Ethnic genomic diversity in esophageal squamous cell carcinoma

Abstract

Esophageal squamous cell carcinoma (ESCC) remains one of the most lethal malignancies worldwide, with pronounced geographic and ethnic disparities in incidence and outcomes. Rapid advances in genome-wide and sequencing technologies have revealed population-specific mutation spectra and risk loci, highlighting the interplay between inherited susceptibility and environmental exposures. The recent Han-Kazakh whole-exome study provided compelling evidence that ethnic background can shape the mutational landscape of Chinese ESCC, identifying population-restricted alterations such as GIGYF1 and distinct mutational signatures related to apolipoprotein B mRNA-editing enzyme catalytic polypeptide activity. These findings underscore the biological consequences of ethnic heterogeneity but also expose critical gaps: Most available data derive from limited Asian cohorts, cross-sectional designs, and coding-region analyses, leaving African, Central Asian, and multi-ancestry populations underrepresented and the functional relevance of non-coding and epigenetic changes unresolved. Building on this foundation, the present review synthesizes current genomic, transcriptomic, and epigenomic evidence across diverse ethnic groups to delineate shared and population-specific drivers of ESCC carcinogenesis. We emphasize how polymorphisms in alcohol-metabolizing enzymes (ADH1B, ALDH2), DNA-repair and oxidative-stress pathways, and immune-related networks interact with lifestyle and environmental factors to influence tumor initiation and progression. By integrating multi-ethnic multi-omics data, we highlight emerging biomarkers and therapeutic targets that may inform ancestry-aware screening, risk stratification, and individualized treatment strategies. Bridging these ethnic and molecular divides is essential for translating genomic discoveries into equitable precision oncology for ESCC.

Key Words: Ethnic diversity; Genetic susceptibility; Mutational signatures; Gene-environment interactions; Esophageal squamous cell carcinoma

Core Tip: Ethnic genomic differences in esophageal squamous cell carcinoma (ESCC) reveal distinct genetic risk loci, mutational signatures, and gene-environment interactions that shape disease susceptibility across populations. Integrating multi-ethnic, multi-omics data is crucial for developing personalized strategies for prevention, diagnosis, and treatment, addressing disparities in ESCC outcomes. Ethnic genomic differences in ESCC reveal distinct genetic risk loci, mutational signatures, and gene-environment interactions that shape disease susceptibility across populations. Integrating multi-ethnic, multi-omics data is crucial for developing personalized strategies for prevention, diagnosis, and treatment, addressing disparities in ESCC outcomes.

INTRODUCTION

Esophageal squamous cell carcinoma (ESCC) remains one of the deadliest malignancies globally, exhibiting marked ethnic and geographic disparities in incidence and outcomes. In particular, the disease burden is disproportionately high in East Asia and sub-Saharan Africa[1,2]. Despite the advances in treatment options, the prognosis for ESCC remains poor, with authoritative epidemiological reports indicating a five-year survival rate commonly below 25% in high-incidence regions[3-5]. Moreover, recent studies have identified survival disparities among different ethnic groups, with certain African and African American populations experiencing comparatively poorer outcomes than some East Asian cohorts, further highlighting the importance of understanding ethnicity-related factors influencing prognosis[6-8]. This grim survival rate is compounded by the distinct genetic landscapes across different ethnic groups, which influence both the risk and progression of the disease[9,10]. The growing understanding of genetic factors influencing ESCC risk, such as mutations in genes like TP53, ADH1B, and ALDH2, underscores the importance of tailoring prevention and treatment strategies to the genetic backgrounds of diverse populations[11,12]. Recent technological advancements, such as genome-wide association studies and next-generation sequencing, have elucidated these ethnic-specific variations, revealing a complex interplay between inherited susceptibility and environmental exposures[2,12]. These major ethnic genomic patterns are illustrated in Figure 1.

Figure 1 A schematic diagram illustrating the ethnic genomic differences in esophageal squamous cell carcinoma. ESCC: Esophageal squamous cell carcinoma; EGFR: Epidermal growth factor receptor.

