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

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Noorani, A 
Bornschein, J 
Lynch, AG 
Secrier, M 
Achilleos, A 

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.

Adenocarcinoma, Aged, Antineoplastic Agents, Cell Transformation, Neoplastic, Computational Biology, DNA Copy Number Variations, Esophageal Neoplasms, Esophagus, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genome, Human, High-Throughput Nucleotide Sequencing, Humans, Male, Middle Aged, Mutation Rate, Neoadjuvant Therapy, Neoplasm Proteins, Point Mutation, Polymorphism, Single Nucleotide, Prospective Studies, Time Factors
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Genome Research
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Cold Spring Harbor Laboratory Press
Cancer Research UK (22720)
Cancer Research UK (22131)
Cancer Research Uk (None)
This study was partly funded by a project grant from Cancer Research UK. R.C.F. is funded by an NIHR Professorship and receives core funding from the Medical Research Council and infrastructure support from the Biomedical Research Centre and the Experimental Cancer Medicine Centre. We acknowledge the support of The University of Cambridge, Cancer Research UK (C14303/A17197) and Hutchison Whampoa Limited.