title: Comprehensive serial molecular profiling of an "N of 1" exceptional non-responder with metastatic prostate cancer progressing to small cell carcinoma on treatment.
abstract: OBJECTIVE
  Small cell carcinoma/neuroendocrine prostate cancer (NePC) is a lethal, poorly understood prostate cancer (PCa) subtype. Controversy exists about the origin of NePC in this setting.
  
  
  OBJECTIVE
  To molecularly profile archived biopsy specimens from a case of early-onset PCa that rapidly progressed to NePC to identify drivers of the aggressive course and mechanisms of NePC origin and progression.
  
  
  METHODS
  A 47-year-old patient presented with metastatic prostatic adenocarcinoma (Gleason score 9). After a 6-month response to androgen deprivation therapy, the patient developed jaundice and liver biopsy revealed exclusively NePC. Targeted next generation sequencing (NGS) from formalin-fixed paraffin-embedded (FFPE)-isolated DNA was performed from the diagnostic prostate biopsy and the liver biopsy at progression.
  
  
  METHODS
  Androgen deprivation therapy for adenocarcinoma followed by multiagent chemotherapy for NePC.
  
  
  METHODS
  Identification of the mutational landscape in primary adenocarcinoma and NePC liver metastasis. Whether the NePC arose independently or was derived from the primary adenocarcinoma was considered based on mutational profiles.
  
  
  RESULTS
  A deleterious somatic SMAD4 L535fs variant was present in both prostate and liver specimens; however, a TP53 R282W mutation was exclusively enriched in the liver specimen. Copy number analysis identified concordant, low-level alterations in both specimens, with focal MYCL amplification and homozygous PTEN, RB1, and MAP2K4 losses identified exclusively in the NePC specimen. Integration with published genomic profiles identified MYCL as a recurrently amplified in NePC.
  
  
  CONCLUSIONS
  NGS of routine biopsy samples from an exceptional non-responder identified SMAD4 as a driver of the aggressive course and supports derivation of NePC from primary adenocarcinoma (transdifferentiation).
authors.affiliation: Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, 7216 Cancer Center, SPC 5948, 1500 East Medical Center Drive, Ann Arbor, MI, 48109, USA. kkadakia@med.umich.edu.
authors.forename: Kunal C
authors.initials: KC
authors.lastname: Kadakia
authors.affiliation: Department of Pathology and Urology, Michigan Center for Translational Pathology; University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, 48109, USA. tomlinss@umich.edu.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Tomlins
authors.affiliation: Boonshoft School of Medicine, Wright State University, Dayton, USA. saagar.sanghvi@wright.edu.
authors.forename: Saagar K
authors.initials: SK
authors.lastname: Sanghvi
authors.affiliation: Department of Pathology, Michigan Center for Translational Pathology, Ann Arbor, MI, 48109, USA. andicani@med.umich.edu.
authors.forename: Andi K
authors.initials: AK
authors.lastname: Cani
authors.affiliation: Department of Pathology, Michigan Center for Translational Pathology, Ann Arbor, MI, 48109, USA. komata@med.umich.edu.
authors.forename: Kei
authors.initials: K
authors.lastname: Omata
authors.affiliation: Department of Pathology, Michigan Center for Translational Pathology, Ann Arbor, MI, 48109, USA. dhovelso@med.umich.edu.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Hovelson
authors.affiliation: Department of Pathology, Michigan Center for Translational Pathology, Ann Arbor, MI, 48109, USA. liuchiaj@med.umich.edu.
authors.forename: Chia-Jen
authors.initials: CJ
authors.lastname: Liu
authors.affiliation: Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, 7216 Cancer Center, SPC 5948, 1500 East Medical Center Drive, Ann Arbor, MI, 48109, USA. kcooney@med.umich.edu.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Cooney
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000726:Androgen Antagonists / Q000627:therapeutic use*; D018288:Carcinoma, Small Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D054338:Cell Transdifferentiation / Q000235:genetics; D018450:Disease Progression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051901:Smad4 Protein / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D000726:Androgen Antagonists; C497796:SMAD4 protein, human; D051901:Smad4 Protein