GENETIC SUSCEPTIBILITY LOCI

Numerous studies have identified shared and distinct genetic risk loci associated with ESCC across ethnic populations. For instance, common susceptibility genes such as TP53, ADH1B, ALDH2, and PIK3CA have been implicated in ESCC risk across diverse groups, with certain alleles showing different prevalence and impacts based on ethnicity[2,11]. For example, the ALDH2 variant exhibits a high allele frequency of approximately 25%-40% in East Asian populations but is nearly absent in African and Caucasian groups, while ADH1B Arg47His shows a frequency above 60% in East Asians compared with < 5% in Africans and Caucasians[13,14]. Genetic variants in alcohol-metabolizing enzymes, especially ADH1B and ALDH2, have been particularly significant in East Asian populations, where these polymorphisms significantly modify the risk of ESCC in those with heavy alcohol consumption[15-17]. Meta-analytic data further demonstrate that carriers of the ALDH2 risk allele who consume alcohol have a markedly elevated risk [odds ratio (OR = 4.0-6.0)], whereas the corresponding OR in non-East Asian cohorts is substantially lower due to minimal allele prevalence[18-20]. These findings emphasize the critical role of gene-environment interactions in determining the risk of ESCC, where genetic predispositions interact with environmental factors such as alcohol and tobacco use[15,21]. However, studies conducted in African cohorts remain limited, and while loci such as CHEK2 have been identified in both African and Chinese populations, there is still insufficient data to fully understand the genetic predisposition to ESCC in these underrepresented groups[22,23]. A comparative overview of these population-specific variations is summarized in Table 1.

Table 1 Genetic variants and mutational signatures in ethnically diverse esophageal squamous cell carcinoma populations.

Study population	Genetic variants	Mutational signatures	Gene-environment interactions	Clinical implications
East Asian (Chinese)	TP53, ADH1B, ALDH2, PIK3CA, PLCE1	APOBEC, alcohol-related signature	Strong interaction with alcohol and tobacco	High risk due to alcohol metabolism variants, targeted therapies
African American	TP53, EGFR, CHEK2, BRCA2	APOBEC, tobacco-related signature	Tobacco and alcohol significantly influence risk	Poor prognosis linked to EGFR mutations and tobacco use
African (sub-Saharan)	CHEK2, ADH1B, ALDH2	Tobacco-related signatures	Limited data on gene-environment interactions	Need for more genetic studies and tailored interventions
Caucasian	TP53, GSTP1, PIK3CA, EGFR	Alcohol-related mutational signature	Tobacco use and genetic interaction with alcohol	Risk assessment models considering both genetic and lifestyle factors
Kazakh	ADH1B, ALDH2, TP53	APOBEC, alcohol-related signature	Tobacco, alcohol, and dietary habits	Gene-environment modeling crucial for prevention strategies

EGFR: Epidermal growth factor receptor.

MUTATIONAL SIGNATURES AND SOMATIC ALTERATIONS

Mutational signature profiling has been a key focus in understanding the genomic landscape of ESCC, revealing a variety of mutations that differ across populations. The APOBEC-related mutational signature, commonly associated with tobacco and alcohol exposure, has been frequently observed in ESCC tumors, particularly in East Asian populations, highlighting the role of environmental carcinogens in shaping the mutational landscape of the disease[24,25]. Representative genomic profiling studies report that APOBEC signatures account for approximately 25%-45% of the total mutational burden in Chinese ESCC samples, compared with 10%-20% in African ESCC cohorts[26]. Studies have shown that mutational signatures, such as those related to alcohol metabolism, correlate with genetic variants in alcohol-metabolizing genes like ALDH2 and ADH1B, especially in populations where alcohol consumption is prevalent[15-17]. Additionally, genomic analyses reveal that mutations in KMT2D and NOTCH1 occur in 20%-30% and 15%-25% of northern Chinese ESCC cases, respectively, but appear at substantially lower frequencies (< 10%) in several African datasets, highlighting geographic and ethnic variation in somatic mutation spectra[27-30]. These mutations, often influenced by regional environmental exposures, contribute to the heterogeneity of ESCC, underscoring the complexity of its pathogenesis across different populations[12,21].

GENE-ENVIRONMENT INTERACTIONS

Gene-environment interactions play a pivotal role in determining the susceptibility to ESCC, with environmental factors such as alcohol, tobacco, and dietary habits influencing the effects of genetic variants. Polymorphisms in ADH1B and ALDH2, which modulate alcohol metabolism, are strongly associated with increased ESCC risk in East Asian populations, particularly among those who consume alcohol[21,31]. These findings highlight the importance of gene-environment interactions in modulating disease risk and suggest that genetic predispositions may amplify the carcinogenic effects of environmental exposures such as tobacco smoking and alcohol consumption[15,32]. In African populations, although tobacco and alcohol consumption are prevalent, gene-environment interaction studies remain sparse[33,34], limiting our understanding of the full scope of these interactions. Some studies have also investigated other lifestyle factors, such as oral health and diet, in Chinese cohorts, showing that genetic risk can be modulated by environmental exposures like smoking and diet[35]. Mechanistically, ALDH2 and ADH1B risk alleles impair the clearance of acetaldehyde, leading to increased intracellular accumulation of this carcinogenic metabolite, which in turn promotes DNA adduct formation, mutagenesis, and chronic epithelial inflammation[36,37]. Tobacco-related carcinogens such as N-nitrosamines and polycyclic aromatic hydrocarbons activate oxidative-stress pathways and overwhelm detoxification systems, particularly in individuals with reduced-function alleles in detoxification genes, thereby enhancing genomic instability[38,39]. Environmental exposures can also induce epigenetic alterations, including promoter hypermethylation of tumor suppressor genes and dysregulated histone modifications, which further contribute to aberrant transcriptional programs in ESCC. In addition, chronic alcohol and tobacco exposure triggers pro-inflammatory signaling and immune microenvironment remodeling, creating a permissive milieu for malignant transformation, especially in genetically susceptible populations. These findings emphasize the need for comprehensive studies that include a broader range of environmental factors, particularly in underrepresented populations.

