Risk Of Esophageal Squamous Cell Carcinoma Research Articles

Relationship between esophageal squamous cell carcinoma risk and alcohol-related ALDH2 and ADH1B polymorphisms: Evidence from a meta-analysis and Mendelian randomization analysis.

Previous studies have shown that ALDH2 and ADH1B genes may be associated with alcohol metabolism and the risk of esophageal squamous cell carcinoma (ESCC), with inconsistent results. This meta-analysis aimed at comprehensively assessing the associations between ALDH2 and ADH1B polymorphisms and the risk of ESCC to synthesize and clarify the evidence. We calculated summary estimates of the associations between four genetic variants (rs671 and rs674 in ALDH2, and rs1229984 and rs1042026 in ADH1B) and the ESCC risk across 23 publications in the additive model and allelic model. Venice criteria, Bayesian false discovery probability (BFDP), and false-positive reporting probability (FPRP) were used to assess the strength of epidemiological evidence. Heterogeneity among studies was evaluated by using the Higgin's I2 statistic, and publication bias was assessed by using funnel plots and Begg's test. A Mendelian randomization (MR) analysis was performed to determine the causal association between alcohol intake and esophageal cancer risk. Data from the HaploReg v4.1 and PolyPhen-2 were analyzed for functional annotations. Of the four genetic variants, rs671 of ALDH2 was associated with a significantly reduced risk of ESCC (OR: 0.60, 95% CI: 0.50-0.73), whereas rs1229984 of ADH1B was associated with a significantly increased risk (2.50, 95% CI: 1.70-3.69) in the additive model. In the allelic model, the variant rs1229984 of ADH1B also increased the risk of ESCC (OR: 1.50; 95% CI: 1.21-1.87). The result for the variant rs671 was considered as strong epidemiological evidence. Functional annotations identified that the four variants were related to the enhancer histone marks and motif changes. The other two variants were not associated with the ESCC risk (rs674 of ALDH2 OR: 1.22, 95% CI: 0.71-2.12; rs1042026 of ADH1B OR: 1.28, 95% CI: 0.52-3.14) in the additive model. The MR analysis did not find a causal effect of alcohol on the esophageal cancer risk. The results showed that ADH1B rs1229984 was significantly associated with an increased the risk of ESCC.

Genetic polymorphisms of CYP24A1 gene and cancer susceptibility: a meta-analysis including 40640 subjects

BackgroundWhether cytochrome P450 24A1 (CYP24A1) polymorphism is associated with cancer susceptibility, the individual study results are still controversial. Therefore, we performed a comprehensive study to identify the association of CYP24A1 polymorphisms (rs4809960, rs6068816, rs2296241, rs4809957, rs2762939) with cancer susceptibility.MethodsElectronic databases including Cochrane Library, PubMed, and Embase were systematically retrieved for relevant publications. Fixed or random-effect model was selected to calculate odds ratios (ORs) with their 95% confidence intervals (95%CI).ResultsEighteen published articles were identified. The results indicated that rs4809960 polymorphism was associated with a decreased cancer risk in Caucasian (TT vs. TC+CC: P=0.035; C vs. T: P=0.016) and Asian population (CC vs. TC+TT: OR P=0.044; TT vs. TC+CC: P=0.021; CC vs. TT: P=0.020; C vs. T: P=0.008) and breast cancer risk (TT vs. TC+CC: P = 0.007; TC vs. TT: P=0.004; C vs. T: P=0.033). A significant association was found between rs2296241 polymorphism and esophageal squamous cell carcinoma risk (AA vs. GG+AG: P = 0.023) and prostate cancer susceptibility (A vs. G: P=0.022). Furthermore, rs4809957 polymorphism was associated with prostate cancer susceptibility in Caucasian (GG vs. GA+AA: P=0.029; GA vs. GG: P=0.022) and breast cancer susceptibility (AA vs. GG+GA: P=0.012; AA vs. GG, P=0.010; A vs. G: P=0.024). Additionally, rs6068816 polymorphism significantly decreased the lung cancer (CC vs. CT+TT: P = 0.016; TT vs. CC: P = 0.044; CT vs. CC: P = 0.036; T vs. C: P = 0.016) and breast cancer risk (TT vs. CC+CT: P = 0.043; TT vs. CC: P = 0.039). No association was found for rs2762939 polymorphism with overall cancer risk. However, for rs2296241, rs4809957, and rs6068816 polymorphisms, there were no significant differences after the Bonferroni correction.ConclusionThe meta-analysis suggested that rs4809960 was associated with cancer risk and might be a genetic marker for predicting cancer risk. More large-scale and large-sample studies are necessary to further confirm these results.

