Genomic analysis of HPV-positive versus HPV-negative oesophageal adenocarcinoma identifies a differential mutational landscape
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.
|ISBN||1468-6244 (Electronic) 0022-2593 (Linking)|
|Authors||Rajendra, S. ; Wang, B. ; Merrett, N. ; Sharma, P. ; Humphris, J. ; Lee, H. C. ; Wu, J.;|
|Responsible Garvan Author|
|Publisher Name||JOURNAL OF MEDICAL GENETICS|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/pubmed/26470716|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/13290|