TRANSCRIPTOMIC AND EPIGENOMIC VARIATION

Transcriptomic analyses across various ethnic populations have uncovered significant differences in gene expression patterns that may contribute to ethnic disparities in ESCC. For instance, African American ESCC tumors exhibit differential expression in immune-related pathways and detoxification processes, such as the NRF2 pathway, which is critical for cellular response to oxidative stress and carcinogen exposure[24,40,41]. Epigenomic studies have also revealed consistent tumor-specific methylation alterations, which are potential biomarkers for early detection and prognosis. For example, methylation changes in genes like PAX9 and SIM2 have been identified across multiple high-incidence populations, suggesting their potential utility as diagnostic or prognostic markers[42]. However, despite these advances, the integration of multi-omics data, including transcriptomic and epigenomic profiles, remains limited, particularly in non-Asian populations. Moreover, there is a lack of longitudinal data to assess how these epigenetic changes evolve during tumor progression[40,41,43].

CLINICAL IMPLICATIONS

The identification of specific genetic mutations and mutational signatures in ESCC has significant clinical implications for diagnosis, prognosis, and treatment. For instance, mutations in genes like NOTCH1, KMT2D, and PIK3CA have been linked to poor prognosis and resistance to chemoradiotherapy in Chinese ESCC patients, highlighting the potential of these markers for guiding treatment decisions[44,45]. Moreover, the discovery of recurrent somatic mutations and copy number alterations, such as epidermal growth factor receptor mutations in African American ESCC, offers promising therapeutic targets[24]. These findings suggest that precision medicine, informed by genetic profiling, could improve treatment outcomes by selecting therapies tailored to the unique genomic landscape of each patient's tumor[46]. However, the clinical application of these findings is often hindered by disparities in access to genomic testing and targeted therapies across different populations[47].

CHALLENGES IN CURRENT RESEARCH

Despite the wealth of information emerging from genomic studies on ESCC, several challenges remain. One significant limitation is the underrepresentation of certain ethnic groups, particularly African populations, in genomic research. This gap in diversity hinders the development of comprehensive, population-wide risk models and therapeutic strategies[34]. Additionally, many studies suffer from small sample sizes, which limit the statistical power of the findings and their generalizability to larger populations[22,44]. Methodological variability across studies, including differences in sequencing platforms, data processing pipelines, and analytical approaches, introduces further challenges in comparing results across studies[34]. The lack of longitudinal data also restricts the ability to track the progression of genetic mutations and their impact on clinical outcomes[26,48].

FUTURE DIRECTIONS

To address these challenges, future research must prioritize large-scale, multi-ethnic studies that incorporate diverse populations, particularly African and mixed-ancestry cohorts, to provide a more comprehensive understanding of ESCC pathogenesis. Additionally, integrating multi-omics approaches, including genomic, transcriptomic, and epigenomic data, will be crucial for uncovering the full complexity of ESCC and its ethnic variations. More robust models of gene-environment interactions are also needed, particularly those that include a broader range of environmental exposures, to improve risk prediction and prevention strategies. Furthermore, functional validation of identified genetic variants and biomarkers is essential for translating genomic findings into clinical practice. Finally, the development of population-specific genetic risk scores, incorporating both genetic and environmental factors, could significantly enhance precision medicine strategies for ESCC.

CONCLUSION

In conclusion, the genetic landscape of ESCC is profoundly shaped by ethnic variations, with distinct mutational signatures and susceptibility loci identified across different populations. While advances in genomic, transcriptomic, and epigenomic profiling have shed light on the complex interplay between genetic predisposition and environmental exposures, significant gaps remain, particularly in underrepresented populations like Africans. These disparities underscore the need for more inclusive, multi-ethnic studies that integrate genetic and environmental factors to better understand ESCC pathogenesis. Future research should focus on functional validation of genetic variants, incorporation of multi-omics approaches, and the development of precision medicine strategies tailored to diverse ethnic groups. Addressing these gaps will be crucial for improving risk stratification, early detection, and personalized therapies for ESCC, ultimately contributing to better clinical outcomes across all populations.