Esophageal Squamous Cell Carcinoma Cases Research Articles

Epigenetic silencing schlafen-11 sensitizes esophageal cancer to ATM inhibitor.

Targeting DNA damage response (DDR) pathway is a cutting-edge strategy. It has been reported that Schlafen-11 (SLFN11) contributes to increase chemosensitivity by participating in DDR. However, the detailed mechanism is unclear. To investigate the role of SLFN11 in DDR and the application of synthetic lethal in esophageal cancer with SLFN11 defects. To reach the purpose, eight esophageal squamous carcinoma cell lines, 142 esophageal dysplasia (ED) and 1007 primary esophageal squamous cell carcinoma (ESCC) samples and various techniques were utilized, including methylation-specific polymerase chain reaction, CRISPR/Cas9 technique, Western blot, colony formation assay, and xenograft mouse model. Methylation of SLFN11 was exhibited in 9.15% of (13/142) ED and 25.62% of primary (258/1007) ESCC cases, and its expression was regulated by promoter region methylation. SLFN11 methylation was significantly associated with tumor differentiation and tumor size (both P < 0.05). However, no significant associations were observed between promoter region methylation and age, gender, smoking, alcohol consumption, TNM stage, or lymph node metastasis. Utilizing DNA damaged model induced by low dose cisplatin, SLFN11 was found to activate non-homologous end-joining and ATR/CHK1 signaling pathways, while inhibiting the ATM/CHK2 signaling pathway. Epigenetic silencing of SLFN11 was found to sensitize the ESCC cells to ATM inhibitor (AZD0156), both in vitro and in vivo. SLFN11 is frequently methylated in human ESCC. Methylation of SLFN11 is sensitive marker of ATM inhibitor in ESCC.

Transcriptionally Active Human Papillomavirus Infection in a Minority of Esophageal Squamous Cell Carcinomas in North America.

The role of Human papillomavirus (HPV) infection in esophageal squamous cell carcinoma (ESCC) is a topic of ongoing debate. This study used two screening approaches to look for evidence of HPV infection in esophageal squamous cell carcinoma. We initially checked for HPV infection in a randomly selected group of 53 ESCC cases. We did not detect any tumors positive for high-risk HPV. However, during clinical practice, we identified an HPV-positive ESCC in the distal esophagus, which tested positive for HPV16. This index case was TP53 wild-type, as determined by next-generation DNA sequencing (NGS). Since TP53 mutations are rare in other HPV-driven cancers, we improved our screening method by limiting our screen to a subset of ESCC cases without TP53 mutations. A second screen of 95 ESCCs (from 93 patients) sequenced by NGS revealed an additional 7 ESCCs with TP53 wild-type status (7.3% of the total). Of the 7 cases, 2 cases were found to be high-risk HPV positive. Both patients also tested positive for circulating cell-free HPV DNA and had a complete response to neoadjuvant chemoradiation. The index patient had microscopic residual tumor following neoadjuvant therapy. The patient underwent adjuvant immunotherapy and remained disease free after 22 months of surveillance. This study affirms the transcriptionally active status of high-risk HPV in a minority of ESCC patients in North America.

PTPN23[Thr] variant reduces susceptibility and tumorigenesis in esophageal squamous cell carcinoma through dephosphorylation of EGFR

Post-translational modifications (PTMs) have emerged as pivotal regulators of the development of cancers, including esophageal squamous cell carcinoma (ESCC). Here, we conducted a comprehensive analysis of PTM-related genetic variants associated with ESCC risk using large-scale genome-wide and exome-wide association datasets. We observed significant enrichment of PTM-related variants in the ESCC risk loci and identified five variants that were significantly associated with ESCC risk. Among them, rs6780013 in PTPN23 exhibited the highest level of significance in ESCC susceptibility in 9,728 ESCC cases and 10,977 controls (odds ratio [OR] = 0.85, 95 % confidence interval [CI] = 0.81– 0.89, P = 9.77 × 10−14). Further functional investigations revealed that PTPN23[Thr] variant binds to EGFR and modulates its phosphorylation at Thr699. PTPN23[Thr] variant substantially inhibited ESCC cell proliferation both in vitro and in vivo. Our findings underscore the critical role of PTPN23[Thr]-EGFR interaction in ESCC development, providing more insights into the pathogenesis of this cancer.

Esophageal squamous cell carcinoma with pagetoid spread: a clinicopathologic study.

