High-risk human papillomavirus (hr-HPV) has been implicated in a subset of patients with oesophageal adenocarcinoma (OAC). 1-3 We therefore hypothesized that HPV associated OAC may have a distinct distribution of molecular aberrations and genomic abnormalities compared with HPV negative oesophageal cancer. As such, whole exome sequencing (WES) was performed to explore the genomic landscape and potential molecular signature of HPV positive versus viral negative OAC.
Four hr-HPV-positive and 8 HPV-negative treatment-naïve fresh frozen OAC tissue specimens and matched normal tissue were analysed by WES to identify somatic genomic mutations. Data were subjected to cancer driver gene identification, pathway analysis and detection of virus genome integration.
The HPV-positive cohort harboured approximately 50% less non-silent somatic mutations than the virus-negative oesophageal cancer patients (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 OAC patients exhibited TP53 mutations. Viral integration analysis identified hybrid sequences containing HPV16 and the human genome. HPV-negative cancers were enriched with non-silent mutations in cancer driver genes, but not HPV-positive tumours. Enriched A>C transversions at AA dinucleotide was observed in 5/7 Siewert class I OAC samples but none (0/5) in Siewert class II tumours (p=0.027).
These findings demonstrate distinct genomic differences between HPV-positive and HPV-negative OAC indicating different biological mechanisms of tumour formation.
1. Rajendra, S. et al. Transcriptionally active human papillomavirus is strongly associated with Barrett's dysplasia and esophageal adenocarcinoma. Am J Gastroenterol 2013; 108: 1082-93.
2. Wang, B. et al. Viral load and integration status of high-risk human papillomaviruses in the Barrett's metaplasia-dysplasia-adenocarcinoma sequence. Am J Gastroenterol 2013; 108: 1814-6.
3. Rajendra, S. et al. Persistence of Human Papillomavirus, Overexpression of p53, and Outcomes of Patients After Endoscopic Ablation of Barrett's Esophagus. Clin Gastroenterol Hepatol 2015; 13: 1364-1368.e5