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Tracking the genomic evolution of esophageal adenocarcinoma through neoadjuvant chemotherapy
- 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
- Subjects :
- Genome instability
DNA Copy Number Variations
Esophageal Neoplasms
medicine.medical_treatment
Context (language use)
Biology
Adenocarcinoma
Bioinformatics
Somatic evolution in cancer
Article
Genomic Instability
Clonal Evolution
Evolution, Molecular
Chromosome instability
Gene duplication
Antineoplastic Combined Chemotherapy Protocols
medicine
Humans
Exome
Neoadjuvant therapy
Platinum
Genome, Human
Gene Amplification
Computational Biology
Genetic Variation
Genomics
medicine.disease
Neoadjuvant Therapy
Oncology
Mutation
Cancer research
Subjects
Details
- ISSN :
- 21598290
- Volume :
- 5
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- Cancer discovery
- Accession number :
- edsair.doi.dedup.....cb1ded981182bf2820e136a0b849bb00