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

Morphologically heterogeneous prostate cancers (PC) that behave clinically like small cell PC (SCPC) share their chemotherapy responsiveness. We asked whether these clinically defined, morphologically diverse, 'aggressive variant PC' (AVPC) also share molecular features with SCPC.

59 PC 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 data sets to arrive at a candidate molecular signature for the AVPC.

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 PC (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.

Clinically defined AVPC share molecular features with SCPC and are characterized by combined alterations in RB1, Tp53 and/or PTEN.

Clinical cancer research : an official journal of the American Association for Cancer Research. 2015 Nov 06 [Epub ahead of print]

Ana M Aparicio, Li Shen, Elsa M Li Ning Tapia, Jing-Fang Lu, Hsiang-Chun Chen, Jiexin Zhang, Guanglin Wu, Xuemei Wang, Patricia Troncoso, Paul Corn, Timothy C Thompson, Bradley Broom, Keith A Baggerly, Sankar N Maity, Christopher Logothetis

Genitourinary Medical Oncology, UT MD Anderson Cancer Center, Bioinformatics & Comp Biology, UT MD Anderson Cancer Center. , Department of Genitourinary Medical Oncology and David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas M. D. Anderson Cancer Center. , Department of Genitourinary Medical Oncology and David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas M. D. Anderson Cancer Center. , Biostatistics, MD Anderson Cancer Center. , Bioinformatics and Computational Biology, University of Texas, MD Anderson Cancer Centre. , Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center. , Biostatistics, The University of Texas M. D. Anderson Cancer Center. , Pathology, MD Anderson Cancer Center. , GU Medical Oncology, Unit 1374, MD Anderson. , Department of Genitourinary Medical Oncology - Research, UT MD Anderson Cancer Center. , Bioinformatics and Computational Biology, University of Texas, MD Anderson Cancer Centre. , Department of Bioinformatics Computer Biology, The University of Texas M. D. Anderson Cancer Center. , Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center. , Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center.

PubMed