Summary We report a comprehensive analysis of 412 muscle-invasive bladder cancers characterized by multiple TCGA analytical platforms. Fifty-eight genes were significantly mutated, and the overall mutational load was associated with APOBEC-signature mutagenesis. Clustering by mutation signature identified a high-mutation subset with 75% 5-year survival. mRNA expression clustering refined prior clustering analyses and identified a poor-survival ‘neuronal’ subtype in which the majority of tumors lacked small cell or neuroendocrine histology. Clustering by mRNA, lncRNA, and miRNA expression converged to identify subsets with differential epithelial-mesenchymal transition status, carcinoma-in-situ scores, histologic features, and survival. Our analyses identified 5 expression subtypes that may stratify response to different treatments.

Prostate cancer (PCA) is one of the most prevalent cancers and a major leading cause of morbidity and mortality in the Western world. The TMPRSS2-ERG fusion was recently identified as a common recurrent chromosomal aberration in this malignancy. In our study, we interrogated a broad spectrum of benign, precursor, and malignant prostatic lesions to assess the TMPRSS2-ERG fusion status using a multicolor interphase fluorescence in situ hybridization assay. Samples from hospital-based cohorts consisted of 237 clinically localized PCA, 34 hormone naive metastases, 9 hormone refractory metastases, 26 high grade prostatic intraepithelial neoplasia lesions, 15 samples of benign prostatic hyperplasia, 38 of proliferative inflammatory atrophy, and 47 of benign prostatic tissue. The TMPRSS2-ERG fusion was present in 48.5% of clinically localized PCA, 30% of hormone naive metastases, 33% of hormone refractory metastases, and in 19% of high grade prostatic intraepithelial neoplasia lesions in intermingling to cancer foci. Almost all these fusion positive cases show a homogenous distribution of the fusion pattern. In contrast, none of the other samples harbored this genetic aberration. If we consider the high incidence of PCA and the high frequency of this gene fusion, TMPRSS2-ERG is the most common genetic aberration so far described in human malignancies. Furthermore, its clinical application as a biomarker and ancillary diagnostic test is promising given its high specificity.

Models of bladder tumor progression have suggested that genetic alterations may determine both phenotype and clinical course.We have applied expression microarray analysis to a divergent set of bladder tumors to further elucidate the course of disease progression and to classify tumors into more homogeneous and clinically relevant subgroups. cDNA microarrays containing 10,368 human gene elements were used to characterize the global gene expression patterns in 80 bladder tumors, 9 bladder cancer cell lines, and 3 normal bladder samples. Robust statistical approaches accounting for the multiple testing problem were used to identify differentially expressed genes. Unsupervised hierarchical clustering successfully separated the samples into two subgroups containing superficial (pT a and pT 1 ) versus muscle-invasive (pT 2 -pT 4 ) tumors. Supervised classification had a 90.5% success rate separating superficial from muscle-invasive tumors based on a limited subset of genes. Tumors could also be classified into transitional versus squamous subtypes (89% success rate) and good versus bad prognosis (78% success rate). The performance of our stage classifiers was confirmed in silico using data from an independent tumor set. Validation of differential expression was done using immunohistochemistry on tissue microarrays for cathepsin E, cyclin A2, and parathyroid hormone^related protein. Genes driving the separation between tumor subsets may prove to be important biomarkers for bladder cancer development and progression and eventually candidates for therapeutic targeting.

Recent prostate-specific antigen-based screening trials indicate an urgent need for novel and noninvasive biomarker identification strategies to improve the prediction of prostate cancer behavior. Noncoding microRNAs (miRNA) in the serum and plasma have been shown to have potential as noninvasive markers for physiologic and pathologic conditions. To identify serum miRNAs that diagnose and correlate with the prognosis of prostate cancer, we developed a multiplex quantitative reverse transcription PCR method involving the purification of multiplex PCR products followed by uniplex analysis on a microfluidics chip to evaluate 384 human miRNAs. Using Dgcr8 and Dicer knockout (small RNA-deficient) mouse ES cells as the benchmark, we confirmed the validity of our technique and uncovered a considerable lack of accuracy in previously published methods. Profiling 48 sera from healthy men and untreated prostate cancer patients with differing CAPRA scores, we identified miRNA signatures that allow us to diagnose cancer patients and correlate with a prognosis. These serum signatures include oncogenic and tumor-suppressive miRNAs, suggesting functional roles in prostate cancer progression. Cancer Res; 71(2); 550-60. Ó2010 AACR.

Epidemiological and prospective studies indicate that comprehensive lifestyle changes may modify the progression of prostate cancer. However, the molecular mechanisms by which improvements in diet and lifestyle might affect the prostate microenvironment are poorly understood. We conducted a pilot study to examine changes in prostate gene expression in a unique population of men with low-risk prostate cancer who declined immediate surgery, hormonal therapy, or radiation and participated in an intensive nutrition and lifestyle intervention while undergoing careful surveillance for tumor progression. Consistent with previous studies, significant improvements in weight, abdominal obesity, blood pressure, and lipid profile were observed (all P < 0.05), and surveillance of low-risk patients was safe. Gene expression profiles were obtained from 30 participants, pairing RNA samples from control prostate needle biopsy taken before intervention to RNA from the same patient's 3-month postintervention biopsy. Quantitative real-time PCR was used to validate array observations for selected transcripts. Two-class paired analysis of global gene expression using significance analysis of microarrays detected 48 up-regulated and 453 down-regulated transcripts after the intervention. Pathway analysis identified significant modulation of biological processes that have critical roles in tumorigenesis, including protein metabolism and modification, intracellular protein traffic, and protein phosphorylation (all P < 0.05). Intensive nutrition and lifestyle changes may modulate gene expression in the prostate. Understanding the prostate molecular response to comprehensive lifestyle changes may strengthen efforts to develop effective prevention and treatment. Larger clinical trials are warranted to confirm the results of this pilot study.exercise ͉ lifestyle changes ͉ prostate cancer ͉ SHOC2 ͉ stress management E pidemiological evidence (1, 2) and migrant studies (3) indicate that the incidence of clinically significant prostate cancer is much lower in parts of the world where people eat a predominantly low-fat, plant-based diet. We (4, 5) and others (6) have shown previously that diet and lifestyle interventions in men with earlystage prostate cancer decrease prostate-specific antigen (PSA) and decrease the rate of PSA increase. These studies provided some evidence that comprehensive lifestyle changes may have therapeutic potential in early prostate cancers. However, although these interventions are associated with decreased circulating insulin-like growth factor 1 (IGF1) (7), and although serum from men after intervention has reduced the ability to stimulate prostate cell-line growth in vitro (4), the actual molecular effects of these interventions in prostate tissue have not been previously examined.Many men with indolent prostate cancers detected by PSA screening will not exhibit disease progression during their lifetime; their treatment and associated side effects are unnecessary (8). We report here the results of the Gene Expressio...