Genome-wide association study of esophageal squamous cell cancer identifies shared and distinct risk variants in African and Chinese populations

Esophageal squamous cell carcinoma (ESCC) has a high disease burden in sub-Saharan Africa and has a very poor prognosis. Genome-wide association studies (GWASs) of ESCC in predominantly East Asian populations indicate a substantial genetic contribution to its etiology, but no genome-wide studies have been done in populations of African ancestry. Here, we report a GWAS in 1,686 African individualswith ESCC and 3,217 population-matched control individuals to investigate its genetic etiology. We identified a genome-wide-significant risk locus on chromosome 9 upstream of FAM120A (rs12379660, p= 4.58×10-8, odds ratio= 1.28, 95% confidence interval= 1.22-1.34), as well as a potential African-specific risk locus on chromosome 2 (rs142741123, p= 5.49×10-8) within MYO1B. FAM120A is a component of oxidative stress-induced survival signals, and the associated variants at the FAM120A locus co-localized withhighly significant cis-eQTLs in FAM120AOS in both esophageal mucosa and esophageal muscularis tissue. A trans-ethnic meta-analysis was then performed with the African ESCC study and a Chinese ESCC study in a combined total of 3,699 ESCC-affected individuals and 5,918 control individuals, which identified three genome-wide-significant loci on chromosome 9 at FAM120A (rs12379660, pmeta= 9.36×10-10), chromosome 10 at PLCE1 (rs7099485, pmeta= 1.48×10-8), and chromosome 22 at CHEK2 (rs1033667, pmeta= 1.47×10-9). This indicates the existence of both shared and distinct genetic risk loci for ESCC in African and Asian populations. Our GWAS of ESCC conducted in a population of African ancestry indicates a substantial genetic contribution to ESCC risk in Africa.

Spatial transcriptomics analysis of esophageal squamous precancerous lesions and their progression to esophageal cancer

Esophageal squamous precancerous lesions (ESPL) are the precursors of esophageal squamous cell carcinoma (ESCC) including low-grade and high-grade intraepithelial neoplasia. Due to the absence of molecular indicators, which ESPL will eventually develop into ESCC and thus should be treated is not well defined. Indicators, for predicting risks of ESCC at ESPL stages, are an urgent need. We perform spatial whole-transcriptome atlas analysis, which can eliminate other tissue interference by sequencing the specific ESPL regions. In this study, the expression of TAGLN2 significantly increases, while CRNN expression level decreases along the progression of ESCC. Additionally, TAGLN2 protein level significantly increases in paired after-progression tissues compared with before-progression samples, while CRNN expression decreases. Functional studies suggest that TAGLN2 promotes ESCC progression, while CRNN inhibits it by regulating cell proliferation. Taken together, TAGLN2 and CRNN are suggested as candidate indicators for the risk of ESCC at ESPL stages.

Local recurrence risk of esophageal squamous cell carcinoma due to intralesional damage during endoscopic submucosal dissection.

It is unclear whether additional treatment should be considered given the recurrence risk after endoscopic submucosal dissection (ESD) for esophageal squamous cell carcinoma (ESCC) when the vertical margin is positive or unclear (VM1/VMX) due to intralesional damage. This study aimed to elucidate the local recurrence risk of ESCC caused by intralesional damage during ESD. Among consecutive patients with pT1a ESCCs initially treated by ESD at our institution between January 2006 and December 2018, ESCCs diagnosed as VM1/VMX were retrospectively reviewed. Exclusion criteria were piecemeal resection and any additional treatment after ESD. Intralesional damage included the following three types: a macroscopic hole inside the lesion, an incision from the lateral margin of the specimen into the lesion, and crushing injury or burn effect into the deepest area of the lesion without an obvious hole. The local recurrence rate after ESD was primarily analyzed. Of 1174 pT1a ESCCs initially treated using ESD, 22 lesions were histopathologically diagnosed as VM1/VMX due to intralesional damage (1.9%; 95% confidence interval [CI], 1.2-2.8%). At a median follow-up period of 60.0 (interquartile range, 15.0-84.0) months, no local recurrence was observed (0.0%; 95% CI, 0.0-13.3%) among 21 lesions finally evaluated. The impact of intralesional damage during ESD for ESCC on local recurrence might be negligible. Follow-up without additional treatment may be acceptable even if intralesional damage occurs and results in VM1/VMX after ESD for pT1a ESCCs.

Elafin as a Prognostic Marker in Esophageal Squamous Cell Carcinoma: A Pilot Study Using Three-Dimensional Imaging and Genomic Profiling.

