Mark Pomerantz

The 8q24 cancer risk variant rs6983267 shows long-range interaction with MYC in colorectal cancer

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.

8q24 prostate, breast, and colon cancer risk loci show tissue-specific long-range interaction with MYC

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.

Functional Enhancers at the Gene-Poor 8q24 Cancer-Linked Locus

Multiple discrete regions at 8q24 were recently shown to contain alleles that predispose to many cancers including prostate, breast, and colon. These regions are far from any annotated gene and their biological activities have been unknown. Here we profiled a 5-megabase chromatin segment encompassing all the risk regions for RNA expression, histone modifications, and locations occupied by RNA polymerase II and androgen receptor (AR). This led to the identification of several transcriptional enhancers, which were verified using reporter assays. Two enhancers in one risk region were occupied by AR and responded to androgen treatment; one contained a single nucleotide polymorphism (rs11986220) that resides within a FoxA1 binding site, with the prostate cancer risk allele facilitating both stronger FoxA1 binding and stronger androgen responsiveness. The study reported here exemplifies an approach that may be applied to any risk-associated allele in non-protein coding regions as it emerges from genome-wide association studies to better understand the genetic predisposition of complex diseases.

SLCO2B1 and SLCO1B3 May Determine Time to Progression for Patients Receiving Androgen Deprivation Therapy for Prostate Cancer

PURPOSE Androgen deprivation therapy (ADT), an important treatment for advanced prostate cancer, is highly variable in its effectiveness. We hypothesized that genetic variants of androgen transporter genes, SLCO2B1 and SLCO1B3, may determine time to progression on ADT. PATIENTS AND METHODS A cohort of 538 patients with prostate cancer treated with ADT was genotyped for SLCO2B1 and SLCO1B3 single nucleotide polymorphisms (SNP). The biologic function of a SLCO2B1 coding SNP in transporting androgen was examined through biochemical assays. RESULTS Three SNPs in SLCO2B1 were associated with time to progression (TTP) on ADT (P < .05). The differences in median TTP for each of these polymorphisms were about 10 months. The SLCO2B1 genotype, which allows more efficient import of androgen, enhances cell growth and is associated with a shorter TTP on ADT. Patients carrying both SLCO2B1 and SLCO1B3 genotypes, which import androgens more efficiently, exhibited a median 2-year shorter TTP on ADT, demonstrating a gene-gene interaction (P(interaction) = .041). CONCLUSION Genetic variants of SLCO2B1 and SLCO1B3 may function as pharmacogenomic determinants of resistance to ADT in prostate cancer.

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

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.

The Role of Genetic Markers in the Management of Prostate Cancer

CONTEXT Despite widespread screening for prostate cancer (PCa) and major advances in the treatment of metastatic disease, PCa remains the second most common cause of cancer death for men in the Western world. In addition, the use of prostate-specific antigen testing has led to the diagnosis of many potentially indolent cancers, and aggressive treatment of these cancers has caused significant morbidity without clinical benefit in many cases. The recent discoveries of inherited and acquired genetic markers associated with PCa initiation and progression provide an opportunity to apply these findings to guide clinical decision making. OBJECTIVE In this review, we discuss the potential use of genetic markers to better define groups of men at high risk of developing PCa, to improve screening techniques, to discriminate indolent versus aggressive disease, and to improve therapeutic strategies in patients with advanced disease. EVIDENCE ACQUISITION PubMed-based literature searches and abstracts through January 2012 provided the basis for this literature review. We also examined secondary sources from reference lists of retrieved articles and data presented at recent congresses. Cited review articles are only from the years 2007-2012, favoring more recent discussions because of the rapidly changing field. Original research articles were curated based on favoring large sample sizes, independent validation, frequent citations, and basic science directly related to potentially clinically relevant prognostic or predictive markers. In addition, all authors on the manuscript evaluated and interpreted the data acquired. EVIDENCE SYNTHESIS We address the use of inherited genetic variants to assess risk of PCa development, risk of advanced disease, and duration of response to hormonal therapies. The potential for using urine measurements such as prostate cancer antigen 3 (PCA3) RNA and the transmembrane protease, serine 2 v-ets erythroblastosis virus E26 oncogene homolog (avian) (TMPRSS2-ERG) gene fusion to aid screening is discussed. Multiple groups have developed gene expression signatures from primary prostate tumors correlating with poor prognosis, and attempts to improve and standardize these signatures as diagnostic tests are presented. Massive sequencing efforts are underway to define important somatic genetic alterations (amplifications, deletions, point mutations, translocations) in PCa, and these alterations hold great promise as prognostic markers and for predicting response to therapy. We provide a rationale for assessing genetic markers in metastatic disease for guiding choice of therapy and for stratifying patients in clinical trials, and discuss challenges in clinical trial design incorporating the use of these markers. CONCLUSIONS The use of genetic markers has the potential to aid disease screening, improve prognostic discrimination, and prediction of response to treatment. However, most markers have not been prospectively validated for providing useful prognostic or predictive information or improvement upon clinicopathologic parameters already in use. Significant efforts are underway to develop these research findings into clinically useful diagnostic tests in order to improve clinical decision making.

