title: Genetic variation in RNASEL associated with prostate cancer risk and progression.
abstract: Variation in genes contributing to the host immune response may mediate the relationship between inflammation and prostate carcinogenesis. RNASEL at chromosome 1q25 encodes ribonuclease L, part of the interferon-mediated immune response to viral infection. We therefore investigated the association between variation in RNASEL and prostate cancer risk and progression in a study of 1286 cases and 1264 controls nested within the prospective Physicians' Health Study. Eleven single-nucleotide polymorphisms (SNPs) were selected using the web-based 'Tagger' in the HapMap CEPH panel (Utah residents of Northern and Western European Ancestry). Unconditional logistic regression models assessed the relationship between each SNP and incident advanced stage (T(3)/T(4), T(0)-T(4)/M(1) and lethal disease) and high Gleason grade (>/=7) prostate cancer. Further analyses were stratified by calendar year of diagnosis. Cox proportional hazards models examined the relationship between genotype and prostate cancer-specific survival. We also explored associations between genotype and serum inflammatory biomarkers interleukin-6 (IL-6), C-reactive protein (CRP) and tumor necrosis factor-alpha receptor 2 using linear regression. Individuals homozygous for the variant allele of rs12757998 had an increased risk of prostate cancer [AA versus GG; odds ratio (OR): 1.63, 95% confidence interval (CI): 1.18-2.25), and more specifically, high-grade tumors (OR: 1.90, 95% CI: 1.25-2.89). The same genotype was associated with increased CRP (P = 0.02) and IL-6 (P = 0.05) levels. Missense mutations R462Q and D541E were associated with an increased risk of advanced stage disease only in the pre-prostate-specific antigen era. There were no significant associations with survival. The results of this study support a link between RNASEL and prostate cancer and suggest that the association may be mediated through inflammation. These novel findings warrant replication in future studies.
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA. mameyer@hsph.harvard.edu
authors.forename: Mara S
authors.initials: MS
authors.lastname: Meyer
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Penney
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Stark
authors.forename: Fredrick R
authors.initials: FR
authors.lastname: Schumacher
authors.forename: Howard D
authors.initials: HD
authors.lastname: Sesso
authors.forename: Massimo
authors.initials: M
authors.lastname: Loda
authors.forename: Michelangelo
authors.initials: M
authors.lastname: Fiorentino
authors.forename: Stephen
authors.initials: S
authors.lastname: Finn
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Flavin
authors.forename: Tobias
authors.initials: T
authors.lastname: Kurth
authors.forename: Alkes L
authors.initials: AL
authors.lastname: Price
authors.forename: Edward L
authors.initials: EL
authors.lastname: Giovannucci
authors.forename: Katja
authors.initials: K
authors.lastname: Fall
authors.forename: Meir J
authors.initials: MJ
authors.lastname: Stampfer
authors.forename: Jing
authors.initials: J
authors.lastname: Ma
authors.forename: Lorelei A
authors.initials: LA
authors.lastname: Mucci
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002097:C-Reactive Protein / Q000378:metabolism; D016022:Case-Control Studies; D018450:Disease Progression; D004722:Endoribonucleases / Q000235:genetics*; D005838:Genotype; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011446:Prospective Studies; D011471:Prostatic Neoplasms / Q000235:genetics*
chemical_list: D015850:Interleukin-6; D002097:C-Reactive Protein; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease