Esophageal squamous cell carcinoma susceptibility of activin A receptor type 1C variants in Chinese population

Abstract

Lin et al’s investigation on the association of activin A receptor type 1C (ACVR1C) (transforming growth factor beta type I receptor) single nucleotide polymorphisms (SNPs) with esophageal squamous cell carcinoma (ESCC) risk in the Chinese population is a scientific approach. This study explores the susceptibility of ACVR1C polymorphism towards ESCC in the Chinese population, highlighting the polymorphism’s potentiality as an early diagnostic and therapeutic target. The author assessed about a thousand ESCC Chinese patients’ samples for ACVR1C SNPs in a hospital-based cohort study using the ligation detection reaction method. Further, the hypothesis was tested using appropriate statistical genetic models and stratified analysis. ACVR1C SNPs can help assess ESCC susceptibility stratification and provide valuable information for individual diagnosis and treatment of ESCC patients. In order to account for confounding variables, find genuine SNP-disease relationships, boost statistical power, and make biological interpretation easier, it is imperative that genetic association studies of ESCC incorporate pertinent clinical aspects.

Key Words: Activin A receptor type 1C; Single nucleotide polymorphism; Cancer; Diagnosis; Gene association

Core Tip: The present hospital-based case-control study investigates the activin A receptor type 1C (ACVR1C) single nucleotide polymorphisms association with the esophageal squamous cell carcinoma (ESCC) risk in a very small population. The author tried to stratify the association with the demographic profile of the patients but lacked association with the clinical characteristics of the test patients. ACVR1C expression should be studied in the samples as it is associated with cancer hallmarks and clinical outcomes in a cancer context-dependent manner. Next, the author should include the patients getting ESCC therapy as one of the groups as ACVR1C expression plays a role in chemotherapeutic response to cancer. These measures will provide useful information for clinical practice.

TO THE EDITOR

I am delighted to read the high-quality article by Lin et al[1], published in the World Journal of Gastrointestinal Oncology. The main focus of this article is to establish an association between activin A receptor type 1C (ACVR1C) single nucleotide polymorphisms (SNPs) esophageal squamous cell carcinoma (ESCC) susceptibility in the Chinese Han population. Through genotyping and statistical analysis utilizing genotypic distribution frequency, demographic characteristics, genetic models (co-dominant, dominant, recessive, and additive), SNP-disease risk association, the effect of hierarchical variables, haplotype, and linkage disequilibrium in a 1043 case group (compared to 1143 normal individuals), two ACVR1C SNPs (SNP rs4556933 and rs77886248) were found to be associated with ESCC susceptibility in the Chinese Han population. The report provides a scientific basis for early diagnostic and therapeutic potential in ACVR1C SNPs.

ACVR1C AND ESCC

This report assesses the association of the ACVR1C SNPs (rs4664229, rs4556933, rs77886248, rs77263459, and rs6734630) with the ESCC susceptibility in the Chinese Han population. The data presented by the authors indicate that the SNPs rs4556933 and rs77886248 are associated with ESCC susceptibility. While their data are interesting, I need to express some concerns regarding the report. There is a lack of clinical characteristics of ESCC patients considered in the study, such as histological grade, tumor size, and lymph node. These clinical features are important for the association of a given SNP with ESCC[2]. If not considered in the study, they can act as confounders, leading to false associations between SNPs and the disease. For example, a SNP may appear linked to ESCC, but it's actually linked to a more aggressive tumor type with a high histological grade, more prevalent in specific populations. ESCC is a diverse disease that shows different symptoms and has different outcomes. If we overlook these factors, we might miss real associations between SNPs and diseases that only occur in certain groups of patients, like those with big tumors or involved lymph nodes. Clinical features can provide valuable information that improves the statistical power of the analysis. For example, if we only look at patients with a particular stage or grade of ESCC, the impact of certain SNPs could be clearer, even if the general link is weak. Moreover, by studying the clinical characteristics of the test tumor sample, one can effectively correlate the association of SNPs with the survival and relapse of the disease. Tan et al[3] revealed in a case-control study that rs13042395 (SLC52A3 SNP) is linked to both relapse-free survival and regional lymph node metastases in patients with ESCC. Interpreting the biological relevance of any discovered SNP-disease relationships becomes difficult if these clinical characteristics are not taken into account. Do these SNPs play a direct role in the formation of tumors, or are they merely indicators of other variables that affect the illness? Other parameters, such as smoking history, alcohol consumption, diet, and other lifestyle factors, are major risk factors for ESCC. Failure to adequately assess and account for these factors in the analysis can confound the true association between SNPs and ESCC. The author included smoking history and alcohol consumption parameters in the demographic profile of test individuals, but other parameters such as body mass index (BMI) and gastric atrophy may also be included. Previous studies report that BMI and ESCC possess a mild to moderate inverse relation, while gastric atrophy possesses a mild positive association with the disease[4]. Next, author used the never/ever concept to differentiate the ESCC patients for smoking history and alcohol consumption parameters. It is suggested that the subgrouping with different risk factors (such as for alcohol consumption and smokers) may have a different genetic susceptibility to ESCC compared to those without these risk factors. Since ESCC is a diverse disease, its underlying molecular pathways and clinical manifestations might vary. Clinical characteristics can distinguish different ESCC subtypes, each with potentially unique genetic predispositions. Ignoring these subtypes can reduce statistical power and make it more difficult to identify specific SNPs linked to different subtypes of ESCC.