Inherited Variation in the Androgen Pathway Is Associated With the Efficacy of Androgen-Deprivation Therapy in Men With Prostate Cancer

PURPOSE Androgen-deprivation therapy (ADT) is the most common and effective systemic therapy for advanced prostate cancer. We hypothesized that germline genetic variation in the androgen axis would improve the efficacy of ADT. PATIENTS AND METHODS A cohort of 529 men with advanced prostate cancer treated with ADT was genotyped for 129 DNA polymorphisms distributed across 20 genes involved in androgen metabolism. RESULTS Three polymorphisms in separate genes (CYP19A1, HSD3B1, and HSD17B4) were significantly (P < .01) associated with time to progression (TTP) during ADT, remaining so in multivariate analyses and after correcting for the number of hypotheses tested. Individuals carrying more than one of the polymorphisms associated with improved TTP demonstrated a better response to therapy than individuals carrying zero or one (P < .0001). CONCLUSION This report is the first to examine the influence of inherited variation in the androgen metabolic pathway on the efficacy of ADT, establishing the importance of pharmacogenomics on individuals response to this therapy. At least two potential clinical benefits may be realized from this study. The first is prognostic -genotyping patients at these loci may yield important information that could improve efficacy prediction. The second is therapeutic -these results shed light on the pathways that govern response to ADT. Drugs could be developed (or may already exist) to inhibit or augment these targets to improve ADT efficacy.

Efficacy of androgen deprivation therapy (ADT) in patients with advanced prostate cancer: association between Gleason score, prostate-specific antigen level, and prior ADT exposure with duration of ADT effect.

The purpose of this study was to compare predictive factors for the efficacy of androgen deprivation therapy (ADT) in men with hormone‐sensitive prostate cancer (HSPC) either with (M+) or without (M−) metastases.

The androgen receptor cistrome is extensively reprogrammed in human prostate tumorigenesis

Master transcription factors interact with DNA to establish cell type identity and to regulate gene expression in mammalian cells. The genome-wide map of these transcription factor binding sites has been termed the cistrome. Here we show that the androgen receptor (AR) cistrome undergoes extensive reprogramming during prostate epithelial transformation in man. Using human prostate tissue, we observed a core set of AR binding sites that are consistently reprogrammed in tumors. FOXA1 and HOXB13 colocalized at the reprogrammed AR binding sites in human tumor tissue. Introduction of FOXA1 and HOXB13 into an immortalized prostate cell line reprogrammed the AR cistrome to resemble that of a prostate tumor, functionally linking these specific factors to AR cistrome reprogramming. These findings offer mechanistic insights into a key set of events that drive normal prostate epithelium toward transformation and establish the centrality of epigenetic reprogramming in human prostate tumorigenesis.

Time to prostate-specific antigen nadir independently predicts overall survival in patients who have metastatic hormone-sensitive prostate cancer treated with androgen-deprivation therapy.

The objective of this study was to evaluate the relation between the kinetics of prostate‐specific antigen (PSA) decline after the initiation of androgen‐deprivation therapy (ADT) and overall survival (OS) in men with metastatic, hormone‐sensitive prostate cancer (HSPC).