Pagetoid spread in esophageal squamous epithelium associated with underlying esophageal adenocarcinoma (EAC) has been well studied. Case reports describing pagetoid spread of esophageal squamous cell carcinomas (ESCC) also exist in the literature. The latter, however, has not been systematically studied. In this study, we report seven cases of pagetoid spread associated with ESCC. The clinical, morphologic, and immunophenotypic profiles of pagetoid spread in the context of ESCC and EAC are compared. Cases of pagetoid spread of ESCC were identified through computerized search of pathology archives at five institutions. Additional cases were identified through manual review of surgical resection cases of treatment naive ESCC in Mass General Brigham (MGB) pathology archive. Clinical history was collected via chart review. Immunohistochemistry for CK7, CK20, CDX2, p53, p63, and p40 was performed on selected cases. A computerized search of pathology archives of five institutions revealed only two cases. A manual review of 76 resected untreated ESCC revealed five additional cases with unequivocal pagetoid spread of ESCC, indicating the condition was not uncommon but rarely reported. Patient age ranged from 54 to 78years (median, 65). There were six women and one man. One case had in situ disease, five had pT1 (1 pT1a and 4 pT1b), and one had pT3 disease. One of the patients with pT1 tumor had a positive lymph node, while the remaining six patients were all N0. Four tumors were in the proximal to mid esophagus, and three in the distal esophagus. Patient survival ranged from 25months to more than 288months. The pagetoid tumor cells demonstrated enlarged, hyperchromatic nuclei with variable amounts of eosinophilic cytoplasm. The cytoplasm was often condensed to the perinuclear area, creating peripheral clearing. By immunohistochemistry, the pagetoid cells were positive for p40 (6/6) and p63 (7/7) and negative for CDX2 (7/7). The tumor cells showed mutant-type staining for p53 in five of seven cases. One of the patients had pagetoid tumor cells at the resection margin and subsequently had recurrent disease 2years later. All other patients had negative resection margins and did not have local recurrence. Four cases of pagetoid spread in the context of EAC were used as a comparison group. Previously published studies were also analyzed. These tumors were all located in the distal esophagus or gastroesophageal junction. All cases were associated with underlying invasive EAC. Pagetoid spread associated with EAC often had cytoplasmic vacuoles or mucin. They were more frequently positive for CK7 than pagetoid ESCC (p = 0.01). Both ESCC and EAC may give rise to pagetoid spread of tumor cells within surface squamous epithelium. Pagetoid spread from ESCC and EAC have overlapping morphologic features. P40 and p63 immunostains can facilitate the distinction between ESCC and EAC. P53 immunostain can aid in confirmation of malignancy. Understanding their overlapping pathologic features will help pathologists avoid pitfalls and diagnose these lesions correctly on biopsy specimens.

Identification of m6A/m5C-related lncRNA signature for prediction of prognosis and immunotherapy efficacy in esophageal squamous cell carcinoma.

N6-methyladenosine (m6A) and 5-methylcytosine (m5C) RNA modifications have garnered significant attention in the field of epigenetic research due to their close association with human cancers. This study we focus on elucidating the expression patterns of m6A/m5C-related long non-coding RNAs (lncRNAs) in esophageal squamous cell carcinoma (ESCC) and assessing their prognostic significance and therapeutic potential. Transcriptomic profiles of ESCC were derived from public resources. m6A/m5C-related lncRNAs were obtained from TCGA using Spearman's correlations analysis. The m6A/m5C-lncRNAs prognostic signature was selected to construct a RiskScore model for survival prediction, and their correlation with the immune microenvironment and immunotherapy response was analyzed. A total of 606 m6A/m5C-lncRNAs were screened, and ESCC cases in the TCGA cohort were stratified into three clusters, which showed significantly distinct in various clinical features and immune landscapes. A RiskScore model comprising ten m6A/m5C-lncRNAs prognostic signature were constructed and displayed good independent prediction ability in validation datasets. Patients in the low-RiskScore group had a better prognosis, a higher abundance of immune cells (CD4 + T cell, CD4 + naive T cell, class-switched memory B cell, and Treg), and enhanced expression of most immune checkpoint genes. Importantly, patients with low-RiskScore were more cline benefit from immune checkpoint inhibitor treatment (P < 0.05). Our findings underscore the potential of RiskScore system comprising ten m6A/m5C-related lncRNAs as effective biomarkers for predicting survival outcomes, characterizing the immune landscape, and assessing response to immunotherapy in ESCC.

Abstract 65: Differential impacts of PD-L1 expression in tumor vs. stroma on survival in esophageal squamous cell carcinoma

