Mutational signature dynamics shaping the evolution of oesophageal adenocarcinoma.

Published version
Repository DOI

Change log
Authors
Abbas, Sujath 
Pich, Oriol 
Katz-Summercorn, Annalise  ORCID logo  https://orcid.org/0000-0002-5031-5153
Abstract

A variety of mutational processes drive cancer development, but their dynamics across the entire disease spectrum from pre-cancerous to advanced neoplasia are poorly understood. We explore the mutagenic processes shaping oesophageal adenocarcinoma tumorigenesis in 997 instances comprising distinct stages of this malignancy, from Barrett Oesophagus to primary tumours and advanced metastatic disease. The mutational landscape is dominated by the C[T > C/G]T substitution enriched signatures SBS17a/b, which are linked with TP53 mutations, increased proliferation, genomic instability and disease progression. The APOBEC mutagenesis signature is a weak but persistent signal amplified in primary tumours. We also identify prevalent alterations in DNA damage repair pathways, with homologous recombination, base and nucleotide excision repair and translesion synthesis mutated in up to 50% of the cohort, and surprisingly uncoupled from transcriptional activity. Among these, the presence of base excision repair deficiencies show remarkably poor prognosis in the cohort. In this work, we provide insights on the mutational aetiology and changes enabling the transition from pre-neoplastic to advanced oesophageal adenocarcinoma.

Description

Acknowledgements: The laboratory of R.C.F. was funded by a Core Programme Grant from the Medical Research Council (RG84369). OCCAMS2 was funded by a Programme Grant from Cancer Research UK (RG81771/84119, A22720/A22131). M.S. was supported by a UKRI Future Leaders Fellowship (MR/T042184/1). S.A. was funded by Cambridge Trust, Trinity College-Henry Barlow Trust and Basil Howard Research studentship from Sidney Sussex College Cambridge. N.L.-B. acknowledges funding from the European Research Council (consolidator grant 682398). IRB Barcelona is a recipient of a Severo Ochoa Centre of Excellence Award from Spanish Ministry of Science, Innovation and Universities (MICINN, Government of Spain) and is supported by CERCA (Generalitat de Catalunya). S.A.Z. is funded by the Gates Cambridge Trust, United Kingdom, and the Jack Kent Cooke Foundation, United States. This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.

Keywords
Humans, Mutation, Mutagenesis, Esophageal Neoplasms, Adenocarcinoma
Journal Title
Nat Commun
Conference Name
Journal ISSN
2041-1723
2041-1723
Volume Title
14
Publisher
Springer Science and Business Media LLC
Sponsorship
National Institute for Health and Care Research (IS-BRC-1215-20014)