Abstract
How chemotherapy affects carcinoma genomes is largely unknown. Here we report whole-exome and deep sequencing of 30 paired oesophageal adenocarcinomas sampled before and after neo-adjuvant chemotherapy. Most, but not all, good responders pass through genetic bottlenecks, a feature associated with higher mutation burden pre-treatment. Some poor responders pass through bottlenecks, but re-grow by the time of surgical resection, suggesting a missed therapeutic opportunity. Cancers often show major changes in driver mutation presence or frequency after treatment, owing to outgrowth persistence or loss of sub-clones, copy number changes, polyclonality and/or spatial genetic heterogeneity. Post-therapy mutation spectrum shifts are also common, particularly C>A and TT>CT changes in good responders or bottleneckers. Post-treatment samples may also acquire mutations in known cancer driver genes (for example, SF3B1, TAF1 and CCND2) that are absent from the paired pre-treatment sample. Neo-adjuvant chemotherapy can rapidly and profoundly affect the oesophageal adenocarcinoma genome. Monitoring molecular changes during treatment may be clinically useful.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / drug therapy
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Adenocarcinoma / genetics*
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Adenocarcinoma / metabolism
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Adenocarcinoma / pathology
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Adult
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Aged
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Antineoplastic Agents / therapeutic use*
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Clonal Evolution / drug effects*
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Cyclin D2 / genetics
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Cyclin D2 / metabolism
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DNA Copy Number Variations / drug effects
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DNA, Neoplasm / genetics*
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DNA, Neoplasm / metabolism
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Esophageal Neoplasms / drug therapy
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Esophageal Neoplasms / genetics*
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Esophageal Neoplasms / metabolism
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Esophageal Neoplasms / pathology
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Exome
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Female
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Gene Expression Regulation, Neoplastic
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Genetic Heterogeneity
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Histone Acetyltransferases / genetics
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Histone Acetyltransferases / metabolism
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Humans
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Male
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Middle Aged
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Mutation / drug effects
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Neoadjuvant Therapy*
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Neoplasm Proteins / genetics*
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Neoplasm Proteins / metabolism
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Neoplasm Recurrence, Local / drug therapy
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Neoplasm Recurrence, Local / genetics*
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Neoplasm Recurrence, Local / metabolism
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Neoplasm Recurrence, Local / pathology
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Phosphoproteins / genetics
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Phosphoproteins / metabolism
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RNA Splicing Factors
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Ribonucleoprotein, U2 Small Nuclear / genetics
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Ribonucleoprotein, U2 Small Nuclear / metabolism
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Sequence Analysis, DNA
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TATA-Binding Protein Associated Factors / genetics
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TATA-Binding Protein Associated Factors / metabolism
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Transcription Factor TFIID / genetics
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Transcription Factor TFIID / metabolism
Substances
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Antineoplastic Agents
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CCND2 protein, human
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Cyclin D2
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DNA, Neoplasm
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Neoplasm Proteins
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Phosphoproteins
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RNA Splicing Factors
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Ribonucleoprotein, U2 Small Nuclear
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SF3B1 protein, human
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TATA-Binding Protein Associated Factors
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Transcription Factor TFIID
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Histone Acetyltransferases
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TATA-binding protein associated factor 250 kDa
Supplementary concepts
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Adenocarcinoma Of Esophagus