Multiregion exome sequencing indicates a monoclonal origin of esophageal spindle‐cell squamous cell carcinoma

• Published in: The Journal of pathology Vol. 264; no. 1; pp. 55 - 67
• Main Authors: Wang, Yulu, Zhu, Qian, Wu, Yaqing, Li, Boyi, Su, Xiaoxing, Xiang, Chan, Han, Yuchen
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.09.2024; Wiley Subscription Services, Inc
• Subjects: Adenomatous polyposis coli; Chromosome 11; Chromosome 5; clinicopathologic features; Esophageal carcinoma; esophageal spindle‐cell squamous cell carcinoma (ESS); Esophagus; Gene frequency; Immunotherapy; LRP2 protein; monoclonal origin; Mutation; Oncogenes; p53 Protein; Phylogeny; Signal transduction; Squamous cell carcinoma; Tumors; Whole genome sequencing; whole‐exome sequencing; monoclonal origin; esophageal spindle‐cell squamous cell carcinoma (ESS); whole‐exome sequencing; clinicopathologic features
• ISSN: 0022-3417; 1096-9896; 1096-9896
• DOI: 10.1002/path.6324

Esophageal spindle‐cell squamous cell carcinoma (ESS) is a rare biphasic neoplasm composed of a carcinomatous component (CaC) and a sarcomatous component (SaC). However, the genomic origin and gene signature of ESS remain unclear. Using whole‐exome sequencing of laser‐capture microdissection (LCM) tumor samples, we determined that CaC and SaC showed high mutational commonality, with the same top high‐frequency mutant genes, mutation signatures, and tumor mutation burden; paired samples shared a median of 25.5% mutation sites. Focal gains were found on chromosomes 3q29, 5p15.33, and 11q13.3. Altered genes were mainly enriched in the RTK–RAS signaling pathway. Phylogenetic trees showed a monoclonal origin of ESS. The most frequently mutated oncogene in the trunk was TP53, followed by NFE2L2, KMT2D, and MUC16. Prognostic associations were found for CDC27, LRP2, APC, and SNAPC4. Our data highlight the monoclonal origin of ESS with TP53 as a potent driver oncogene, suggesting new targeted therapies and immunotherapies as treatment options. © 2024 The Pathological Society of Great Britain and Ireland.