title: Neuroendocrine Merkel cell carcinoma is associated with mutations in key DNA repair, epigenetic and apoptosis pathways: a case-based study using targeted massively parallel sequencing.
abstract: BACKGROUND
  Merkel cell carcinoma (MCC) is a rare neuroendocrine carcinoma with a poorly understood molecular etiology. We implemented a comprehensive deep sequencing approach to identify mutations in the tumor DNA from a cohort of patients treated at our institution over the past 15 years. Our results indicate mutations that may constitute therapeutic targets in MCC.
  
  
  METHODS
  Five patients were treated for MCC within the study interval. Patients with adequate tissue (n = 4), positive neuroendocrine differentiation (chromogranin, synaptophysin, and cytokeratin 20), and histopathological confirmation of MCC were included in the study. DNA was extracted from archival tumor tissue samples and analyzed by massively parallel sequencing using a targeted, multiplex PCR approach followed by semiconductor sequencing.
  
  
  RESULTS
  We demonstrate high-penetrance nonsense mutations in PDE4DIP (n = 4) as well as various missense mutations in the DNA damage response (PRKDC, AURKB, ERCC5, ATR, and ATRX) and epigenetic modulating enzymes (MLL3).
  
  
  CONCLUSIONS
  We describe several mutations in potential disease-relevant genes and pathways. These targets should be evaluated in a larger cohort to determine their role in the molecular pathogenesis of MCC.
authors.affiliation: University of South Carolina School of Medicine, Columbia, S.C., USA.
authors.forename: Christian A
authors.initials: CA
authors.lastname: Graves
authors.forename: Ashley
authors.initials: A
authors.lastname: Jones
authors.forename: Justin
authors.initials: J
authors.lastname: Reynolds
authors.forename: Jeremy
authors.initials: J
authors.lastname: Stuart
authors.forename: Lucia
authors.initials: L
authors.lastname: Pirisi
authors.forename: Peter
authors.initials: P
authors.lastname: Botrous
authors.forename: James
authors.initials: J
authors.lastname: Wells
mesh_terms: D000369:Aged, 80 and over; D017209:Apoptosis / Q000235:genetics; D015266:Carcinoma, Merkel Cell / Q000235:genetics* / Q000473:pathology; D018278:Carcinoma, Neuroendocrine / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D004260:DNA Repair; D044127:Epigenesis, Genetic; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D012189:Retrospective Studies; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D044465:White People / Q000235:genetics