A comparative analysis of whole genome sequencing of oesophageal adenocarcinoma pre- and post-chemotherapy

Research output: Contribution to journalArticlepeer-review

Authors

  • Ayesha Noorani
  • Jan Bornschein
  • Andy G Lynch
  • Maria Secrier
  • Achilleas Achilleos
  • Matthew Eldridge
  • Lawrence Bower
  • Jamie M J Weaver
  • Jason Crawte
  • Chin-Ann Ong
  • Nicholas Shannon
  • Shona MacRae
  • Nicola Grehan
  • Barbara Nutzinger
  • Maria O'Donovan
  • Richard Hardwick
  • Simon Tavaré
  • Rebecca C Fitzgerald
  • Rachael Fels Elliott
  • Paul A W Edwards
  • Xiaodun Li
  • Hamza Chettouh
  • Gianmarco Contini
  • Eleanor Gregson
  • Sebastian Zeki
  • Laura Smith
  • Zarah Abdullahi
  • Rachel de la Rue
  • Ahmad Miremadi
  • Shalini Malhotra
  • Mike L Smith
  • Jim Davies
  • Charles Crichton
  • Nick Carroll
  • Peter Safranek
  • Andrew Hindmarsh
  • Vijayendran Sujendran
  • Richard Turkington
  • Stephen J Hayes
  • Yeng Ang
  • Shaun R Preston
  • Sarah Oakes
  • Izhar Bagwan
  • Vicki Save
  • Richard J E Skipworth
  • Ted R Hupp
  • J Robert O'Neill
  • Olga Tucker
  • Andrew Beggs
  • Philippe Taniere
  • Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium

Colleges, School and Institutes

External organisations

  • University of Cambridge
  • Oesophago-Gastric Unit, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom.
  • Oxford ComLab, University of Oxford, OX1 2JD, United Kingdom.
  • Department of Computer Science, University of Oxford, OX1 3QD, United Kingdom.
  • Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, United Kingdom.
  • Centre for Cancer Research and Cell Biology, Queen's University Belfast, BT9 7AB, Northern Ireland, United Kingdom.
  • Salford Royal NHS Foundation Trust, Salford, M6 8HD, United Kingdom.
  • Royal Surrey County Hospital NHS Foundation Trust, Guildford, GU2 7XX, United Kingdom.
  • Edinburgh Royal Infirmary, Edinburgh, EH16 4SA, United Kingdom.
  • University Hospitals Birmingham NHS Foundation Trust, Birmingham, B15 2GW, United Kingdom.

Abstract

The scientific community has avoided using tissue samples from patients that have been exposed to systemic chemotherapy to infer the genomic landscape of a given cancer. Esophageal adenocarcinoma is a heterogeneous, chemoresistant tumor for which the availability and size of pretreatment endoscopic samples are limiting. This study compares whole-genome sequencing data obtained from chemo-naive and chemo-treated samples. The quality of whole-genomic sequencing data is comparable across all samples regardless of chemotherapy status. Inclusion of samples collected post-chemotherapy increased the proportion of late-stage tumors. When comparing matched pre- and post-chemotherapy samples from 10 cases, the mutational signatures, copy number, and SNV mutational profiles reflect the expected heterogeneity in this disease. Analysis of SNVs in relation to allele-specific copy-number changes pinpoints the common ancestor to a point prior to chemotherapy. For cases in which pre- and post-chemotherapy samples do show substantial differences, the timing of the divergence is near-synchronous with endoreduplication. Comparison across a large prospective cohort (62 treatment-naive, 58 chemotherapy-treated samples) reveals no significant differences in the overall mutation rate, mutation signatures, specific recurrent point mutations, or copy-number events in respect to chemotherapy status. In conclusion, whole-genome sequencing of samples obtained following neoadjuvant chemotherapy is representative of the genomic landscape of esophageal adenocarcinoma. Excluding these samples reduces the material available for cataloging and introduces a bias toward the earlier stages of cancer.

Details

Original languageEnglish
Pages (from-to)902-912
JournalGenome Research
Volume27
Issue number6
Early online date2 May 2017
Publication statusPublished - Jun 2017

Keywords

  • Journal Article