The Evolving Genomic Landscape of Esophageal Squamous Cell Carcinoma Under Chemoradiotherapy

Abstract

Esophageal squamous cell carcinoma (ESCC) often recurs after chemoradiotherapy, and the prognosis of ESCC after chemoradiotherapy has not improved over the past few decades. The mutation process in chemoradiotherapy-resistant clones and the functional relevance of genetic alterations remain unclear. To address these problems, we performed whole-exome sequencing of 52 tumor samples from 33 patients with ESCC who received radiotherapy combined with 5-fluorouracil/platinum. In multiregion analyses of pretreatment and locally recurrent lesions from five cases, most driver gene-altered clones remained under chemoradiotherapy selection pressure, while few driver gene alterations were acquired at recurrence. The mutation signatures of recurrent ESCC, including increased deletion frequency and platinum dose-dependent base substitution signatures, were substantially different from those of primary ESCC and reflected the iatrogenic impacts of chemoradiotherapy. Single-region analysis of 28 pretreatment tumors indicated that focal copy-number gain at the MYC locus was significantly associated with poor progression-free survival and overall survival after chemoradiotherapy. MYC gain remained throughout the chemoradiotherapy course and potentially contributes to intrinsic resistance to chemoradiotherapy. Consistent with these findings, MYC copy number and mRNA and protein levels in ESCC cell lines correlated positively with resistance to radiotherapy, and MYC knockdown improved sensitivity to radiotherapy. Overall, these data characterize the clonal evolution process induced by chemoradiotherapy and clinically relevant associations for genetic alterations in ESCC. These findings increase our understanding of therapeutic resistance and support the rationale for precision chemoradiotherapy. Significance: Whole-exome sequencing reveals the genetic evolution of ESCC during chemoradiotherapy, highlighting MYC gain in pretreatment tumors as a potential marker of therapy resistance.

Single-cell mapping of N6-methyladenosine in esophageal squamous cell carcinoma and exploration of the risk model for immune infiltration

“…In recent years, although the incidence and mortality rates of esophageal cancer have been significantly reduced, the overall survival rate of esophageal cancer patients after surgery is still low and the prognosis is poor. The study of the molecular biology of esophageal cancer development can provide new targeted therapeutic strategies for the precise treatment of esophageal cancer and improve the prognosis and overall survival time of patients, and is therefore a hot research topic in the field of esophageal cancer ( 21 , 22 ). m6A methylated modification, as one of the most common RNA modifications, can regulate gene expression at the post-transcriptional level, and in recent years its related enzymes or proteins have also been investigated for their role in the development of esophageal cancer.…”

Cancer type-specific prioritization strategy for targetable dependencies developed from the DepMap profile of head and neck cancer

“…All HPV-negative head and neck squamous cell carcinoma (HNSCC) cell lines annotated in DepMap were selected for analysis (n=63). The size of this panel was increased to 87 by adding all 24 cell lines from esophageal squamous cell carcinoma (ESCC), which have closely comparable etiology, tissue of origin, and genetic landscape to HPV(-) HNSCCs 5, 6 . DepMap reports a gene probability score as the probability (0-1) that knocking out a gene has a true effect on cell line survival, and they use a score > 0.5 to designate a gene as essential to a specific cell line.…”

Potent molecular-targeted therapies for advanced esophageal squamous cell carcinoma

“… 69 In ESCC, MYC contributes not only to cell proliferation, 70 but also to the driver of cancer stem-like cells (CSCs) 71 and intrinsic resistance to chemoradiotherapy. 72 …”