Abstract Background: Esophageal squamous cell carcinoma (ESCC) has high incidence and recurrence rates, particularly in advanced stages. While the combined positive score (CPS) and tumor proportional score (TPS) are standard benchmarks for PD-L1 assessment in ESCCs, they face challenges such as reliance on subjective human interpretation and the uncertain clinical significance of strong staining intensities. Our study utilizes H-scores for PD-L1 expression and separates analysis of tumor and stroma, providing additional layers of information that complement current methods and contribute to a more comprehensive understanding of the role of PD-L1 in ESCC. Methods: This retrospective single-center cohort analysis involved 194 cases of ESCC who underwent surgical resection. We performed a comprehensive evaluation of PD-L1 expression within the tumor and stroma using whole slide images (WSI). QuPath image analysis software was used to classify regions as tumor or stroma and quantify the PD-L1 expression H-score. Results: Using optimal H-score cutoffs determined from the minimum P-value method, the Kaplan-Meier survival analysis showed that higher PD-L1 expression was significantly linked with better post-operative survival across all compartments. This correlation was most pronounced in the stroma (P&amp;lt;0.001). However, in multivariate Cox regression analysis, only high tumoral PD-L1 expression emerged as an independent predictor of favorable prognosis (HR=0.47, 95% CI: 0.27-0.81, P=0.007). The non-significant contribution of stromal PD-L1 in this model could be attributed to its association with advanced pT and pN stages, and the presence of lymphatic and venous invasion (P&amp;lt;0.001, respectively). Interestingly, stromal PD-L1 expression was associated with a longer duration of cytotoxic chemotherapy (cutoff 8 months, Median H-score 98.28 vs 55.24, P=0.026), but no significant correlation was observed with the duration of immune checkpoint inhibitor treatment. Conclusions: The study underscores the complex role of PD-L1 in ESCC, with tumoral PD-L1 expression emerging as an independent prognostic factor, and stromal PD-L1 expression found to be related with tumor progression and the duration of cytotoxic chemotherapy response. Citation Format: Tomohiro Murakami, Satoru Furuhashi, Yuuki Sakai, Kenichi Sekimori, Ryoma Haneda, Eisuke Booka, Tomohiro Matsumoto, Hirotoshi Kikuchi, Yoshihiro Hiramatsu, Hiroya Takeuchi. Differential impacts of PD-L1 expression in tumor vs. stroma on survival in esophageal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 65.

En1 promotes cell proliferation and migration via Hedgehog signaling pathway in esophageal squamous cell carcinoma

Objective: To explore the function and mechanism of transcription factor En1 in esophageal squamous cell carcinoma (ESCC). Methods: The correlations of En1 with prognosis were analyzed using the overall survival data of 9 397 pan-cancer patients and progression-free survival data of 4 349 pan-cancer patients from The Cancer Genome Atlas (TCGA) database. The En1 expression data in 53 and 155 cases of ESCC and their paired adjacent tissues were from Gene Expression Omnibus (GEO) database and National Genomics Data Center-Genome Sequence Archive(NGDC-GSA)database. Lentivirus was used to generate En1 stable knockout cell lines KYSE180 and KYSE450. The proliferation ability of the cells was detected by cell counting kit 8 and clone formation assay. The migration ability of the cells was detected by Transwell assay. The effect of En1 on the proliferation of ESCC was detected by xenograft experiment in BALB/c-nu/nu mice. Real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) was used to detect the expressions of En1, glioma-associated oncogene family zinc finger 1 (GLI1), glioma-associated oncogene family zinc finger 2 (GLI2) and smoothened (SMO). Results: Pan-cancer data from TCGA showed that patients with low En1 expression had longer overall survival and progression-free survival than patients with high En1 expression (P< 0.001). Data from GEO and GSA databases also showed a high expression level of En1 in ESCC tissues compared with paired tissues (P＜0.001). Proliferation was inhibited after knockout of En1 in KYSE180 and KYSE450 cells (P＜0.001). The colony formation numbers decreased. The colony formation numbers of KYSE180 cells in the shEn1#1 group and the shEn1#2 group were 138.33±23.07 and 127.00±19.70, respectively, significantly lower than that of the shNC group 340.67±12.06 (P<0.001). The colony formation numbers of KYSE450 cells in the shEn1#1 group and the shEn1#2 group were 65.33±2.52 and 9.00±3.00, respectively, significantly lower than that of the shNC group 139.00±13.00 (P<0.001). The migration numbers was inhibited after knockout of En1 [the Transwell numbers of KYSE180 cells in the shEn1#1 group and the shEn1#2 group were 66.67±12.66 and 71.33±11.02, respectively, significantly lower than that of the shNC group 334.67±16.56 (P<0.001). The Transwell numbers of KYSE450 cells in the shEn1#1 group and the shEn1#2 group were 112.33±14.57 and 54.33±5.51, respectively, significantly lower than that of the shNC group 253.33±21.03 (P<0.001)]. Xenograft model showed a slower growth rate of shEn1#1 and shEn1#2 cell lines (P＜0.001). The tumor weights of KYSE450 cells in the shEn1#1 group and the shEn1#2 group were (0.046±0.026)g and (0.047±0.025)g, respectively, significantly lower than that of the shNC group (0.130±0.038)g (P＜0.001). After knockdown of En1, the relative expression levels of GLI1 in KYSE180 cells of the shEn1#1 group and the shEn1#2 group were 0.326±0.162 and 0.322±0.133, and the relative expression levels of GLI1 in KYSE450 cells of the shEn1#1 and shEn1#2 groups were 0.131±0.006 and 0.352±0.050, respectively, which were all lower than that in the shNC group (P＜0.01). After knockdown of En1, overexpression of GLI1 attenuated the inhibitory effect of knockdown of En1 on cell proliferation (P＜0.001), colony formation[the colony formation numbers of the shEn1#1-GLI1 group were 151.00±9.54, higher than 102.33±10.02 (P=0.004) of the shEn1#1-vector group] and migration [the migration numbers of the shEn1#1-GLI1 group were 193.67±10.07, higher than 109.33±11.50 (P<0.001) in the shEn1#1-vector group]. In clinical samples of ESCC, major regulatory factors of the Hedgehog pathway were up-regulated and the pathway was activated. Conclusion: En1 promotes the proliferation and migration of ESCC cells by regulating the Hedgehog pathway and can be used as a new potential target for targeted therapy of ESCC.

