title: 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.
authors.affiliation: Laboratory of Cancer Genetics, Institute of Medical Technology, Temepere University, and Tempere University Hospital, Tempere, Finland. annika.rokman@uta.fi
authors.forename: Annika
authors.initials: A
authors.lastname: Rökman
authors.forename: Tarja
authors.initials: T
authors.lastname: Ikonen
authors.forename: Eija H
authors.initials: EH
authors.lastname: Seppälä
authors.forename: Nina
authors.initials: N
authors.lastname: Nupponen
authors.forename: Ville
authors.initials: V
authors.lastname: Autio
authors.forename: Nina
authors.initials: N
authors.lastname: Mononen
authors.forename: Joan
authors.initials: J
authors.lastname: Bailey-Wilson
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Trent
authors.forename: John
authors.initials: J
authors.lastname: Carpten
authors.forename: Mika P
authors.initials: MP
authors.lastname: Matikainen
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Koivisto
authors.forename: Teuvo L J
authors.initials: TL
authors.lastname: Tammela
authors.forename: Olli-P
authors.initials: OP
authors.lastname: Kallioniemi
authors.forename: Johanna
authors.initials: J
authors.lastname: Schleutker
mesh_terms: D017668:Age of Onset; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D004252:DNA Mutational Analysis; D004722:Endoribonucleases / Q000737:chemistry / Q000235:genetics*; D005260:Female; D005387:Finland; D005787:Gene Frequency; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D008297:Male; D020125:Mutation, Missense / Q000235:genetics; D010375:Pedigree; D018807:Polymorphism, Single-Stranded Conformational; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology
chemical_list: D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease