Differential clonal evolution in oesophageal cancers in response to neo-adjuvant chemotherapy.
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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.
AuthorsFindlay, JM; Castro-Giner, F; Makino, S; Rayner, E; Kartsonaki, C; Cross, W; Kovac, M; Ulahannan, D; Palles, C; Gillies, RS; MacGregor, TP; Church, D; Maynard, ND; Buffa, F; Cazier, JB; Graham, TA; Wang, LM; Sharma, RA; Middleton, M; Tomlinson, I
- College Publications