Dataset Information

Combined Tumor Suppressor Defects Characterize Clinically Defined Aggressive Variant Prostate Cancers.

ABSTRACT: PURPOSE:Morphologically heterogeneous prostate cancers that behave clinically like small-cell prostate cancers (SCPC) share their chemotherapy responsiveness. We asked whether these clinically defined, morphologically diverse, "aggressive variant prostate cancer (AVPC)" also share molecular features with SCPC. EXPERIMENTAL DESIGN:Fifty-nine prostate cancer samples from 40 clinical trial participants meeting AVPC criteria, and 8 patient-tumor derived xenografts (PDX) from 6 of them, were stained for markers aberrantly expressed in SCPC. DNA from 36 and 8 PDX was analyzed by Oncoscan for copy number gains (CNG) and losses (CNL). We used the AVPC PDX to expand observations and referenced publicly available datasets to arrive at a candidate molecular signature for the AVPC. RESULTS:Irrespective of morphology, Ki67 and Tp53 stained ?10% cells in 80% and 41% of samples, respectively. RB1 stained <10% cells in 61% of samples and AR in 36%. MYC (surrogate for 8q) CNG and RB1 CNL showed in 54% of 44 samples each and PTEN CNL in 48%. All but 1 of 8 PDX bore Tp53 missense mutations. RB1 CNL was the strongest discriminator between unselected castration-resistant prostate cancer (CRPC) and the AVPC. Combined alterations in RB1, Tp53, and/or PTEN were more frequent in the AVPC than in unselected CRPC and in The Cancer Genome Atlas samples. CONCLUSIONS:Clinically defined AVPC share molecular features with SCPC and are characterized by combined alterations in RB1, Tp53, and/or PTEN.

SUBMITTER: Aparicio AM

PROVIDER: S-EPMC4794379 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Combined Tumor Suppressor Defects Characterize Clinically Defined Aggressive Variant Prostate Cancers.

Aparicio Ana M AM Shen Li L Tapia Elsa Li Ning EL Lu Jing-Fang JF Chen Hsiang-Chun HC Zhang Jiexin J Wu Guanglin G Wang Xuemei X Troncoso Patricia P Corn Paul P Thompson Timothy C TC Broom Bradley B Baggerly Keith K Maity Sankar N SN Logothetis Christopher J CJ

Clinical cancer research : an official journal of the American Association for Cancer Research 20151106 6

<h4>Purpose</h4>Morphologically heterogeneous prostate cancers that behave clinically like small-cell prostate cancers (SCPC) share their chemotherapy responsiveness. We asked whether these clinically defined, morphologically diverse, "aggressive variant prostate cancer (AVPC)" also share molecular features with SCPC.<h4>Experimental design</h4>Fifty-nine prostate cancer samples from 40 clinical trial participants meeting AVPC criteria, and 8 patient-tumor derived xenografts (PDX) from 6 of them ...[more]

PMID: 26546618

Similar Datasets

Project description:Progression of conventional urothelial carcinoma of the bladder to a tumor with unique microscopic features referred to as micropapillary carcinoma is coupled with aggressive clinical behavior signified by a high propensity for metastasis to regional lymph nodes and distant organs resulting in shorter survival.To analyze the expression profile of micropapillary cancer and define its molecular features relevant to clinical behavior.We retrospectively identified 43 patients with micropapillary bladder cancers and a reference set of 89 patients with conventional urothelial carcinomas and performed whole-genome expression messenger RNA profiling.The tumors were segregated into distinct groups according to hierarchical clustering analyses. They were also classified according to luminal, p53-like, and basal categories using a previously described algorithm. We applied Ingenuity Pathway Analysis software (Qiagen, Redwood City, CA, USA) and gene set enrichment analysis for pathway analyses. Cox proportional hazards models and Kaplan-Meier methods were used to assess the relationship between survival and molecular subtypes. The expression profile of micropapillary cancer was validated for selected markers by immunohistochemistry on parallel tissue microarrays.We show that the striking features of micropapillary cancer are downregulation of miR-296 and activation of chromatin-remodeling complex RUVBL1. In contrast to conventional urothelial carcinomas that based on their expression can be equally divided into luminal and basal subtypes, micropapillary cancer is almost exclusively luminal, displaying enrichment of active peroxisome proliferator-activated receptor ? and suppression of p63 target genes. As with conventional luminal urothelial carcinomas, a subset of micropapillary cancers exhibit activation of wild-type p53 downstream genes and represent the most aggressive molecular subtype of the disease with the shortest survival. The involvement of miR-296 and RUVBL1 in the development of micropapillary bladder cancer was identified by the analyses of correlative associations of genome expression profiles and requires mechanistic validation.Micropapillary cancer evolves through the luminal pathway and is characterized by the activation of miR-296 and RUVBL1 target genes.Our observations have important implications for prognosis and for possible future development of more effective therapies for micropapillary bladder cancer.

Dataset Information

Combined Tumor Suppressor Defects Characterize Clinically Defined Aggressive Variant Prostate Cancers.

Publications

Combined Tumor Suppressor Defects Characterize Clinically Defined Aggressive Variant Prostate Cancers.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure