Mutational signatures in esophageal adenocarcinoma define etiologically distinct subgroups with therapeutic relevance
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Published: 05 September 2016
Nature Genetics volume 48, pages 1131–1141 (2016) | Download Citation
Esophageal adenocarcinoma (EAC) has a poor outcome, and targeted therapy trials have thus far been disappointing owing to a lack of robust stratification methods. Whole-genome sequencing (WGS) analysis of 129 cases demonstrated that this is a heterogeneous cancer dominated by copy number alterations with frequent large-scale rearrangements. Co-amplification of receptor tyrosine kinases (RTKs) and/or downstream mitogenic activation is almost ubiquitous; thus tailored combination RTK inhibitor (RTKi) therapy might be required, as we demonstrate in vitro. However, mutational signatures showed three distinct molecular subtypes with potential therapeutic relevance, which we verified in an independent cohort (n = 87): (i) enrichment for BRCA signature with prevalent defects in the homologous recombination pathway; (ii) dominant T>G mutational pattern associated with a high mutational load and neoantigen burden; and (iii) C>A/T mutational pattern with evidence of an aging imprint. These subtypes could be ascertained using a clinically applicable sequencing strategy (low coverage) as a basis for therapy selection.
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In the version of this article initially published online, the mutation signature illustrations for S1 and S2 in Figure 3a were switched. Additionally, in the Online Methods, the text originally stated that structural variants were called using BWA-MEM, when it should have stated that these were called using BWA. These errors have been corrected for the print, PDF and HTML versions of this article.
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This paper is dedicated to Nadeera de Silva, who tragically and unexpectedly died while this paper was undergoing revision. He made an important contribution to this research, particularly bringing his clinical oncology perspective to bear on the translational relevance of the findings.
Whole-genome sequencing of esophageal adenocarcinoma samples was carried out in concert with the International Cancer Genome Consortium (ICGC) through the OCCAMS Consortium and was funded by program grants from Cancer Research UK (RG66287, RG81771, RG84119). We thank the ICGC members for their input on verification standards as part of the benchmarking exercise. We thank the Human Research Tissue Bank, which is supported by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, from Addenbrooke’s Hospital and UCL. We also thank the University Hospital of Southampton Trust; the Southampton, Birmingham, Edinburgh and UCL Experimental Cancer Medicine Centres; and the QEHB charities. R.C.F. is funded by an NIHR Professorship (RG67258) and receives core funding from the Medical Research Council (RG84369) and infrastructure support from the Biomedical Research Centre (RG64237) and the Experimental Cancer Medicine Centre (RG62923). We acknowledge the support of the University of Cambridge, Cancer Research UK (C14303/A17197) and Hutchison Whampoa Limited. We thank P. Van Loo for providing the NGS version of ASCAT for copy number calling. We are grateful to all the patients who provided written consent for participation in this study and to the staff at all participating centres.
Some of the work was undertaken at UCLH/UCL, which received a proportion of funding from the Department of Health’s NIHR Biomedical Research Centres funding scheme. The views expressed in this publication are those of the authors and are not necessarily those of the Department of Health. The work at UCLH/UCL was also supported by the CRUK UCL Early Cancer Medicine Centre.
These authors contributed equally to this work.
R.C.F. conceived the overall study. M.S., X.L. and P.A.W.E. analyzed the data. R.C.F., M.S., X.L., N.d.S., P.A.W.E. and A.G.L. conceived and designed the experiments. M.S. performed the statistical analysis. X.L., G.C., S.M., M.O., A.M., J.C. and N.G.-D. performed the experiments. M.D.E. performed benchmarking studies on the variant calls, and implemented and ran several variant-calling and analysis pipelines. G.C. contributed to the structural variant analysis. J.B. contributed expression data and curated the clinical data collection. S.M. and N.G. coordinated sample processing with clinical centers and was responsible for sample collections. T.-P.Y. performed the BFB analysis. L.B. ran the variant-calling pipelines. H.C. contributed to the RTK analysis. A.G., J.S. and T.U. contributed cell lines. N.W. and A.P.B. contributed sequencing data for validation. B.N. coordinated data and tissue collection from centers for the study. A.A. helped develop the copy-number-calling pipeline. R.C.F. and S.T. jointly supervised the research. M.S., N.d.S., X.L. and R.C.F. wrote the manuscript. All authors approved the final version of the manuscript.
The authors declare no competing financial interests.
Correspondence to Rebecca C Fitzgerald.
Supplementary Figures 1–28, Supplementary Tables 1, 2, 4–9, 11 and 12 and Supplementary Note
Significantly deleted loci in the cohort according to GISTIC2.0. Loci with residual q-value
Microsatellite instability analysis results. The potentially microsatellite unstable samples that were removed from the analysis are highlighted at the top.
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03 June 2016
05 August 2016
05 September 2016
https://doi.org/10.1038/ng.3659
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