A comparative analysis of whole genome sequencing of esophageal adenocarcinoma pre- and post-chemotherapy
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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.
Noorani , A , Bornschein , J , Lynch , A G , Secrier , M , Achilleos , A , Eldridge , M , Bower , L , Weaver , J M J , Crawte , J , Ong , C-A , Shannon , N , MacRae , S , Grehan , N , Nutzinger , B , O'Donovan , M , Hardwick , R , Tavaré , S , Fitzgerald , R C & on behalf of the Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium 2017 , ' A comparative analysis of whole genome sequencing of esophageal adenocarcinoma pre- and post-chemotherapy ' Genome Research , vol 27 , no. 6 , pp. 902-912 . DOI: 10.1101/gr.214296.116
© 2017 Noorani et al. This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
The whole-genome sequencing data from this study have been submitted to the European Genome-phenome Archive (EGA; https://www.ebi.ac.uk/ega/home) under accession number EGAD00001002241. Mutation calls can be found within the ICGC data portal (https://dcc.icgc.org/) under project ID ESADUK and library IDs listed in Supplemental Table S2.
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