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The genomic complexity of primary human prostate cancer.

ABSTRACT: Prostate cancer is the second most common cause of male cancer deaths in the United States. However, the full range of prostate cancer genomic alterations is incompletely characterized. Here we present the complete sequence of seven primary human prostate cancers and their paired normal counterparts. Several tumours contained complex chains of balanced (that is, 'copy-neutral') rearrangements that occurred within or adjacent to known cancer genes. Rearrangement breakpoints were enriched near open chromatin, androgen receptor and ERG DNA binding sites in the setting of the ETS gene fusion TMPRSS2-ERG, but inversely correlated with these regions in tumours lacking ETS fusions. This observation suggests a link between chromatin or transcriptional regulation and the genesis of genomic aberrations. Three tumours contained rearrangements that disrupted CADM2, and four harboured events disrupting either PTEN (unbalanced events), a prostate tumour suppressor, or MAGI2 (balanced events), a PTEN interacting protein not previously implicated in prostate tumorigenesis. Thus, genomic rearrangements may arise from transcriptional or chromatin aberrancies and engage prostate tumorigenic mechanisms.

SUBMITTER: Berger MF

PROVIDER: S-EPMC3075885 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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The genomic complexity of primary human prostate cancer.

Berger Michael F MF Lawrence Michael S MS Demichelis Francesca F Drier Yotam Y Cibulskis Kristian K Sivachenko Andrey Y AY Sboner Andrea A Esgueva Raquel R Pflueger Dorothee D Sougnez Carrie C Onofrio Robert R Carter Scott L SL Park Kyung K Habegger Lukas L Ambrogio Lauren L Fennell Timothy T Parkin Melissa M Saksena Gordon G Voet Douglas D Ramos Alex H AH Pugh Trevor J TJ Wilkinson Jane J Fisher Sheila S Winckler Wendy W Mahan Scott S Ardlie Kristin K Baldwin Jennifer J Simons Jonathan W JW Kitabayashi Naoki N MacDonald Theresa Y TY Kantoff Philip W PW Chin Lynda L Gabriel Stacey B SB Gerstein Mark B MB Golub Todd R TR Meyerson Matthew M Tewari Ashutosh A Lander Eric S ES Getz Gad G Rubin Mark A MA Garraway Levi A LA

Nature 20110201 7333

Prostate cancer is the second most common cause of male cancer deaths in the United States. However, the full range of prostate cancer genomic alterations is incompletely characterized. Here we present the complete sequence of seven primary human prostate cancers and their paired normal counterparts. Several tumours contained complex chains of balanced (that is, 'copy-neutral') rearrangements that occurred within or adjacent to known cancer genes. Rearrangement breakpoints were enriched near ope ...[more]

PMID: 21307934

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Project description:Ultraconserved regions (UCR) are genomic segments of more than 200 base pairs that are evolutionarily conserved among mammalian species. They are thought to have functions as transcriptional enhancers and regulators of alternative splicing. Recently, it was shown that numerous RNAs are transcribed from these regions. These UCR-encoded transcripts (ucRNAs) were found to be expressed in a tissue- and disease-specific manner and may interfere with the function of other RNAs through RNA: RNA interactions. We hypothesized that ucRNAs have unidentified roles in the pathogenesis of human prostate cancer. In a pilot study, we examined ucRNA expression profiles in human prostate tumors.Using a custom microarray with 962 probesets representing sense and antisense sequences for the 481 human UCRs, we examined ucRNA expression in resected, fresh-frozen human prostate tissues (57 tumors, 7 non-cancerous prostate tissues) and in cultured prostate cancer cells treated with either epigenetic drugs (the hypomethylating agent, 5-Aza 2'deoxycytidine, and the histone deacetylase inhibitor, trichostatin A) or a synthetic androgen, R1881. Expression of selected ucRNAs was also assessed by qRT-PCR and NanoString®-based assays. Because ucRNAs may function as RNAs that target protein-coding genes through direct and inhibitory RNA: RNA interactions, computational analyses were applied to identify candidate ucRNA:mRNA binding pairs.We observed altered ucRNA expression in prostate cancer (e.g., uc.106+, uc.477+, uc.363 + A, uc.454 + A) and found that these ucRNAs were associated with cancer development, Gleason score, and extraprostatic extension after controlling for false discovery (false discovery rate < 5% for many of the transcripts). We also identified several ucRNAs that were responsive to treatment with either epigenetic drugs or androgen (R1881). For example, experiments with LNCaP human prostate cancer cells showed that uc.287+ is induced by R1881 (P < 0.05) whereas uc.283 + A was up-regulated following treatment with combined 5-Aza 2'deoxycytidine and trichostatin A (P < 0.05). Additional computational analyses predicted RNA loop-loop interactions of 302 different sense and antisense ucRNAs with 1058 different mRNAs, inferring possible functions of ucRNAs via direct interactions with mRNAs.This first study of ucRNA expression in human prostate cancer indicates an altered transcript expression in the disease.

Dataset Information

The genomic complexity of primary human prostate cancer.

Publications

The genomic complexity of primary human prostate cancer.

Similar Datasets

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