Journal Article

Genetic variation in <i>RNASEL</i> associated with prostate cancer risk and progression

Mara S. Meyer, Kathryn L. Penney, Jennifer R. Stark, Fredrick R. Schumacher, Howard D. Sesso, Massimo Loda, Michelangelo Fiorentino, Stephen Finn, Richard J. Flavin, Tobias Kurth, Alkes L. Price, Edward L. Giovannucci, Katja Fall, Meir J. Stampfer, Jing Ma and Lorelei A. Mucci

in Carcinogenesis

Volume 31, issue 9, pages 1597-1603
Published in print September 2010 | ISSN: 0143-3334
Published online June 2010 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgq132
Genetic variation in RNASEL associated with prostate cancer risk and progression

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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 (T3/T4, T0-T4/M1 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.

Journal Article.  5358 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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