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Tracking the genomic evolution of esophageal adenocarcinoma through neoadjuvant chemotherapy

Authors :
Thomas B.K. Watkins
Nicholas McGranahan
Charles Swanton
Jennifer Biggs
Gareth A. Wilson
Nima Abbassi-Ghadi
Daniel Hochhauser
Sacheen Kumar
Benjamin Phillimore
Nik Matthews
Andrew Rowan
Max Salm
Richard Mitter
Nicolai Juul Birkbak
George B. Hanna
Sharmin Begum
Stuart Horswell
Nirupa Murugaesu
Source :
Cancer discovery. 5(8)
Publication Year :
2015

Abstract

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

Details

ISSN :
21598290
Volume :
5
Issue :
8
Database :
OpenAIRE
Journal :
Cancer discovery
Accession number :
edsair.doi.dedup.....cb1ded981182bf2820e136a0b849bb00