Esophageal cancers are globally the sixth deadliest malignancy, with limited curative options. The association of high serum elafin levels, a molecule produced by epithelial cells, with esophageal squamous cell carcinoma (ESCC) risk is established, but its link to poor ESCC prognosis remains unclear. To explore this question, we first used three-dimensional confocal imaging to create a model of the spatial distribution of elafin inside locoregional ESCC tissues. Then, after analyzing data obtained from whole-genome microarrays for ESCC cell lines and their more invasive sublines, we performed in vitro experiments using RNA sequencing to identify possible elafin-related pathways. Three-dimensional tissue imaging showed elafin distributed as an interweaved-like fibrous structure in the stroma of tissue obtained from patients with high serum levels of elafin and poorer prognoses. By contrast, the signal was confined inside or around the tumor nest in patients who had lower serum levels and better survival. The analysis of a TCGA dataset revealed that higher levels of elafin mRNA in stage I-IIIA ESCC patients were associated with shorter survival. The in vitro studies revealed that elafin promoted ESCC cell proliferation, migration, and invasion via the epithelial-mesenchymal transition pathway. Thus, elafin inhibition could potentially be used therapeutically to improve survival in patients with locoregional ESCC.

Increased risk of esophageal squamous cell carcinoma in patients with squamous dysplasia: a nationwide cohort study in the Netherlands.

Squamous dysplasia is the histological precursor of esophageal squamous cell carcinoma (ESCC). The optimal management for distinct squamous dysplasia grades remains unclear because the corresponding risk of developing ESCC is unknown. We aimed to assess the ESCC risk in patients with esophageal squamous dysplasia in a Western country. This nationwide cohort study included all patients with esophageal squamous dysplasia, diagnosed between 1991 and 2020 in the Dutch nationwide pathology databank (Palga). Squamous dysplasia was divided in mild-to-moderate dysplasia (mild, low-grade, and moderate dysplasia) and higher-grade dysplasia (high-grade dysplasia, severe dysplasia, carcinoma in situ). ESCC were identified in Palga and the Netherlands Cancer Registry. The primary endpoint was diagnosis of prevalent (≤6months) and incident (>6months after squamous dysplasia) ESCC. In total, 873 patients (55% male, aged 68years SD ± 13.2) were diagnosed with esophageal squamous dysplasia, comprising mild-to-moderate dysplasia (n = 456), higher-grade dysplasia (n = 393), and dysplasia not otherwise specified (n = 24). ESCC was diagnosed in 77 (17%) patients with mild-to-moderate dysplasia (49 prevalent, 28 incident ESCC) and in 162 (41%) patients with higher-grade dysplasia (128 prevalent, 34 incident ESCC). After excluding prevalent ESCC, the annual risk of ESCC was 4.0% (95% CI: 2.7-5.7%) in patients with mild-to-moderate dysplasia and 8.5% (95% CI: 5.9-11.7%) in patients with higher-grade dysplasia. All patients with squamous dysplasia, including those with mild-to-moderate dysplasia, have a substantial risk of developing ESCC. Consequently, endoscopic surveillance of the esophageal mucosa or endoscopic resection of dysplasia should be considered for patients with mild-to-moderate dysplasia in Western countries. KEY MESSAGES What is already known on this topic? Squamous dysplasia is the histological precursor of ESCC and is divided in distinct grades, based on the proportion of the squamous epithelium with histopathological abnormalities. In Western countries, the optimal management for distinct squamous dysplasia grades remains unclear because the corresponding risk of developing ESCC is unknown. What this study adds The ESCC risk of patients with squamous dysplasia was increased for all patients with squamous dysplasia in a Western country; 2.1% for patients with mild dysplasia, 5.1% for low-grade dysplasia, and 5.2% for moderate dysplasia. Increasing grades of squamous dysplasia were associated with an increased ESCC risk. How this study might affect research, practice, or policy We recommend that endoscopic follow-up or treatment should be considered in all patients with esophageal squamous dysplasia in Western countries: 1) for patients with mild, low-grade, and moderate dysplasia, endoscopic surveillance with careful inspection with narrow band imaging or dye-based chromoendoscopy of the esophageal mucosa is indicated; and 2) for patients with high-grade dysplasia, severe dysplasia and carcinoma in situ adequate endoscopic staging and in case of suspected neoplasia endoscopic treatment should be performed.

Statin use and its association with decreased risk of esophageal squamous cell carcinoma in betel nut chewers.