Single-cell analysis identified POSTN+ cells associated with the aggressive phenotype and risk of esophageal squamous cell carcinoma

Tumors are intricate and heterogeneous systems characterized by mosaic cancer cell populations with diverse expression profiles. Leveraging single-cell technologies, we employed the Scissor algorithm to delineate an epithelial subpopulation associated with the aggressive phenotype in esophageal squamous cell carcinoma (ESCC). This identified subpopulation exhibited elevated expression of genes involved in critical pathways, such as epithelial-mesenchymal transition and PI3K-Akt. Key signature genes within this subpopulation, namely CAV1, COL3A1, COL6A1, POSTN, and TAGLN, demonstrated significant upregulation concomitant with both tumorigenesis and tumor progression across independent single-cell datasets. Furthermore, we selected 1,450 expression quantitative trait loci of the top 62 signature genes of this cell subpopulation to investigate their potential in predicting ESCC risk. The results showed that the POSTN loci were predominantly associated with ESCC susceptibility. Through functional annotation and replication analyses, we identified that the rs1028728 in the POSTN promoter was significantly associated with increased ESCC risk in 7,049 ESCC cases and 8,063 controls (odds ratio= 1.29, 95% confidence interval: 1.18-1.42, p= 4.03×10-8). Subsequent biochemical experiments showed that the rs1028728[T] allele enhanced POSTN expression by affecting the binding of PRRX1 in the POSTN promoter. In summary, our meticulous single-cell analysis delineates an invasive epithelial subpopulation in ESCC, with POSTN emerging as an important marker for the aggressive phenotype. These findings offer more insights into potential strategies for the prevention and intervention of ESCC, enriching our understanding of this complex cancer landscape.

Anlotinib plus TQB2450 as adjuvant therapy in patients with esophageal squamous cell carcinoma: A phase II study (ALTER-E005).

347 Background: There is currently a limited range of therapeutic options available for postoperative patients (pts) with esophageal squamous cell carcinoma (ESCC), emphasizing the urgent requirement to investigate more efficient and safer postoperative treatment regimens for resectable ESCC. TQB2450, a novel PD-L1 blockade, has shown promising activity when combined with anlotinib, an antiangiogenic agent, in the treatment of various tumors, including advanced ESCC,1 and biliary tract cancer.2 The ALTER-E005 study aimed to evaluate the efficacy and safety of combining anlotinib with TQB2450 as adjuvant therapy in pts with ESCC. Methods: This was a single-arm, multi-center phase II clinical trial. 30 pts (≥18 years) with histologically confirmed T1-2N1-3M0 or T3-4NanyM0 ESCC who had undergone radical (R0) resection with no recurrence 6 to 12 weeks after surgery and ECOG PS ≤ 1 would been rolled. Enrolled pts received oral anlotinib 12 mg on days 1-14 and intravenous TQB2450 1200 mg on day 1every 3 weeks for up to 16 cycles, until disease recurrence. The primary endpoint was disease recurrence free (DFS). The secondary endpoints included safety, 1-year DFS rate, 3-year DFS rate, 1-year overall survival (OS) rate, and 3-year OS rate. Results: Between August 18, 2022, and August 25, 2023, a total of 12 patients were enrolled. Out of the 12 surgically resected cases of ESCC, 11 (91.7%) had an ECOG score of 1, 10 (83.3%) were male, and 6 (50%) were under the age of 65. According to the eighth edition of the AJCC Cancer Staging Manual, 7 (58.3%) were classified as stage II, and 5 (41.7%) were classified as stage III. As of the data cut-off date (August 25, 2023), the median follow-up time was 5.1 months (95% CI: 3.4-6.8). 2 pts experienced disease recurrence, and the median duration of DFS has not yet been reached. Currently, 9 pts are still undergoing therapy, with treatment durations ranging from 0.3 months to 9.6 months. 2 pts discontinued therapy due to adverse events (AE), which subsequently improved after treatment. One patient experienced immune-related myocarditis, while the other patient had mouth ulcers and hand-foot syndrome. Additionally, one patient voluntarily withdrew from the study. Out of the total 12 patients, 3 (25%) experienced grade 3 treatment-emergent adverse events (TEAEs). There was no grade 4 or higher TEAEs reported. The grade 3 TEAEs included hand-foot syndrome (16.7%), abnormal liver function (8.3%), and immune-related hepatitis (8.3%). Conclusions: The study demonstrated the preliminary efficacy and safety of combining anlotinib with TQB2450 as adjuvant therapy in patients with ESCC who had undergone radical (R0) resection and showed no recurrence 6 to 12 weeks after surgery. 1. Zhi-Ye Zhang, et al. poster 4041: ASCO 2023. 2. Zhou J, et al. Hepatology 2022. Clinical trial information: NCT05252078 .

