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Evaluation of the 8q24 Prostate Cancer Risk Locus and MYC Expression

Departments of ¹ Medical Oncology and ² Biostatistics and Computational Biology, Dana-Farber Cancer Institute; and ³ Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts; ⁴ Division of Human Biology, ⁵ Public Health Sciences Division, and ⁶ Division of Clinical Research, Fred Hutchinson Cancer Research Center; ⁷ Department of Urology, University of Washington; and ⁸ Department of Veterans Affairs Puget Sound Health Care System, Seattle, Washington; ⁹ Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Rockville, Maryland; ¹⁰ Departments of Pathology and Laboratory Medicine, Clinical Neurosciences, and Oncology, University of Calgary, Calgary, Alberta, Canada; and ¹¹ Broad Institute of Harvard and MIT, Cambridge, Massachusetts

Requests for reprints: Matthew L. Freedman, Dana-Farber Cancer Institute, Dana Bldg Rm 710A, 44 Binney Street, Boston, MA 02115. Phone: 617-582-8598; Fax: 617-582-8157; E-mail: matthew_freedman{at}dfci.harvard.edu.

Key Words: chromosome 8q24 • MYC • prostate cancer

Polymorphisms at 8q24 are robustly associated with prostate cancer risk. The risk variants are located in nonprotein coding regions and their mechanism has not been fully elucidated. To further dissect the function of this locus, we tested two hypotheses: (a) unannotated microRNAs (miRNA) are transcribed in the region, and (b) this region is a cis-acting enhancer. Using next generation sequencing, 8q24 risk regions were interrogated for known and novel miRNAs in histologically normal radical prostatectomy tissue. We also evaluated the association between the risk variants and transcript levels of multiple genes, focusing on the proto-oncogene, MYC. RNA expression was measured in histologically normal and tumor tissue from 280 prostatectomy specimens (from 234 European American and 46 African American patients), and paired germline DNA from each individual was genotyped for six 8q24 risk single nucleotide polymorphisms. No evidence was found for significant miRNA transcription within 8q24 prostate cancer risk loci. Likewise, no convincing association between RNA expression and risk allele status was detected in either histologically normal or tumor tissue. To our knowledge, this is one of the first and largest studies to directly assess miRNA in this region and to systematically measure MYC expression levels in prostate tissue in relation to inherited risk variants. These data will help to direct the future study of this risk locus. [Cancer Res 2009;69(13):5568–74]