Betel nut chewing involves the chewing of areca nuts or betel quid (areca nuts wrapped in betel leaves), which is associated with an increased risk of esophageal squamous cell carcinoma (ESCC). Statins have anticancer properties. We investigated the association between statin use and ESCC risk in betel nut chewers. The study included 105 387 betel nut chewers matched statin users and nonusers. Statin use was defined as the use of ≥28 cumulative defined daily doses (cDDDs) of statin. The primary outcome was incidence of ESCC. The incidence rate of ESCC was significantly lower in statin users than in nonusers (2.03 vs. 3.02 per 100 000 person-years). Statin users had a lower incidence rate ratio of 0.66 for ESCC (95% confidence interval [CI]: 0.43-0.85) relative to nonusers. After potential confounders were adjusted for, statin use was determined to be associated with a reduced risk of ESCC (adjusted hazard ratio [aHR], 0.68; 95% CI: 0.51-0.91). A dose-response relationship was observed between statin use and ESCC risk; the aHRs for statin use at 28-182 cDDDs, 183-488 cDDDs, 489-1043 cDDDs, and > 1043 cDDDs were 0.92, 0.89, 0.66, and 0.64, respectively. Statin use was revealed to be associated with a reduced risk of ESCC in betel nut chewers.

A single-center prospective study evaluating the usefulness of artificial intelligence for the diagnosis of esophageal squamous cell carcinoma in a real-time setting

BackgroundSeveral pre-clinical studies have reported the usefulness of artificial intelligence (AI) systems in the diagnosis of esophageal squamous cell carcinoma (ESCC). We conducted this study to evaluate the usefulness of an AI system for real-time diagnosis of ESCC in a clinical setting.MethodsThis study followed a single-center prospective single-arm non-inferiority design. Patients at high risk for ESCC were recruited and real-time diagnosis by the AI system was compared with that of endoscopists for lesions suspected to be ESCC. The primary outcomes were the diagnostic accuracy of the AI system and endoscopists. The secondary outcomes were sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and adverse events.ResultsA total of 237 lesions were evaluated. The accuracy, sensitivity, and specificity of the AI system were 80.6%, 68.2%, and 83.4%, respectively. The accuracy, sensitivity, and specificity of endoscopists were 85.7%, 61.4%, and 91.2%, respectively. The difference between the accuracy of the AI system and that of the endoscopists was − 5.1%, and the lower limit of the 90% confidence interval was less than the non-inferiority margin.ConclusionsThe non-inferiority of the AI system in comparison with endoscopists in the real-time diagnosis of ESCC in a clinical setting was not proven.Trial registrationJapan Registry of Clinical Trials (jRCTs052200015, 18/05/2020).

A variant in CYP26B1 associated with esophageal squamous cell carcinoma risk by affecting retinoic acid metabolism.

All-trans retinoic acid (ATRA) is the natural and synthetic analogue of vitamin A, playing an essential tumor suppressive role in multiple cancers including the esophageal squamous cell carcinoma (ESCC). Cytochrome P450 family 26 subfamily B member 1 (CYP26B1) exerts a critical regulator of ATRA levels through specific inactivation of ATRA to hydroxylated forms. Our previous exome-wide analyses revealed a rare missense variant in CYP26B1 significantly associated with ESCC risk in the Chinese population. However, it is still unclear whether there are common variants in CYP26B1 affect the susceptibility of ESCC and the tumor promotion role of CYP26B1 in vivo. In this research, we conducted a two-stage case-control study comprised of 5057 ESCC cases and 5397 controls, followed by a series of biochemical experiments to explore the function of CYP26B1 and its common variants in the tumorigenesis of ESCC. Intriguingly, we identified a missense variant rs2241057[A>G] in the fourth exon of CYP26B1 significantly associated with the ESCC risk (combined odds ratio = 1.28; 95% confidence interval = 1.15-1.42; p = 2.96 × 10-6 ). Through further functional analysis, we demonstrated that ESCC cells with the overexpression of rs2241057[G] had a significant lower level of retinoic acid, compared with the overexpression of rs2241057[A] or the control vector. In addition, the CYP26B1 overexpression and knock-out ESCC cells affected cell proliferation rate both in vitro and in vivo. These results highlighted the carcinogenicity of CYP26B1 related to the ATRA metabolism in ESCC risk.

Blue light imaging and linked color imaging as a screening mode for esophageal squamous cell carcinoma in high-risk patients: Multicenter randomized trial.