A Study of the Risk Factors for 402 Patients with Esophageal Squamous Cell Carcinoma - A Retrospective Comparison with Health Checkup Participants.

Objective Esophageal cancer is a gastrointestinal cancer with a poor prognosis. However, it is curable and can be treated endoscopically if it is detected at an early stage. The objective of this study was to identify the factors that contribute to early detection. Methods From April 2011 to December 2019, we retrospectively investigated consecutive patients diagnosed with esophageal squamous cell carcinoma (ESCC) through upper gastrointestinal endoscopy at two hospitals of Kawasaki Medical University based on medical records. The factors contributing to the early detection of ESCC were investigated by comparing patients with ESCC with those undergoing health checkups in whom no organic lesions were found in the upper gastrointestinal tract on endoscopy (controls). Patients Factors contributing to early detection were examined in 402 ESCC cases and 391 sex- and age-matched controls, and early and advanced cancers were compared along with the risk factors for ESCC. Results A multivariate analysis showed that alcohol consumption and smoking, concomitant cancer of other organs, and a low body mass index (BMI) were factors associated with ESCC (odds ratio [OR], 4.65; 95% confidence interval [CI], 2.880-7.520, OR,3.63; 95% CI, 2.380-5.540, OR, 2.09; 95% CI, 1.330-3.270, OR, 6.38; 95% CI, 3.780-10.800), whereas dyslipidemia was significantly less common in patients with ESCC (OR, 0.545; 95% CI, 0.348-0.853). Comparing early and advanced cancers, a history of endoscopic screening was the only factor involved in early detection (OR, 7.93; 95% CI, 4.480-14.00). Conclusion The factors associated with ESCC include alcohol consumption, smoking, concomitant cancer of other organs, and a low BMI. Endoscopy in subjects with these factors may therefore be recommended for the early detection of ESCC.

A prognosis model for predicting immunotherapy response of esophageal cancer based on oxidative stress-related signatures.

Oxidative stress (OS) is intimately associated with tumorigenesis and has been considered a potential therapeutic strategy. However, the OS-associated therapeutic target for esophageal squamous cell carcinoma (ESCC) remains unconfirmed. In our study, gene expression data of ESCC and clinical information from public databases were downloaded. Through LASSO-Cox regression analysis, a risk score (RS) signature map of prognosis was constructed and performed external verification with the GSE53625 cohort. The ESTIMATE, xCell, CIBERSORT, TIMER, and ImmuCellAI algorithms were employed to analyze infiltrating immune cells and generate an immune microenvironment (IM). Afterward, functional enrichment analysis clarified the underlying mechanism of the model. Nomogram was utilized for forecasting the survival rate of individual ESCC cases. As a result, we successfully constructed an OS-related genes (OSRGs) model and found that the survival rate of high-risk groups was lower than that of low-risk groups. The AUC of the ROC verified the strong prediction performance of the signal in these two cohorts further. According to independent prognostic analysis, the RS was identified as an independent risk factor for ESCC. The nomogram and follow-up data revealed that the RS possesses favorable predictive value for the prognosis of ESCC patients. qRT-PCR detection demonstrated increased expression of MPC1, COX6C, CYB5R3, CASP7, and CYCS in esophageal cancer patients. In conclusion, we have constructed an OSRGs model for ESCC to predict patients' prognosis, offering a novel insight into the potential application of the OSRGs model in ESCC.

Iron, Copper, and Magnesium Concentration in Hair and Risk of Esophageal Cancer: A Nested Case-Control Study.

