Dataset Information

Integrated genome and transcriptome sequencing identifies a novel form of hybrid and aggressive prostate cancer.

ABSTRACT: Next-generation sequencing is making sequence-based molecular pathology and personalized oncology viable. We selected an individual initially diagnosed with conventional but aggressive prostate adenocarcinoma and sequenced the genome and transcriptome from primary and metastatic tissues collected prior to hormone therapy. The histology-pathology and copy number profiles were remarkably homogeneous, yet it was possible to propose the quadrant of the prostate tumour that likely seeded the metastatic diaspora. Despite a homogeneous cell type, our transcriptome analysis revealed signatures of both luminal and neuroendocrine cell types. Remarkably, the repertoire of expressed but apparently private gene fusions, including C15orf21:MYC, recapitulated this biology. We hypothesize that the amplification and over-expression of the stem cell gene MSI2 may have contributed to the stable hybrid cellular identity. This hybrid luminal-neuroendocrine tumour appears to represent a novel and highly aggressive case of prostate cancer with unique biological features and, conceivably, a propensity for rapid progression to castrate-resistance. Overall, this work highlights the importance of integrated analyses of genome, exome and transcriptome sequences for basic tumour biology, sequence-based molecular pathology and personalized oncology.

SUBMITTER: Wu C

PROVIDER: S-EPMC3768138 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Integrated genome and transcriptome sequencing identifies a novel form of hybrid and aggressive prostate cancer.

Wu Chunxiao C Wyatt Alexander W AW Lapuk Anna V AV McPherson Andrew A McConeghy Brian J BJ Bell Robert H RH Anderson Shawn S Haegert Anne A Brahmbhatt Sonal S Shukin Robert R Mo Fan F Li Estelle E Fazli Ladan L Hurtado-Coll Antonio A Jones Edward C EC Butterfield Yaron S YS Hach Faraz F Hormozdiari Fereydoun F Hajirasouliha Iman I Boutros Paul C PC Bristow Robert G RG Jones Steven Jm SJ Hirst Martin M Marra Marco A MA Maher Christopher A CA Chinnaiyan Arul M AM Sahinalp S Cenk SC Gleave Martin E ME Volik Stanislav V SV Collins Colin C CC

The Journal of pathology 20120321 1

Next-generation sequencing is making sequence-based molecular pathology and personalized oncology viable. We selected an individual initially diagnosed with conventional but aggressive prostate adenocarcinoma and sequenced the genome and transcriptome from primary and metastatic tissues collected prior to hormone therapy. The histology-pathology and copy number profiles were remarkably homogeneous, yet it was possible to propose the quadrant of the prostate tumour that likely seeded the metastat ...[more]

PMID: 22294438

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Project description:Although prostate cancer typically runs an indolent course, a subset of men develop aggressive, fatal forms of this disease. We hypothesize that germline variation modulates susceptibility to aggressive prostate cancer. The goal of this work is to identify susceptibility genes using the C57BL/6-Tg(TRAMP)8247Ng/J (TRAMP) mouse model of neuroendocrine prostate cancer. Quantitative trait locus (QTL) mapping was performed in transgene-positive (TRAMPxNOD/ShiLtJ) F2 intercross males (n = 228), which facilitated identification of 11 loci associated with aggressive disease development. Microarray data derived from 126 (TRAMPxNOD/ShiLtJ) F2 primary tumors were used to prioritize candidate genes within QTLs, with candidate genes deemed as being high priority when possessing both high levels of expression-trait correlation and a proximal expression QTL. This process enabled the identification of 35 aggressive prostate tumorigenesis candidate genes. The role of these genes in aggressive forms of human prostate cancer was investigated using two concurrent approaches. First, logistic regression analysis in two human prostate gene expression datasets revealed that expression levels of five genes (CXCL14, ITGAX, LPCAT2, RNASEH2A, and ZNF322) were positively correlated with aggressive prostate cancer and two genes (CCL19 and HIST1H1A) were protective for aggressive prostate cancer. Higher than average levels of expression of the five genes that were positively correlated with aggressive disease were consistently associated with patient outcome in both human prostate cancer tumor gene expression datasets. Second, three of these five genes (CXCL14, ITGAX, and LPCAT2) harbored polymorphisms associated with aggressive disease development in a human GWAS cohort consisting of 1,172 prostate cancer patients. This study is the first example of using a systems genetics approach to successfully identify novel susceptibility genes for aggressive prostate cancer. Such approaches will facilitate the identification of novel germline factors driving aggressive disease susceptibility and allow for new insights into these deadly forms of prostate cancer.

Dataset Information

Integrated genome and transcriptome sequencing identifies a novel form of hybrid and aggressive prostate cancer.

Publications

Integrated genome and transcriptome sequencing identifies a novel form of hybrid and aggressive prostate cancer.

Similar Datasets

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