Blue light imaging (BLI) and linked color imaging (LCI) are superior to conventional white light imaging for detecting esophageal squamous cell carcinoma (ESCC). Hence, we compared their diagnostic performances in ESCC screening. This open-labeled, randomized controlled trial was performed at seven hospitals. Patients with a high risk of ESCC were randomly assigned to the BLI group (BLI followed by LCI) and LCI group (LCI followed by BLI). The primary end-point was the detection rate of ESCC in the primary mode. The main secondary end-point was its miss rate in the primary mode. In total, 699 patients were enrolled. The detection rate of ESCC did not significantly differ between the BLI and LCI groups (4.0% [14/351] vs. 4.9% [17/348]; P=0.565); however, the number of patients with ESCC tended to be smaller in the BLI group (19 vs. 30). Notably, the miss rate of ESCC was lower in the BLI group (26.3% [5/19] vs. 63.3% [19/30]; P=0.012) and LCI detected no ESCCs missed by BLI. The sensitivity was higher in BLI (75.0% vs. 47.6%; P=0.042); on the other hand, the positive predictive value in BLI tended to be lower (28.8% vs. 45.5%; P=0.092). The detection rates of ESCC did not significantly differ between BLI and LCI. Although BLI may have the potential to be advantageous over LCI for the diagnosis of ESCC, it is still unclear whether BLI is superior to LCI, and a further large-scale study is needed. Japan Registry of Clinical Trials (jRCT1022190018-1).

Association of Antihistamine Use with Increased Risk of Esophageal Squamous Cell Carcinoma: A Nationwide, Long-Term Follow-Up Study Using Propensity Score Matching.

To examine the association between H1-antihistamines (AHs) use and the incidence of esophageal squamous cell carcinoma (ESCC) in a head-to-head propensity score matching (PSM) comparative study. Retrospective cohort study. Nationwide population-based study in Taiwan. 1289,526 adults from the National Health Insurance Research Database from 2008 to 2018. AH use. Incidence rates (IRs), incidence rate ratios (IRRs), and adjusted hazard ratios (aHRs) of ESCC in AH users compared with nonusers. AH users had a significantly higher IR of ESCC than nonusers (1.47 vs. 1.36 per 100,000 person-years). The IRR (95% CI) for ESCC was 1.18 (1.08-1.28) in AH users compared with nonusers. After adjustment for age, sex, income levels, urbanization, cigarettes smoking, alcoholic related diseases, comorbidities, medication use, and Charlson Comorbidity Index scores, the aHR (95% CI) for ESCC was 1.22 (1.12-1.33) in AH users compared with nonusers. A dose-response relationship was also observed, with aHRs for AH use at 28-182, 183-488, 489-1043, and >1043 cumulative defined daily doses (cDDDs) of 1.12, 1.20, 1.25, and 1.37, respectively, compared with <28 cDDDs. Our study found a significant association between AH use and the increased risk of ESCC, with a dose-response relationship. This study suggests that AH use may increase the risk of ESCC, especially at high doses, and highlights the importance of caution when prescribing AHs.

Development and Validation of Esophageal Squamous Cell Carcinoma Risk Prediction Models Based on an Endoscopic Screening Program

Assessment tools are lacking for screening of esophageal squamous cell cancer (ESCC) in China, especially for the follow-up stage. Risk prediction to optimize the screening procedure is urgently needed. To develop and validate ESCC prediction models for identifying people at high risk for follow-up decision-making. This open, prospective multicenter diagnostic study has been performed since September 1, 2006, in Shandong Province, China. This study used baseline and follow-up data until December 31, 2021. The data were analyzed between April 6 and May 31, 2022. Eligibility criteria consisted of rural residents aged 40 to 69 years who had no contraindications for endoscopy. Among 161 212 eligible participants, those diagnosed with cancer or who had cancer at baseline, did not complete the questionnaire, were younger than 40 years or older than 69 years, or were detected with severe dysplasia or worse lesions were eliminated from the analysis. Risk factors obtained by questionnaire and endoscopy. Pathological diagnosis of ESCC and confirmation by cancer registry data. In this diagnostic study of 104 129 participants (56.39% women; mean [SD] age, 54.31 [7.64] years), 59 481 (mean [SD] age, 53.83 [7.64] years; 58.55% women) formed the derivation set while 44 648 (mean [SD] age, 54.95 [7.60] years; 53.51% women) formed the validation set. A total of 252 new cases of ESCC were diagnosed during 424 903.50 person-years of follow-up in the derivation cohort and 61 new cases from 177 094.10 person-years follow-up in the validation cohort. Model A included the covariates age, sex, and number of lesions; model B included age, sex, smoking status, alcohol use status, body mass index, annual household income, history of gastrointestinal tract diseases, consumption of pickled food, number of lesions, distinct lesions, and mild or moderate dysplasia. The Harrell C statistic of model A was 0.80 (95% CI, 0.77-0.83) in the derivation set and 0.90 (95% CI, 0.87-0.93) in the validation set; the Harrell C statistic of model B was 0.83 (95% CI, 0.81-0.86) and 0.91 (95% CI, 0.88-0.95), respectively. The models also had good calibration performance and clinical usefulness. The findings of this diagnostic study suggest that the models developed are suitable for selecting high-risk populations for follow-up decision-making and optimizing the cancer screening process.

