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Genomic analysis of HPV-positive versus HPV-negative oesophageal adenocarcinoma identifies a differential mutational landscape
  1. Shanmugarajah Rajendra1,2,3,
  2. Bin Wang1,2,
  3. Neil Merrett4,5,
  4. Prateek Sharma6,
  5. Jeremy Humphris3,
  6. Hong Ching Lee7,8,
  7. Jianmin Wu7,8
  1. 1Gastro-Intestinal Viral Oncology Group, Ingham Institute for Applied Medical Research, Sydney, New South Wales, Australia
  2. 2South Western Sydney Clinical School, University of New South Wales, Sydney, New South Wales, Australia
  3. 3Department of Gastroenterology & Hepatology, Bankstown-Lidcombe Hospital, South Western Sydney Local Health Network, Sydney, New South Wales, Australia
  4. 4Department of Surgery, Bankstown Hospital,  Sydney, New South Wales, Australia
  5. 5Discipline of Surgery, University of Western Sydney, Campbelltown, New South Wales, Australia
  6. 6Division of Gastroenterology and Hepatology, Veterans Affairs Medical Center and University of Kansas City, Kansas City, Missouri, USA
  7. 7Kinghorn Cancer Centre & Cancer Division, Garvan Institute of Medical Research, Sydney, New South Wales, Australia
  8. 8St Vincent's Clinical School, University of New South Wales Sydney, New South Wales, Australia
  1. Correspondence to Professor Shanmugarajah Rajendra, Department of Gastroenterology & Hepatology, Bankstown-Lidcombe Hospital, South Western Sydney Local Health Network, Bankstown, Sydney, New South Wales 2200, Australia; Shan.Rajendra{at}sswahs.nsw.gov.au Bin Wang, Gastro-Intestinal Viral Oncology Group, Ingham Institute for Applied Medical Research, Liverpool, Sydney, New South Wales, 2170, Australia; bin.wang1{at}unsw.edu.au Jianmin Wu, Kinghorn Cancer Centre & Cancer Division, Garvan Institute of Medical Research, Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia; j.wu{at}garvan.org.au

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.

  • Cancer: oesophageal
  • Clinical genetics
  • Infection

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