ABSTRACT
The 8q24 gene desert contains risk loci for multiple epithelial cancers, including colon, breast, and prostate. Recent evidence suggests these risk loci contain enhancers. In this study, data are presented showing that each risk locus bears epigenetic marks consistent with enhancer elements and forms a long-range chromatin loop with the MYC proto-oncogene located several hundred kilobases telomeric and that these interactions are tissue-specific. We therefore propose that the 8q24 risk loci operate through a common mechanism-as tissue-specific enhancers of MYC.
Subject(s)
Breast Neoplasms/genetics , Chromosomes, Human, Pair 8 , Colonic Neoplasms/genetics , Epigenesis, Genetic , Gene Expression Regulation, Neoplastic , Proto-Oncogene Proteins c-myc/genetics , Cell Line, Tumor , Genetic Loci , Genome, Human , Humans , Organ Specificity , Proto-Oncogene Mas , Risk FactorsABSTRACT
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.
Subject(s)
Chromosomes, Human, Pair 8 , Gene Expression Regulation, Neoplastic , Genes, myc , Prostatic Neoplasms/genetics , Chromosome Mapping , DNA Primers , DNA, Neoplasm/genetics , Humans , Male , MicroRNAs/genetics , Polymorphism, Single Nucleotide , Prostatectomy , Prostatic Neoplasms/epidemiology , Prostatic Neoplasms/surgery , Proto-Oncogene Mas , RNA, Neoplasm/genetics , Risk , Transcription, GeneticABSTRACT
An inherited variant on chromosome 8q24, rs6983267, is significantly associated with cancer pathogenesis. We present evidence that the region harboring this variant is a transcriptional enhancer, that the alleles of rs6983267 differentially bind transcription factor 7-like 2 (TCF7L2) and that the risk region physically interacts with the MYC proto-oncogene. These data provide strong support for a biological mechanism underlying this non-protein-coding risk variant.
Subject(s)
Chromosomes, Human, Pair 8/genetics , Colorectal Neoplasms/genetics , Genetic Predisposition to Disease , Polymorphism, Single Nucleotide/genetics , Proto-Oncogene Proteins c-myc/genetics , Alleles , Cell Line, Tumor , Enhancer Elements, Genetic/genetics , Humans , Protein Binding , Proto-Oncogene Mas , TCF Transcription Factors/metabolism , Transcription Factor 7-Like 2 ProteinABSTRACT
PURPOSE: Variants at chromosomal loci 8q24 and 17q are established risk factors for prostate cancer. Many studies have confirmed the findings for risk, but few have examined aggressiveness and other clinical variables in detail. Additionally, Gleason score is typically used as a surrogate for the primary end point of prostate cancer mortality. We investigated whether the 8q24 and 17q risk variants are associated with clinical variables as well as prostate cancer mortality. EXPERIMENTAL DESIGN: In the Physicians' Health Study (1,347 cases and 1,462 controls), the Dana-Farber Harvard Cancer Center Specialized Program of Research Excellence (Gelb Center; 3,714 cases), and the Fred Hutchinson Cancer Research Center King County Case-Control Studies (1,308 cases and 1,266 controls), we examined eight previously identified 8q24 and 17q risk variants for association with prostate cancer mortality in men of European ancestry. We considered associations with other surrogate markers of prostate cancer aggressiveness, such as Gleason score, pathologic stage, prostate-specific antigen at diagnosis, and age at diagnosis. RESULTS: Six of the eight variants were confirmed as prostate cancer risk factors. Several variants were nominally associated with age at diagnosis; when totaling all alleles for single nucleotide polymorphisms significantly associated with risk, each additional allele decreased age at diagnosis by an average of 6 months in the Physicians' Health Study (P = 0.0005) and 4 months in the Dana-Farber Harvard Cancer Center Specialized Program of Research Excellence (Gelb Center) cohort (P = 0.0016). However, there were no statistically significant associations with prostate cancer mortality. CONCLUSIONS: Our results suggest that the 8q24 and 17q prostate cancer risk variants may influence age at diagnosis but not disease aggressiveness.