Metformin attenuates the progression of esophageal squamous cell carcinoma by downregulating miR-141-3p to enhance SCEL

IntroductionMetformin (Met), a first-line oral anti-type 2 diabetes medication used globally, has been shown to hinder cancer progression via regulation of microRNAs (miRNAs). The previous reports on the relationship between Met use and the risk of esophageal squamous cell carcinoma (ESCC) have been controversial. Hence, this study aimed to explore how Met affected ESCC progression and the underlying molecular mechanism.Material and methodsCell migration, viability and invasiveness were respectively investigated using wound healing, CCK-8 and transwell assay. The expressions of miR-141-3p and Sciellin (SCEL) mRNA were examined by mean of quantitative real-time PCR (qRT-PCR) assay, and SCEL protein level was quantified by western blotting. In vivo tests of Met were performed on animals. The predicted binding of miR-141-3p to SCEL was more evidenced by dual-luciferase assay.ResultsMet treatment in ESCC cell largely impaired cell viability, migration and invasiveness. MiR-141-3p showed high expression in ESCC and was downregulated in ESCC cells after Met treatment. MiR-141-3p upregulation in Met-administered ESCC cells largely restored cell proliferative ability, migration and invasiveness. MiR-141-3p also attenuated the anti-tumor effect of Met in vivo. MiR-141-3p targeted SCEL whose expression was declined in ESCC, and SCEL expression was reinforced in ESCC cells after Met treatment. MiR-141-3p upregulation depleted SCEL expression and thus partially abolished the anti-cancer impacts of SCEL in Met-treated ESCC cells.ConclusionsMet restrains the progression of ESCC by regulating the miR-141-3p/SCEL axis. Our findings clearly show that Met is associated with a lower risk of ESCC, and its anticancer effect could potentially be used to treat ESCC.

Long-term Incidence Rates of Esophageal Squamous Cell Carcinoma in Chinese Patients With Low-grade Intraepithelial Neoplasia and Association of Surveillance Endoscopy With Incidence

Surveillance endoscopy is recommended for patients with low-grade intraepithelial neoplasia (LGIN); high-quality evidence about the use of surveillance endoscopy and esophageal squamous cell carcinoma (ESCC) incidence in patients with LGIN is important but limited. To estimate long-term ESCC incidence rates in patients with LGIN and the association between surveillance endoscopy and ESCC incidence. This community-based, multicenter, prospective cohort study in 9 regions in rural China included patients with LGIN diagnosed by endoscopic screening between July 1, 2007, and December 31, 2016; all participants were followed up until December 31, 2021. The primary outcome was ESCC incidence. The ESCC standardized incidence ratio (SIR) was estimated using sex- and age-specific incidence in the general population of rural China in 2010 and hazard ratios (HRs) and 95% CIs were calculated using Cox proportional hazards models. A total of 3258 patients with LGIN were included; 1772 (54.39%) were men, with a mean (SD) age of 58.21 (6.97) years. Among them, 1378 patients (42.30%) underwent at least 1 surveillance endoscopy (surveillance group) and 1880 (57.70%) did not undergo any surveillance endoscopy (nonsurveillance group). During the follow-up period (median, 7.96 years; IQR, 6.08-10.54 years), 170 ESCC cases were diagnosed, with a cumulative incidence of 6.28 per 1000 person-years. A higher incidence of ESCC (incidence rate, 7.07 per 1000 person-years) was observed in the nonsurveillance group than in the surveillance group (incidence rate, 5.14 per 1000 person-years). Patients with LGIN in the surveillance group had a lower SIR (SIR, 4.07; 95% CI, 1.13-10.34) than those in the nonsurveillance group (SIR, 5.65; 95% CI, 2.00-12.58); however, patients with LGIN in both groups had a higher risk of ESCC than the general population. Patients in the surveillance group had a 31% decreased risk of ESCC incidence (HR, 0.69; 95% CI, 0.50-0.95) compared with those in the nonsurveillance group, after adjusting for baseline risk factors. In this prospective cohort study, patients with LGIN had a higher risk of developing ESCC than the general population, and endoscopic surveillance was associated with a decrease in ESCC incidence in these patients.

