Summary Increased androgen receptor (AR) activity drives therapeutic resistance in advanced prostate cancer. The most common resistance mechanism is amplification of this locus presumably targeting the AR gene. Here, we identify and characterize a somatically acquired AR enhancer located 650 kilobases centromeric to the AR. Systematic perturbation of this enhancer using genome editing decreased proliferation by suppressing AR levels. Insertion of an additional copy of this region sufficed to increase proliferation under low androgen conditions and to decrease sensitivity to enzalutamide. Epigenetic data generated in localized prostate tumors and benign specimens support the notion that this region is a developmental enhancer. Collectively, these observations underscore the importance of epigenomic profiling in primary specimens and the value of deploying genome editing to functionally characterize noncoding elements. More broadly, this work identifies a therapeutic vulnerability for targeting the AR and emphasizes the importance of regulatory elements as highly recurrent oncogenic drivers.
Background BRCA2-associated breast and ovarian cancers are sensitive to platinum-based chemotherapy. It is unknown whether BRCA2-associated prostate cancer responds favorably to such treatment. Methods Retrospective analysis of a single-institution cohort of men with castration-resistant metastatic prostate cancer was performed to determine the association between carrier status of pathogenic BRCA2 germline variants and prostate-specific antigen response to carboplatin-based chemotherapy. From 2001-2015, 8,081 adult men with prostate cancer seen in consultation and/or treated at Dana-Farber Cancer Institute provided blood samples and consented to analysis of biological material and clinical records. A subgroup of 141 received at least two doses of carboplatin and docetaxel for castration-resistant disease (94% were also taxane refractory). These subjects were categorized according to absence or presence of pathogenic germline mutations in BRCA2, based on DNA sequencing from whole blood. Primary outcome was response rate to carboplatin/docetaxel chemotherapy as defined by decline in prostate-specific antigen exceeding 50% within 12 weeks of initiating this regimen. Association between BRCA2 mutation status and response to carboplatin-based chemotherapy was tested, using Fisher’s exact test, with a two-sided p-value of <0.05 as threshold for significance. Results Pathogenic germline BRCA2 variants were observed in 8/141 (5.7%; 95% CI=2.5%-10.9%) participants. Six of eight (75%) BRCA2 carriers experienced prostate-specific antigen decline >50% within 12 weeks, compared to 23 of 133 (17%) non-carriers (absolute difference 58%; 95% CI=27%-88%; P<0.001). Prostate cancer cell lines functionally corroborate these clinical findings. Conclusions BRCA2-associated castration-resistant prostate cancer is associated with higher likelihood of response to carboplatin-based chemotherapy than non-BRCA2 associated prostate cancer.
Gene expression analysis of colon biopsies using high-density oligonucleotide microarrays can contribute to the understanding of local pathophysiological alterations and to functional classification of adenoma (15 samples), colorectal carcinomas (CRC) (15) and inflammatory bowel diseases (IBD) (14). Total RNA was extracted, amplified and biotinylated from frozen colonic biopsies. Genome-wide gene expression profile was evaluated by HGU133plus2 microarrays and verified by RT-PCR. We applied two independent methods for data normalization and used PAM for feature selection. Leave one-out stepwise discriminant analysis was performed. Top validated genes included collagenIVα1, lipocalin-2, calumenin, aquaporin-8 genes in CRC; CD44, met proto-oncogene, chemokine ligand-12, ADAM-like decysin-1 and ATP-binding casette-A8 genes in adenoma; and lipocalin-2, ubiquitin D and IFITM2 genes in IBD. Best differentiating markers between Ulcerative colitis and Crohn's disease were cyclin-G2; tripartite motif-containing-31; TNFR shedding aminopeptidase regulator-1 and AMICA. The discriminant analysis was able to classify the samples in overall 96.2% using 7 discriminatory genes (indoleamine-pyrrole-2,3-dioxygenase, ectodermal-neural cortex, TIMP3, fucosyltransferase-8, collectin sub-family member 12, carboxypeptidase D, and transglutaminase-2). Using routine biopsy samples we successfully performed whole genomic microarray analysis to identify discriminative signatures. Our results provide further insight into the pathophysiological background of colonic diseases. The results set up data warehouse which can be mined further.
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