Spatial intra-tumour heterogeneity and treatment-induced genomic evolution in oesophageal adenocarcinoma: implications for prognosis and therapy

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2024年7月17日

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Sandra Brosda,
Lauren G. Aoude,
Vanessa F. Bonazzi,
Kalpana Patel,
James M. Lonie,
Clemence J. Belle,
Felicity Newell,
Lambros T. Koufariotis,
Venkateswar Addala,
Marjan M. Naeini,
John Simes,
Euan T. Walpole,
Gang T. Mai,
David I. Watson,
Chris S. Karapetis,
Val Gebski,
Elizabeth H. Barnes,
Martijn Oostendorp,
Kate Wilson,
Stephen P. Ackland,
Jenny Shannon,
Gavin Marx,
Matthew Burge,
Robert Finch,
Janine Thomas,
Suresh Varma,
Louise Nott,
John V. Pearson,
Lutz Krause,
Nicola Waddell,
Andrew P. Barbour

摘要

Background

Oesophageal adenocarcinoma (OAC) is a highly heterogeneous cancer with poor survival. Standard curative treatment is chemotherapy with or without radiotherapy followed by oesophagectomy. Genomic heterogeneity is a feature of OAC and has been linked to treatment resistance.

Methods

Whole-genome sequencing data from 59 treatment-naïve and 18 post-treatment samples from 29 OAC patients was analysed. Twenty-seven of these were enrolled in the DOCTOR trial, sponsored by the Australasian Gastro-Intestinal Trials Group. Two biopsies from each treatment-naïve tumour were assessed to define ‘shared’ (between both samples) and ‘private’ (present in one sample) mutations.

Results

Mutational signatures SBS2/13 (APOBEC) and SBS3 (BRCA) were almost exclusively detected in private mutation populations of treatment-naïve tumours. Patients presenting these signatures had significantly worse disease specific survival. Furthermore, mutational signatures associated with platinum-based chemotherapy treatment as well as high platinum enrichment scores were only detected in post-treatment samples. Additionally, clones with high putative neoantigen binding scores were detected in some treatment-naïve samples suggesting immunoediting of clones.

Conclusions

This study demonstrates the high intra-tumour heterogeneity in OAC, as well as indicators for treatment-induced changes during tumour evolution. Intra-tumour heterogeneity remains a problem for successful treatment strategies in OAC.