Dietary Inflammatory Nutrients and Esophageal Squamous Cell Carcinoma Risk: A Case-Control Study

We conducted a case-control study (532 cases and 532 control) in Chinese adults to investigate the independent and interactive effects of dietary nutrients (pro- or anti-inflammation) on Esophageal Squamous Cell Carcinoma (ESCC) risk. Dietary data were collected using a food questionnaire survey that included 171 items. Two algorithms, the Least Absolute Shrinkage and Selector Operation (LASSO) and Bayesian Kernel Machine Regression (BKMR) were employed to select indicators and evaluate the interactive effect of nutrients' mixture on ESCC risk. Thirteen nutrients were selected, including three pro-inflammatory nutrients (protein, fat and carbohydrate) and ten anti-inflammatory nutrients (fiber, Vitamin A, riboflavin, niacin, Vitamin C, Fe, Se, MUFA, n-3 PUFA and n-6 PUFA). Single-exposure effects of fat, carbohydrate and fiber significantly contributed to ESCC risk. The pro-inflammatory nutrients' submodel discovered that the combined effect was statistically associated with increased ESCC risk. In addition, a higher fat level was significantly associated with ESCC risk. On the contrary, for fiber and riboflavin, the anti-inflammatory nutrients' submodel delineated a significant negative effect on the risk of ESCC. Our result implies that dietary nutrients and their inflammatory traits significantly impacted ESCC occurrence. Additional studies are warranted to verify our findings.

Genetic variant in miR-17-92 cluster binding sites is associated with esophageal squamous cell carcinoma risk in Chinese population

BackgroundSingle nucleotide polymorphisms (SNPs) located in microRNA (miRNA) binding sites can affect the interactions between miRNAs and target genes, which is related to cancer susceptibility and tumorigenesis. However, the association between SNPs located in miR-17-92 cluster binding sites and ESCC risk remains unclear. Therefore, we aimed to explore the relationship between polymorphisms in miR-17-92 cluster binding sites and ESCC susceptibility.MethodsSix SNPs in the binding sites of miR-17-92 cluster were selected using bioinformatics databases, and their association with ESCC risk was investigated in a case-control study (including 488 cases and 512 controls) based on the population from high incidence areas of ESCC in China. We evaluated the SNP-SNP and SNP-smoking interactions using generalized multifactor dimensionality reduction (GMDR). Moreover, the expression of the miR-17-92 cluster and its target genes was determined in ESCC and adjacent normal tissues by quantitative real-time polymerase chain reaction (qRT-PCR). The dual-luciferase reporter assay was conducted to verify the effect of SNPs on the binding affinity between miRNAs and target genes.ResultsWe found that the SNP rs1804506 C > T had a significant association with the decreased ESCC risk. The SNP rs1804506 T allele was associated with a significantly decreased risk of ESCC in the additive model (OR = 0.817, 95% CI = 0.681–0.981, P = 0.030). The rs1804506 T allele had more striking effects on reducing ESCC risk in older individuals, female or non-smoker subgroups. We also found a significant interaction effect between rs1366600 and smoking by GMDR methods (P = 0.011). Additionally, the expression levels of miR-19a-3p and TGFBR3 were significantly downregulated in ESCC tissues compared with normal tissues, and the carriers of rs1804506 TT genotype had lower expression level of TGFBR3 than those of rs1804506 CC/CT genotype. Following dual-luciferase reporter assay showed that the rs1804506 T allele reduced the binding of miR-19a-3p and TGFBR3 3′-UTR.ConclusionsOur findings suggest that the rs1804506 polymorphism in miR-17-92 cluster binding sites contributes to the susceptibility of ESCC, which might provide new clues and scientific evidence for the etiology and biomarkers for the prevention and treatment of ESCC.

Sex and smoking differences in the association between gastroesophageal reflux and risk of esophageal squamous cell carcinoma in a high-incidence area: Golestan Cohort Study.

Prior studies have conflicting findings regarding the association between gastroesophageal reflux disease (GERD) and esophageal squamous cell carcinoma (ESCC). We examined this relationship in a prospective cohort in a region of high ESCC incidence. Baseline exposure data were collected from 50 045 individuals using in-person interviews at the time of cohort entry. Participants were followed until they developed cancer, died, or were lost to follow up. Participants with GERD symptoms were categorized into any GERD (heartburn or regurgitation), mixed symptoms, or heartburn alone. Multivariable Cox regression was used to assess the relationship between GERD symptom group and histologically confirmed ESCC. The model was adjusted for known risk factors for GERD and ESCC. 49 559 individuals were included in this study, of which 9005 had GERD symptoms. Over 13.0 years of median follow up, 290 individuals were diagnosed with ESCC. We found no association between any GERD and risk of ESCC (aHR 0.90, 95% CI: 0.66-1.24, P=.54). Similar findings were observed for the GERD symptom subtypes. Significant interactions between any GERD and sex (P=.013) as well as tobacco smoking (P=.028) were observed. In post-hoc analyses, GERD was associated with a decreased risk of ESCC in men (aHR 0.51, 95% CI: 0.27-0.98 P=.04) and in smokers (aHR 0.26, 95% CI: 0.08-0.83 P=.02). While there was little evidence for an overall association between GERD symptoms and ESCC risk, significant interactions with sex and smoking were observed. Men and smokers with GERD symptoms had a lower risk of ESCC development.

