Genomic comparison of esophageal squamous cell carcinoma and its precursor lesions by multi-region whole-exome sequencing

TLDR

Esophageal squamous dysplasia is considered the precursor of ESCC, yet the genetic steps leading from dysplasia to carcinoma—including the critical role of TP53 inactivation—remain largely undefined. The study aims to map the genetic evolution from dysplastic lesions to ESCC using multi‑region exome sequencing. Multi‑region whole‑exome sequencing was performed on 45 ESCC patients with matched dysplasia and carcinoma samples and on 13 dysplasia‑only patients. The analysis revealed that dysplastic lesions are heavily mutated, harbor most ESCC driver events.

Abstract

Esophageal squamous dysplasia is believed to be the precursor lesion of esophageal squamous cell carcinoma (ESCC); however, the genetic evolution from dysplasia to ESCC remains poorly understood. Here, we applied multi-region whole-exome sequencing to samples from two cohorts, 45 ESCC patients with matched dysplasia and carcinoma samples, and 13 tumor-free patients with only dysplasia samples. Our analysis reveals that dysplasia is heavily mutated and harbors most of the driver events reported in ESCC. Moreover, dysplasia is polyclonal, and remarkable heterogeneity is often observed between tumors and their neighboring dysplasia samples. Notably, copy number alterations are prevalent in dysplasia and persist during the ESCC progression, which is distinct from the development of esophageal adenocarcinoma. The sharp contrast in the prevalence of the 'two-hit' event on TP53 between the two cohorts suggests that the complete inactivation of TP53 is essential in promoting the development of ESCC.The pathogenesis of oesophageal squamous cell carcinoma is a multi-step process but the genetic determinants behind this progression are unknown. Here the authors use multi-region exome sequencing to comprehensively investigate the genetic evolution of precursor dysplastic lesions and untransformed oesophagus.