One of the most prevalent malignant tumors, esophageal cancer is highly invasive, metastatic, and has a terrible prognosis. ESCC causes 80% of esophageal cancers and has a 15%-25% 5-year survival rate. There is growing evidence that certain genetic and epigenetic alterations contribute to the carcinogenesis of ESCC[5]. SNPs are a major source of genetic variability in humans. SNPs in genes that regulate DNA mismatch repair, cell cycle regulation, metabolism, and immunology are connected to cancer propensity. Comprehending the processes by which SNPs contribute to cancer susceptibility is essential for elucidating the molecular etiology of many malignancies. From a clinical standpoint, SNPs serve as possible diagnostic and therapeutic biomarkers across many cancer types[6]. SNPs, found in various regions of genes like promoters, exons, introns, and, 5′ UTRs and 3′ UTRs, alter gene expression and affect cancer susceptibility. They affect the binding of transcription factors, promoter function, DNA modification, and miRNA binding[6].

By activating the downstream signaling pathways, activin receptors clearly control cellular proliferation, chemoresistance, stemness, and other cancer hallmarks. ACVR1C inhibits cell proliferation in breast, endometrial, ovarian, and other cancer cells. Sometimes ACVR1C inhibits cancer cell proliferation in a cancer context-dependent manner[7]. In general, ACVR1C induces apoptosis in cancer cells through SMAD2/3-dependent gene expression (Bax/Bcl2 and Xiap) regulation and signaling pathway (mitogen activated protein kinase) regulation[7]. Reports also highlight the contrasting roles of activin receptors in inducing apoptosis in cancer cells[8]. ACVR1C downregulation significantly reduced cell invasion and metastasis in poor differentiated adenocarcinoma (PDAC), retinoblastoma and breast cancer pre-clinical models[7]. Pre-clinical studies established cancer context dependent response of ACVR1C expression on chemotherapeutic responsiveness[7,8]. It is confirmed that the clinical characteristics of cancer patients are much correlated with the presence of activin receptors. Activin receptor expression levels can be employed to predict cancer patient (breast, pulmonary neuroendocrine tumors, glioblastoma, breast cancer, and PDAC) survival parameters, such as overall/recurrence-free/disease-free/progression-free survival. ACVR1C downregulation was associated with shorter survival times[9-12]. On the other hand, high expression of ACVR1C is found to be significantly associated with deep submucosal invasion in ESCC patients[13].

CONCLUSION

The present clinical study-based association of ACVR1C SNPs with the ESCC risk is in need of improvement. It lacks the presentation of overall understanding of ACVR1C in cancer subjects, which is being presented here in a disease-biased manner. An updated study should be designed in the future by including clinical characteristics of the test samples, a more heterogeneous population, and patients getting ESCC therapy. Including these recommendations will provide better understanding and association of ACVR1C SNPs in the ESCC context.

ACKNOWLEDGEMENTS

Author acknowledges, Central University of Punjab, Bathinda, Punjab, India for providing necessary infrastructure.