 (HPC1) and was recently shown to harbor truncating mutations in two families with linkage to HPC1. Here, we screened for RNASEL germline mutations in 66 Finnish patients with HPC, and we determined the frequency of the changes in the index patients from 116 families with HPC, in 492 patients with unselected prostate cancer (PRCA), in 223 patients with benign prostatic hyperplasia (BPH), and in 566 controls. A truncating mutation, E265X, was found in 5 (4.3%) of the 116 patients from families with HPC. This was significantly higher (odds ratio [OR] =4.56; P=.04) than the frequency of E265X in controls (1.8%). The highest mutation frequency (9.5%) was found in patients from families with four or more affected members. Possible segregation was detected only in a single family. However, the median age at disease onset for E265X carriers was 11 years less than that for noncarriers in the same families. In addition, of the four missense variants found, R462Q showed an association with HPC (OR=1.96; P=.07). None of the variants showed any differences between controls and either patients with BPH or patients with PRCA. We conclude that, although RNASEL mutations do not explain disease segregation in Finnish families with HPC, the variants are enriched in families with HPC that include more than two affected members and may also be associated with the age at disease onset. This suggests a possible modifying role in cancer predisposition. The impact that the RNASEL sequence variants have on PRCA burden at the population level seems small but deserves further study.

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

“…Truncating mutation E265X was reported to cosegregate in highrisk US families with hereditary prostate cancer . E265X was also associated with hereditary prostate cancer in Finnish patients (Rökman et al, 2002). In the present study, E265X mutation was not observed in cases and controls.…”

“…In Finnish patients, the truncation mutation at base pair position 793 (Glu265-stop) was associated with hereditary prostate cancer (Rökman et al, 2002). Wang et al (2002) reported the association of the Arg462Gln genotype with familial prostate cancer risk in a United States population.…”

A scientific journey through the 2-5A/RNase L system

“…However, specific evidence of a role for RNase L in the suppression of cancer had to wait almost 10 years, until the long sought, hereditary prostate cancer 1 (HPC1) was mapped to the RNase L gene by the group of Jeff Trent [92]. Several germline mutations or variants in HPC1/RNASEL have been observed in hereditary prostate cancer [92][93][94][95] (reviewed in ref. [96]), including a common (35% allelic frequency) missense variant of RNase L, in which a G to A transition at nucleotide position 1385 (G1385A) results in a glutamine instead of arginine at amino acid position 462 (R462Q).…”

“…The RNase L "Q" variant had a 3-fold decrease in catalytic activity compared to the wild-type enzyme [95,97]. Although several genetic and epidemiologic studies support the involvement of RNASEL (and notably the R462Q variant) in prostate cancer etiology [92][93][94][95], others did not [98][99][100], suggesting that either population differences or environmental factors such as infections may modulate the impact of RNASEL on prostatic carcinogenesis.…”

CHEK2 variants associate with hereditary prostate cancer

“…So far, only two genes have been identified from these chromosomal regions: ELAC2 from HPC2 -locus (Tavtigian et al, 2001) and RNASEL (MIM 180435) from HPC1 -locus . In Finland neither ELAC2 nor RNASEL did explain the disease segregation in HPC families, but seemed to have some kind of modifying role in prostate carcinogenesis (Rokman et al, 2001;Rokman et al, 2002). Xu et al (2001) identified a new locus at 8p22 -23, and mutations in MSR1 gene (MIM 153622) were reported to associate with prostate cancer .…”