Letter to the Editor: Not one disease - ethnic-specific mutational pathways redefine precision oncology in esophageal cancer

Abstract

Precision oncology in esophageal squamous cell carcinoma has long operated under the implicit assumption that it is a single biological entity. In a study published in the World Journal of Gastroenterology, Wei et al provide a compelling and definitive challenge to this monolithic view. Through whole-exome sequencing of Han and Kazakh populations, they revealed not just different driver genes, but fundamentally distinct carcinogenic processes: A predominance of the apolipoprotein B messenger RNA-editing enzyme catalytic polypeptide-related mutational signatures in the Han cohort vs signatures of defective DNA mismatch repair in the Kazakh group. This finding transcends descriptive genomics; it suggests that esophageal squamous cell carcinoma in these populations may represent two different diseases at the molecular level. Clinically, this has profound implications. It questions the global applicability of clinical trial data derived from homogeneous populations and argues for the urgent need to incorporate ethnic diversity into genomic databases and trial design. Most provocatively, the authors uncover a crucial paradox: The Kazakh cohort, despite having poorer historical survival, exhibits a higher tumor mutational burden, a biomarker that paradoxically suggests the potential for heightened sensitivity to immune checkpoint inhibitors. This study is therefore a landmark, shifting the paradigm from treating a single cancer type to tailoring therapy based on distinct, ethnic-specific mutational etiologies.

Key Words: Esophageal squamous cell carcinoma; Ethnic genomics; Mutational signatures; Precision oncology; Tumor mutational burden; Health equity

Core Tip: This letter highlights that esophageal squamous cell carcinoma is not a single entity but comprises ethnically distinct molecular subtypes. While Han patients exhibit the apolipoprotein B messenger RNA-editing enzyme catalytic polypeptide-related signatures, Kazakh patients show defective mismatch repair. We emphasize a critical paradox: Despite worse historical survival, Kazakh tumors display high tumor mutational burden, suggesting potential sensitivity to immunotherapy. These findings urge the integration of ethnic genomics into clinical trial design to transform therapeutic strategies for underrepresented populations.

TO THE EDITOR

The concept of precision oncology in esophageal squamous cell carcinoma (ESCC) has long relied on the assumption that ESCC represents a single biological entity. However, the marked geographical and ethnic disparities in ESCC incidence and mortality revealed by global cancer statistics strongly suggest that this uniform view may conceal deeper molecular heterogeneity[1]. The recent study published in the World Journal of Gastroenterology by Wei et al[2] offers important insight into this question by presenting the first high-resolution genomic comparison between Han and Kazakh populations in China, two groups with distinct epidemiological profiles.

Using whole-exome sequencing, the authors identified profound ethnic differences in the mutational landscape of ESCC. Among Han Chinese patients, the predominant mutational signatures, identified as single base substitutions 2 and 13, were linked to the apolipoprotein B messenger RNA-editing enzyme catalytic polypeptide family of cytidine deaminases, a well-recognized driver of mutation clusters in human cancers and often associated with inflammation or viral infection[3]. This pattern supports an “environment-inflammation-genomic damage” axis underlying ESCC pathogenesis in the Han population. In contrast, tumors from Kazakh patients were dominated by the substitution 6 signature, indicative of defective DNA mismatch repair, a hallmark of endogenous genomic instability resembling Lynch syndrome and microsatellite instability-high colorectal cancer. This duality reveals that ESCC may follow distinct carcinogenic trajectories across ethnicities, shaped by both environmental exposures and ancestral genetic background. Such findings echo emerging evidence from other malignancies, including prostate, gastric, and lung cancers, where ancestry-specific mutational processes have been identified[4]. The study by Wei et al[2] thus extends this paradigm to ESCC, establishing a foundation for ancestry-informed precision oncology.

Of particular clinical significance is the paradox the authors uncovered. Although historical data show that Kazakh ESCC patients experience poorer survival outcomes, their tumors exhibit a markedly higher tumor mutational burden. High tumor mutational burden has been associated with enhanced immunogenicity and increased responsiveness to immune checkpoint inhibitors in multiple tumor types[5]. This observation raises a clinically provocative question: Could the historically poor prognosis among Kazakh patients be due not to intrinsically aggressive tumor biology, but to a therapeutic mismatch, i.e., receiving cytotoxic regimens in place of potentially effective immunotherapy? If validated, these results could transform this high-risk population into a high-potential group for immune checkpoint inhibitor-based therapy.

While the small Kazakh cohort (n = 9) appropriately positions this investigation as hypothesis-generating, its implications are nonetheless compelling. Future clinical trials in ESCC should incorporate ethnically stratified subgroup analyses to detect ancestry-related treatment responses that might otherwise be obscured. Moreover, the study reinforces a growing consensus that global cancer genomics databases must be diversified to reflect the full spectrum of human ancestry[6]. Without such inclusion, therapeutic inequities will persist, and the promise of precision oncology will remain incomplete.

From a mechanistic standpoint, the interplay between mutational processes, diet, and climate-adaptive biology suggested by the enrichment of genes such as GIGYF1, CACNA1D, and ACOT11 in Kazakh patients deserves further exploration. These findings highlight that environmental adaptation and metabolism-related genes may act as ethnic modulators of tumor evolution, offering a tangible bridge between lifestyle, geography, and the cancer genome.

Conclusion

The work by Wei et al[2] provides persuasive genomic evidence that ESCC is not a monolithic disease but a constellation of biologically distinct entities driven by ethnic-specific mutational mechanisms. Recognizing ethnicity as a biological determinant, rather than merely a demographic variable, is the next critical step toward equitable precision oncology. Incorporating genomic ancestry into trial design, treatment selection, and data repositories will be essential to deliver the right therapy to the right patient, everywhere.