title: Genomic analysis of HPV-positive versus HPV-negative oesophageal adenocarcinoma identifies a differential mutational landscape.
abstract: BACKGROUND
  High-risk human papillomavirus (hr-HPV) has been implicated in a subset of patients with oesophageal adenocarcinoma (OAC). We therefore hypothesised that HPV associated OAC may have distinct genomic aberrations compared with viral negative oesophageal cancer.
  
  
  METHODS
  Whole exome sequencing was performed to explore the mutational landscape and potential molecular signature of HPV-positive versus HPV-negative OAC. Four hr-HPV-positive and 8 HPV-negative treatment-naive fresh-frozen OAC tissue specimens and matched normal tissue were analysed to identify somatic genomic mutations. Data were subjected to cancer driver gene identification and pathway analysis.
  
  
  RESULTS
  The HPV-positive cohort harboured approximately 50% less non-silent somatic mutations than the virus-negative patients with oesophageal cancer (1.31 mutations/Mb vs 2.56 mutations/Mb, p=0.048). TP53 aberrations were absent in the HPV-positive OAC group whereas 50% of the HPV-negative patients with OAC exhibited TP53 mutations. HPV-negative cancers were enriched with non-silent mutations in cancer driver genes, but not HPV-positive tumours. Enriched A>C transversions at adenine-adenine (AA) dinucleotide was observed in 5/7 Siewert class I OAC samples but none (0/5) in Siewert class II tumours (p=0.027).
  
  
  CONCLUSIONS
  These findings demonstrate distinct genomic differences between HPV-positive and HPV-negative OACs indicating different biological mechanisms of tumour formation.
authors.affiliation: Gastro-Intestinal Viral Oncology Group, Ingham Institute for Applied Medical Research, Sydney, New South Wales, Australia South Western Sydney Clinical School, University of New South Wales, Sydney, New South Wales, Australia Department of Gastroenterology & Hepatology, Bankstown-Lidcombe Hospital, South Western Sydney Local Health Network, Sydney, New South Wales, Australia.
authors.forename: Shanmugarajah
authors.initials: S
authors.lastname: Rajendra
authors.affiliation: Gastro-Intestinal Viral Oncology Group, Ingham Institute for Applied Medical Research, Sydney, New South Wales, Australia South Western Sydney Clinical School, University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Surgery, Bankstown Hospital,  Sydney, New South Wales, Australia Discipline of Surgery, University of Western Sydney, Campbelltown, New South Wales, Australia.
authors.forename: Neil
authors.initials: N
authors.lastname: Merrett
authors.affiliation: Division of Gastroenterology and Hepatology, Veterans Affairs Medical Center and University of Kansas City, Kansas City, Missouri, USA.
authors.forename: Prateek
authors.initials: P
authors.lastname: Sharma
authors.affiliation: Department of Gastroenterology & Hepatology, Bankstown-Lidcombe Hospital, South Western Sydney Local Health Network, Sydney, New South Wales, Australia.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Humphris
authors.affiliation: Kinghorn Cancer Centre & Cancer Division, Garvan Institute of Medical Research, Sydney, New South Wales, Australia St Vincent's Clinical School, University of New South Wales Sydney, New South Wales, Australia.
authors.forename: Hong Ching
authors.initials: HC
authors.lastname: Lee
authors.affiliation: Kinghorn Cancer Centre & Cancer Division, Garvan Institute of Medical Research, Sydney, New South Wales, Australia St Vincent's Clinical School, University of New South Wales Sydney, New South Wales, Australia.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Wu
mesh_terms: D000368:Aged; D004252:DNA Mutational Analysis; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology / Q000821:virology; D059472:Exome / Q000235:genetics; D005260:Female; D015894:Genome, Human; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D027383:Papillomaviridae / Q000235:genetics* / Q000472:pathogenicity; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D016662:Virus Integration / Q000235:genetics*
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
keywords: Cancer: oesophageal; Clinical genetics; Infection