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Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity

Abstract

The incidence of esophageal adenocarcinoma (EAC) has risen 600% over the last 30 years. With a 5-year survival rate of 15%, the identification of new therapeutic targets for EAC is greatly important. We analyze the mutation spectra from whole-exome sequencing of 149 EAC tumor-normal pairs, 15 of which have also been subjected to whole-genome sequencing. We identify a mutational signature defined by a high prevalence of A>C transversions at AA dinucleotides. Statistical analysis of exome data identified 26 significantly mutated genes. Of these genes, five (TP53, CDKN2A, SMAD4, ARID1A and PIK3CA) have previously been implicated in EAC. The new significantly mutated genes include chromatin-modifying factors and candidate contributors SPG20, TLR4, ELMO1 and DOCK2. Functional analyses of EAC-derived mutations in ELMO1 identifies increased cellular invasion. Therefore, we suggest the potential activation of the RAC1 pathway as a contributor to EAC tumorigenesis.

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Figure 1: High frequencies of A>C transversions at AA sites identified from whole-genome sequencing are observed in less expressed regions of the genome.
Figure 2: Mutation frequencies and significantly mutated genes in EAC as identified by whole-exome sequencing.
Figure 3: Recurrent somatic alterations in ELMO1, DOCK2 and other RAC1 GEFs.
Figure 4: Somatic mutations in frequently altered pathways in cancer, putative therapeutic targets and treatment biomarkers.
Figure 5: Genetic alterations identified by whole-exome sequencing across 145 EACs affecting the Wnt/β-catenin, RTK-RAS-PI3K, TGF-β/SMAD4, chromatin-remodeling enzyme, G1 to S progression and p53 pathways.

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Acknowledgements

We thank M. Meyerson for helpful discussions and review of the manuscript and members of the Broad Institute Biological Samples Platform, Genetic Analysis Platform and Genome Sequencing Platform for their assistance. We are also grateful for the physicians and hospital staff whose efforts in collecting these samples are essential to this research. This work was supported by the US National Human Genome Research Institute (NHGRI) Large-Scale Sequencing Program (U54 HG003067 to the Broad Institute, E.S.L.), the National Cancer Institute (K08 CA134931 to A.J.B.), the DeGregorio Family Foundation (A.J.B.), the Karin Grunebaum Cancer Research Foundation (A.J.B.), the Target Cancer (A.J.B.) and Connecticut Conquers Cancer (A.J.B.). S.O. and Y.I. are supported by the National Cancer Institute (R01 CA151993 to S.O.) and the Dana-Farber/Harvard Cancer Center GI Cancer Specialized Programs of Research Excellence (US National Institutes of Health (NIH) grant P50 CA127003). D.G.B. is supported by NIH grants CA163059 and CA46592. J.D.L. is supported by NIH grant CA090665. T.E.G. is supported by NIH grant CA130853.

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P.S., S.P., M.S.L., C.F., C. Stewart, S.E.S., A.M., K.C., A.S., S.L.C., G.S., D.V., A.H.R. and R.B. performed computational analyses. E.S., D.A., K.T., C. Sougnez, R.C.O., C.G. and S.B.G. processed samples and supervised exome sequencing. A.M.D., S.B., D.Z., L.L., J.L., R.R., A.C., R.L., J.D.L., A.P., D.G.B., T.E.G. and A.J.B. coordinated sample acquisition, processing, pathological review and analysis. Y.I. and S.O. performed MSI testing. A.M.D., P.S., T.R.G., S.B.G., E.S.L., G.G. and A.J.B. designed the study. A.M.D., P.S., S.P., M.S.L., G.G. and A.J.B. analyzed the data and wrote the manuscript.

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Correspondence to Gad Getz or Adam J Bass.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Note, Supplementary Figures 1–6 and Supplementary Tables 1–3, 5, 6, 8, 10–13 and 16–18 (PDF 1263 kb)

Supplementary Table 4

Predicted rearrangements by dRanger algorithm (XLSX 394 kb)

Supplementary Table 7

Frequencies of all middle-base mutations with 5' and 3' base context identified by WGS (n=16) (XLSX 51 kb)

Supplementary Table 9

Rates of all middle-base mutations with 5' and 3' base context identified by WGS in exons (XLSX 50 kb)

Supplementary Table 14

Somatic mutations in MSI positive samples detected by WES (n=4) (XLSX 1317 kb)

Supplementary Table 15

Somatic mutations in non-MSI positive samples detected by WES (n=145) (XLSX 6264 kb)

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Dulak, A., Stojanov, P., Peng, S. et al. Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity. Nat Genet 45, 478–486 (2013). https://doi.org/10.1038/ng.2591

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