American Association for Cancer Research
21598290cd150412-sup-suppmat0412.pdf (4.5 MB)

Supplementary Methods, Tables S1 - S2, S4, Figures S1 - S11 from Tracking the Genomic Evolution of Esophageal Adenocarcinoma through Neoadjuvant Chemotherapy

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journal contribution
posted on 2023-04-03, 21:05 authored by Nirupa Murugaesu, Gareth A. Wilson, Nicolai J. Birkbak, Thomas B.K. Watkins, Nicholas McGranahan, Sacheen Kumar, Nima Abbassi-Ghadi, Max Salm, Richard Mitter, Stuart Horswell, Andrew Rowan, Benjamin Phillimore, Jennifer Biggs, Sharmin Begum, Nik Matthews, Daniel Hochhauser, George B. Hanna, Charles Swanton

Supplementary Materials and Methods Supplementary Table S1 - Sequencing coverage for tumor regions and germline samples Supplementary Table S2 - Clinical characteristics of patients with EAC Supplementary Table S4 - Annotation of chromosomal segments that overlap with TCGA ESCA recurrent amplifications and tumor regions in our EAC cohort Supplementary Figure S1 - Mutations identified using M-seq compared with a single biopsy Supplementary Figure S2 - Relationship of intratumor heterogeneity and response to NAC treatment Supplementary Figure S3 - Tumor Phylograms Supplementary Figure S4 - Copy number events lead to mutational heterogeneity Supplementary Figure S5 - Heatmap of the all driver mutations identified across all tumor regions Supplementary Figure S6 - Driver mutations identified using M-seq compared with a single biopsy Supplementary Figure S7 - Copy number states across the genome for each tumor region Supplementary Figure S8 - Chromosome view of chromosome 19, tumor sample EAC017, region R1, demonstrating chromothripsis Supplementary Figure S9 - wGII scores for the TCGA ESCA cohort and M-seq EAC cohort Supplementary Figure S10 - The trinucleotide context for temporally dissected combined EAC cohort Supplementary Figure S11 - Assessing copy number heterogeneity using a minimum consecutive segment method



Esophageal adenocarcinomas are associated with a dismal prognosis. Deciphering the evolutionary history of this disease may shed light on therapeutically tractable targets and reveal dynamic mutational processes during the disease course and following neoadjuvant chemotherapy (NAC). We exome sequenced 40 tumor regions from 8 patients with operable esophageal adenocarcinomas, before and after platinum-containing NAC. This revealed the evolutionary genomic landscape of esophageal adenocarcinomas with the presence of heterogeneous driver mutations, parallel evolution, early genome-doubling events, and an association between high intratumor heterogeneity and poor response to NAC. Multiregion sequencing demonstrated a significant reduction in thymine to guanine mutations within a CpTpT context when comparing early and late mutational processes and the presence of a platinum signature with enrichment of cytosine to adenine mutations within a CpC context following NAC. Esophageal adenocarcinomas are characterized by early chromosomal instability leading to amplifications containing targetable oncogenes persisting through chemotherapy, providing a rationale for future therapeutic approaches.Significance: This work illustrates dynamic mutational processes occurring during esophageal adenocarcinoma evolution and following selective pressures of platinum exposure, emphasizing the iatrogenic impact of therapy on cancer evolution. Identification of amplifications encoding targetable oncogenes maintained through NAC suggests the presence of stable vulnerabilities, unimpeded by cytotoxics, suitable for therapeutic intervention. Cancer Discov; 5(8); 821–31. ©2015 AACR.See related commentary by Devarakonda and Govindan, p. 796.This article is highlighted in the In This Issue feature, p. 783

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