An association has already been hypothesized between iron, copper, and magnesium status assessed through food frequency questionnaires (FFQs) and the risk of esophageal squamous cell carcinoma (ESCC). However, self-reported dietary assessment methods are prone to measurement errors. We studied the association between iron, copper, and magnesium status and ESCC risk, using hair samples as a long exposure biomarker. We designed a nested case-control study within the Golestan Cohort Study, that recruited about 50000 participants in 2004-2008, and collected biospecimens at baseline. We identified 96 incident cases of ESCC with available hair samples. They were age-matched with cancer-free controls from the cohort. We used inductively coupled plasma mass spectrometry (ICP-MS) to measure iron, copper, and magnesium concentrations in hair samples. We used multiple logistic regression models to determine odds ratios and 95% confidence intervals. Median concentrations of iron, copper, and magnesium were 35.4, 19.3, and 41.7 ppm in cases and 25.8, 18.3, and 50.0 ppm in controls, respectively. Iron was significantly associated with the risk of ESCC in continuous analysis (OR=1.41, 95% CI=1.03-1.92), but not in the tertiles analyses (ORT3 vs. T1=1.81, 95% CI=0.77-4.28). No associations were observed between copper and magnesium and ESCC risk, in either the tertiles models or the continuous estimate (copper: ORT3 vs. T1=2.56, 95% CI=1.00-6.54; magnesium: ORT3 vs. T1=0.75, 95% CI=0.32-1.78). Higher iron status may be related to a higher risk of ESCC in this population.

DASES: a database of alternative splicing for esophageal squamous cell carcinoma.

Esophageal carcinoma ranks as the sixth leading cause of cancer-related mortality globally, with esophageal squamous cell carcinoma (ESCC) being particularly prevalent among Asian populations. Alternative splicing (AS) plays a pivotal role in ESCC development and progression by generating diverse transcript isoforms. However, the current landscape lacks a specialized database focusing on alternative splicing events (ASEs) derived from a large number of ESCC cases. Additionally, most existing AS databases overlook the contribution of long non-coding RNAs (lncRNAs) in ESCC molecular mechanisms, predominantly focusing on mRNA-based ASE identification. To address these limitations, we deployed DASES (http://www.hxdsjzx.cn/DASES). Employing a combination of publicly available and in-house ESCC RNA-seq datasets, our extensive analysis of 346 samples, with 93% being paired tumor and adjacent non-tumor tissues, led to the identification of 257 novel lncRNAs in esophageal squamous cell carcinoma. Leveraging a paired comparison of tumor and adjacent normal tissues, DASES identified 59,094 ASEs that may be associated with ESCC. DASES fills a critical gap by providing comprehensive insights into ASEs in ESCC, encompassing lncRNAs and mRNA, thus facilitating a deeper understanding of ESCC molecular mechanisms and serving as a valuable resource for ESCC research communities.

A Single nucleotide polymorphism in the ALDH2 gene modifies the risk of esophageal squamous cell carcinoma in BRCA2 p.K3326* carriers.

Esophageal squamous cell carcinoma (ESCC) has a very high incidence rate in northeastern Iran. Our team previously reported the BReast CAncer gene 2 (BRCA2) p.K3326* mutation as a moderately penetrant ESCC susceptibility variant in northern Iran (odds ratio (OR) = 3.64, 95% confidence interval (CI) = 1.74-7.59, P = 0.0003). Recently, it has been reported that aldehydes can induce BRCA2 haploinsufficiency in cells with a heterozygous pathogenic BRCA2 mutation and predispose them to carcinogenic effects. Based on this observation, we speculate that dysfunctional variants in Aldehyde Dehydrogenase 2 Family Member (ALDH2) may result in aldehyde-induced BRCA2 haploinsufficiency and increase cancer risk in BRCA2 mutation carriers. In support of this hypothesis, our team recently reported the breast cancer risk modifying effect of an ALDH2 common polymorphism, rs10744777, among Polish carriers of the BRCA2 p.K3326* mutation. In the current case-control study, we aimed to investigate the ESCC risk modifying effect of this ALDH2 polymorphism among BRCA2 p.K3326* mutation carriers. We assessed the interaction between the ALDH2 rs10744777 polymorphism and BRCA2 p.K3326* mutation in ESCC risk by genotyping this ALDH2 variant in the germline DNA of 746 ESCC cases and 1,373 controls from northern Iran who were previously genotyped for the BRCA2 p.K3326* mutation. Among a total of 464 individuals with TT genotype of the ALDH2 rs10744777 polymorphism, which is associated with lower ALDH2 expression, we found 9 of 164 cases versus 3 of 300 controls who carried the BRCA2 p.K3326* variant (OR = 5.66, 95% CI = 1.22-26.2, P = 0.018). This finding supports our hypothesis that the ALDH2-rs10744777 TT genotype may be a significant risk modifier of ESCC in individuals with a BRCA2 p.K3326* mutation.