Gene polymorphisms of cyclin-dependent kinase inhibitor and matrix metalloproteinase-9 in Sudanese patients with esophageal squamous cell carcinoma.

The polymorphisms of the cyclin-dependent kinase inhibitor (CDKN1A) gene and matrix metalloproteinase-9 (MMP9) gene may increase one's susceptibility to malignancies. In this study, the association of the single nucleotide polymorphisms (SNPs) CDKN1A rs1059234 c.70C>T at the 3' untranslated region and MMP9 rs17576 (c.836A>G, p.Gln279Arg) with esophageal squamous cell carcinoma (ESCC) in Sudanese individuals were investigated. A case-control study involving age- and gender-matched groups were conducted in a cancer center in eastern Sudan (Gadarif) between April and October 2020. The case group consisted of ESCC patients, whereas the control group comprised healthy subjects. Polymerase chain reaction-restriction fragment length polymorphism was performed for the genotyping of the CDKN1A rs1059234 and MMP9 rs17576 SNPs. The genotyping results were confirmed by Sanger sequencing. The genotype distributions for CDKN1A rs1059234 and MMP9 rs17576 were in agreement with the Hardy-Weinberg equilibrium. The variant allele T in CDKN1 rs1059234 c.70C>T was significantly more prevalent in the ESCC patients than in the healthy controls [51.3% vs. 19.2%; OR=4.4; 95% CI (2.6-7.4); p < 0.001]. Moreover, in CDKN1A rs1059234, the genotype TC + TT [76.9% vs. 38.4%; OR=5.3; 95% CI (2.6-10.7); p < 0.001] was more frequent in the cases than in the controls, and it was significantly associated with ESCC risk. In MMP9 rs17576, the variant allele G was also significantly prevalent in the cases relative to the controls, and it was significantly associated with increased ESCC risk in the cases compared with the controls [27.5% vs. 1.9%; OR=19.4; 95%CI (5.8-64.1); p < 0.001]. Both genotypes containing the allele G (AG + GG) were the most common genotypes in the cases [48.7% vs. 3.8%; OR=23.7; 95%CI (6.8-81.7); p < 0.001], and they significantly increased the risk of ESCC. A significant increase in ESCC risk is associated with the SNPs CDKN1A rs1059234 and MMP9 rs17576.

The role of dietary carotenoids in preventing the development of esophageal squamous cell carcinoma.

Background and aims: Experimental studies showed that carotenoids had anti-carcinogenic properties, but epidemiological studies on the association between dietary carotenoids and esophageal squamous cell carcinoma (ESCC) risk were limited, and the findings were inconsistent. This study aimed to investigate the roles of intake of dietary carotenoids in the development of ESCC among a rural Chinese population. Methods: A population-based case-control study was conducted in Southwest China. A total of 915 incident ESCC cases and 925 community-based controls were included. A validated food frequency questionnaire with 76-item was adopted to collect information about dietary consumption. Intake of dietary calories and each carotenoid was calculated according to the China food composition tables. Odds ratios (OR) with 95% confidence intervals (CI) were calculated by a logistic regression model, with adjustments for age, gender, body mass index, family cancer history, cigarette smoking, alcohol drinking, education, marital status, prudent pattern score, and total calories. Results: In comparison to the highest with lowest intake quartiles, intake of total carotenes (OR: 0.70, 95% CI: 0.52-0.96, Ptrend: 0.024), α-carotene (OR: 0.62, 95% CI: 0.46-0.83, Ptrend: 0.014), β-carotene (OR: 0.63, 95% CI: 0.46-0.86, P-trend: 0.005), and the sum of lutein and zeaxanthin (OR: 0.41, 95% CI: 0.29-0.56, Ptrend<0.001) was significantly associated with a decreased risk of ESCC after adjustment for confounders. Conclusions: The results indicated that a higher intake of total carotene, α-carotene, β-carotene, and the sum of lutein and zeaxanthin was associated with a lower risk of ESCC.