Data from Combined Tumor Suppressor Defects Characterize Clinically Defined Aggressive Variant Prostate Cancers

Abstract

<div>Abstract<p><b>Purpose:</b> 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.</p><p><b>Experimental Design:</b> 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.</p><p><b>Results:</b> 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%. <i>MYC</i> (surrogate for 8q) CNG and <i>RB1</i> CNL showed in 54% of 44 samples each and <i>PTEN</i> CNL in 48%. All but 1 of 8 PDX bore Tp53 missense mutations. <i>RB1</i> CNL was the strongest discriminator between unselected castration-resistant prostate cancer (CRPC) and the AVPC. Combined alterations in <i>RB1</i>, <i>Tp53</i>, and/or <i>PTEN</i> were more frequent in the AVPC than in unselected CRPC and in The Cancer Genome Atlas samples.</p><p><b>Conclusions:</b> Clinically defined AVPC share molecular features with SCPC and are characterized by combined alterations in <i>RB1</i>, <i>Tp53</i>, and/or <i>PTEN</i>. <i>Clin Cancer Res; 22(6); 1520–30. ©2015 AACR</i>.</p></div>