The predicting role of serum tumor-specific growth factor for prognosis of esophageal squamous cell carcinoma

ObjectiveTumor-specific growth factor (TSGF) is an immune-related factor that offers good performance in the clinical management of human cancers. However, the role of serum TSGF in esophageal squamous cell carcinoma (ESCC) has not been fully clarified.MethodsA total of 562 ESCC cases were collected in our study, with available information on preoperative serum levels of TSGF at diagnosis. Preoperative serum TSGF was detected using the rate method. We retrospectively analyzed its correlation with clinicopathological features of ESCC and survival.ResultsThe cut-off value of serum TSGF was determined to be 60.5 U/mL by receiver operating characteristic (ROC) analysis. Serum TSGF was associated with gender (P < 0.001), tumor location (P = 0.022), tobacco use (P < 0.001), alcohol consumption (P < 0.001), lymph node involvement (P = 0.007), and TNM staging (P = 0.004). The survival analysis revealed that ESCC patients with high levels of serum TSGF had poorer prognosis than those with high TSGF (P = 0.006), especially for male ESCC cases (P = 0.001), under 60 year (P = 0.036), male middle location (P = 0.023), tobacco consumption (P = 0.004), G1 + G2 (P = 0.031), advanced T staging (P = 0.033), lymph node involvement (P = 0.003), TNM staging (P = 0.003). Univariate Cox regression analysis indicated that exposure to smoking and drinking, tumor grade, T staging, lymph node metastasis, TNM staging, and serum TSGF level were the prognosis-related factors of ESCC. Multivariate regression analysis revealed that smoking history, higher serum TSGF levels, and advanced T stage enhanced the risk of ESCC-related death.ConclusionIn brief, serum TSGF levels had in relation to malignant features of ESCC. It was positively correlated with survival but was identified as an independent risk factor for ESCC.

Concordance between four PD-L1 immunohistochemical assays and 22C3 pharmDx assay in esophageal squamous cell carcinoma in a multicenter study

BackgroundThe prediction of response to immunotherapy mostly depends on the programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) status, and the 22C3 pharmDx assay has been approved in esophageal squamous cell carcinoma (ESCC). However, the widespread use of the 22C3 pharmDx assay is limited due to its availability. Thus, alternative PD-L1 assays are needed. We aimed to investigate the analytical and clinical diagnostic performances of four PD-L1 assays and to compare their concordances with the 22C3 pharmDx assay. MethodsThe PD-L1 22C3 pharmDx assay was performed on the Dako Autostainer Link 48 platform, three testing assays (PD-L1 E1L3N XP antibody [Ab], PD-L1 BP6099 Ab and PD-L1 CST E1L3N Ab) on the Leica BOND-MAX/III platform, and one testing assay (PD-L1 MXR006 Ab) on the Roche VENTANA Benchmark Ultra platform. A total of 218 ESCC cases from four centers were included in this retrospective study. Professionals from each center stained and read the IHC slides independently and determined combined positive score (CPS) and tumor proportion score (TPS). ResultsRegarding analytical performance, the four testing assays demonstrated good correlations with the 22C3 pharmDx assay when evaluated by the TPS or CPS (ρ > 0.8 for all four assays). Regarding diagnostic performance (CPS ≥ 10 was used as the cutoff), the four testing assays showed moderate concordances with the 22C3 pharmDx assay (kappa > 0.7 for all four assays). The overall percent agreements between each testing assay and the 22C3 pharmDx assay was at least 87.2 %. ConclusionThis study provides insight into the potential interchangeability of the four PD-L1 assays with the 22C3 pharmDx assay.

TP53 Mutations in Esophageal Squamous Cell Carcinoma.

The occurrence and development of esophageal cancer involve multiple genetic abnormalities that contribute to the malignant transformation of esophageal epithelial cells, followed by invasion and metastasis, leading to a poor outcome. Esophageal squamous cell carcinoma (ESCC) is the predominant histological subtype of esophageal malignancy in East Asia, with approximately half of newly diagnosed ESCC cases occurring in China. The TP53 tumor suppressor gene mutation is one of the most common mutations in ESCC. TP53 mutations are observed even in the early phases of esophageal carcinogenesis. Normal functions of the p53 network are lost in cells of ESCC patients who harbor the mutant TP53 gene, inducing tumor development, radiation resistance, chemotherapy resistance, and immune suppression, promoting progression and metastasis, thereby resulting in an overall poor prognosis. Although clinical trials of several pharmacological compounds targeting mutational TP53 have been explored, novel approaches are still urgently required to improve the observed dismal survival. A better understanding of the role of the mutant TP53 gene in human ESCC might lead to the discovery of innovative targeted therapies to treat this malignancy.

