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

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, Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)902-912
Number of pages11
JournalGenome Research
Volume27
Issue number6
Early online date2 May 2017
DOIs
Publication statusPublished - 1 Jun 2017

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