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Tracking the Genomic Evolution of Esophageal Adenocarcinoma through Neoadjuvant Chemotherapy

2015; American Association for Cancer Research; Volume: 5; Issue: 8 Linguagem: Inglês

10.1158/2159-8290.cd-15-0412

2159-8290

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,

Gastrointestinal Tumor Research and Treatment

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.