title: Combined Tumor Suppressor Defects Characterize Clinically Defined Aggressive Variant Prostate Cancers.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. aaparicio@mdanderson.org.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Aparicio
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Li
authors.initials: L
authors.lastname: Shen
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Elsa Li Ning
authors.initials: EL
authors.lastname: Tapia
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jing-Fang
authors.initials: JF
authors.lastname: Lu
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Hsiang-Chun
authors.initials: HC
authors.lastname: Chen
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jiexin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Guanglin
authors.initials: G
authors.lastname: Wu
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Patricia
authors.initials: P
authors.lastname: Troncoso
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Paul
authors.initials: P
authors.lastname: Corn
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Thompson
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Bradley
authors.initials: B
authors.lastname: Broom
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Human and Molecular Genetics Program, The University of Texas Graduate School of Biomedical Sciences, Houston, Texas.
authors.forename: Keith
authors.initials: K
authors.lastname: Baggerly
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Clinical and Translational Sciences Graduate Program, The University of Texas Graduate School of Biomedical Sciences, Houston, Texas.
authors.forename: Sankar N
authors.initials: SN
authors.lastname: Maity
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Logothetis
mesh_terms: D014408:Biomarkers, Tumor; D001706:Biopsy; D016000:Cluster Analysis; D056915:DNA Copy Number Variations; D018450:Disease Progression; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009154:Mutation; D009367:Neoplasm Staging; D011471:Prostatic Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D011944:Receptors, Androgen; D025521:Tumor Suppressor Proteins