DNA damage repair profiling of esophageal squamous cell carcinoma uncovers clinically relevant molecular subtypes with distinct prognoses and therapeutic vulnerabilities

DNA damage repair (DDR) is a critical process that maintains genomic integrity and plays essential roles at both the cellular and organismic levels. Here, we aimed to characterize the DDR profiling of esophageal squamous cell carcinoma (ESCC), investigate the prognostic value of DDR-related features, and explore their potential for guiding personalized treatment strategies. We analyzed bulk and single-cell transcriptomics data from 377 ESCC cases from our institution and other publicly available cohorts to identify major DDR subtypes. The heterogeneity in cellular and functional properties, tumor microenvironment (TME) characteristics, and prognostic significance of these DDR subtypes were investigated using immunogenomic analysis and invitro experiments. Additionally, we experimentally validated a combinatorial immunotherapy strategy using syngeneic mouse models of ESCC. DDR alteration profiling enabled us to identify two distinct DDR subtypes, DDRactive and DDRsilent, which exhibited independent prognostic values in locoregional ESCC but not in metastatic ESCC. The DDRsilent subtype was characterized by an inflamed but immune-suppressed microenvironment with relatively high immune cell infiltration, abnormal immune checkpoint expression, T-cell exhaustion, and enrichment of cancer-related pathways. Moreover, DDR subtyping indicates that BRCA1 and HFM1 are robust and independent prognostic factors in locoregional ESCC. Finally, we proposed and verified that the concomitant triggering of GITR or blockade of BTLA with PD-1 blockade or cisplatin chemotherapy represents effective combination strategies for high-risk locoregional ESCC tumors. Our discovery of DDR-based molecular subtypes will enhance our understanding of tumor heterogeneity and have significant clinical implications for the therapeutic and management strategies of locoregional ESCC. This study was supported by the National Key R&D Program of China (2021YFC2501000, 2022YFC3401003), National Natural Science Foundation of China (82172882), the Beijing Natural Science Foundation (7212085), the CAMS Innovation Fund for Medical Sciences (2021-I2M-1-018, 2021-I2M-1-067), the Fundamental Research Funds for the Central Universities (3332021091), and the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2019PT310027).

Perioperative immunotherapy for esophageal squamous cell carcinoma: Now and future.

Esophageal cancer (EC) ranks among the most prevalent malignant tumors affecting the digestive tract. Esophageal squamous cell carcinoma (ESCC) stands as the prevailing pathological subtype, encompassing approximately 90% of all EC patients. In clinical stage II-IVA locally advanced ESCC cases, the primary approach to treatment involves a combination of neoadjuvant therapy and surgical resection. Despite concerted efforts, the long-term outcomes for ESCC patients remain unsatisfactory, with dismal prognoses. However, recent years have witnessed remarkable strides in immunotherapy, particularly in the second- and first-line treatment of advanced or metastatic ESCC, with the development of monoclonal antibodies that inhibit programmed death 1 or programmed death ligand 1 demonstrating encouraging responses and perioperative clinical benefits for various malignancies, including ESCC. This comprehensive review aims to present the current landscape of perioperative immunotherapy for resectable ESCC, focusing specifically on the role of immune checkpoint inhibitors during the perioperative period. Additionally, the review will explore promising biomarkers and offer insights into future prospects.

Survival After Diagnosis of Esophageal Squamous Cell Carcinoma in Malawi.

Esophageal cancer (EC) is the second most common cancer in Malawi, with esophageal squamous cell carcinoma (ESCC) representing >90% of all ECs. Despite significant morbidity and mortality, little is known about disease outcomes. In this study, we assess survival after ESCC diagnosis in Malawi. We report on ESCC cases enrolled in a case-control study at Kamuzu Central Hospital in Lilongwe from August 2017 to April 2020. Suspected cases completed a questionnaire interview; provided blood, urine, and saliva specimens; and underwent a tumor biopsy for histologic confirmation. Cases were followed up by phone biweekly from enrollment to the study end date (December 31, 2020), date of death, or loss to follow-up. Survival was assessed using Kaplan-Meier analysis with the log-rank test. We also examined associations between treatment and ESCC mortality using Cox regression models. There were 300 patients with ESCC enrolled in this study, of whom 290 (97%) had known vital status at the end of follow-up and 10 (3%) were lost to follow-up. Among the 290 patients, 282 (97%) died during follow-up. The median age at enrollment was 55 years (IQR, 48-66), and the median time to death was 106 days (95% CI, 92 to 127). The 1-year, 2-year, and 3-year survival rates were 11% (95% CI, 8 to 15), 3% (95% CI, 1 to 6), and 0.9% (95% CI, 0.8 to 4), respectively. Palliative chemotherapy significantly improved the overall survival of patients with ESCC (Plog-rank = .038) and was significantly associated with reduced mortality (adjusted hazard ratio, 0.71 [95% CI, 0.51 to 0.99]). No significant association was observed between tobacco use, alcohol consumption, or HIV status and mortality. Survival after diagnosis of ESCC was poor in Malawi. Although palliative chemotherapy was associated with improved survival, prevention and earlier detection remain key priorities to improve ESCC mortality at a population level.