Karyotype evolution in response to chemoradiotherapy and upon recurrence of esophageal adenocarcinomas

• Published in: Cell reports (Cambridge) Vol. 43; no. 11; p. 114981
• Main Authors: van der Sluis, Karen, van Sandick, Johanna W., Koemans, Willem J., van den Bosch, Tom, Broeks, Annegien, Peters, Dennis, Seignette, Iris M., Rausch, Christian R., van Dijk, Erik, Snaebjornsson, Petur, van den Berg, José G., van Grieken, Nicole C.T., Ylstra, Bauke, Carvalho, Beatriz, Miedema, Daniël M., Kodach, Liudmila L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2024; Elsevier
• Subjects: chromosomal instability; CP: Cancer; CP: Genomics; esophageal cancer; therapy resistance; tumor evolution; tumor evolution; CP: Genomics; esophageal cancer; chromosomal instability; CP: Cancer; therapy resistance
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.114981

The genome of esophageal adenocarcinoma (EAC) is highly unstable and might evolve over time. Here, we track karyotype evolution in EACs in response to treatment and upon recurrence through multi-region and longitudinal analysis. To this end, we introduce L-PAC (low-purity inference of absolute copy-number alterations [CNAs]), a bio-informatics technique that allows inference of absolute CNAs of low-purity samples by leveraging the information of high-purity samples from the same cancer. Quantitative analysis of matched absolute CNAs reveals that the amount of karyotype evolution induced by chemoradiotherapy (CRT) is predictive for early recurrence and depends on the initial level of karyotype intra-tumor heterogeneity. We observe that CNAs acquired in response to CRT are partially reversed back to the initial state upon recurrence. Hence, CRT alters the fitness landscape to which tumors can adjust by adapting their karyotype. Together, our results indicate that karyotype plasticity contributes to the therapy resistance of EACs. [Display omitted] •Longitudinal measurements of tumor karyotype evolution•L-PAC method is introduced for inference of absolute CNAs from low-purity samples•Large changes in karyotype during treatment are predictive of early recurrence•Karyotype changes are partially reversed after withdrawal of treatment Van der Sluis et al. track karyotype evolution by shallow WGS applied to tumor biopsies acquired longitudinally from patients with esophageal adenocarcinomas. They develop a new bio-informatics tool to infer absolute copy numbers at low tumor cell percentages. This study finds the plasticity of karyotypes, suggesting adaptive evolution.