Mutational Landscape of Esophageal Squamous Cell Carcinoma in an Indian Cohort

Mangalaparthi, Kiran K.; Patel, Krishna; Khan, Aafaque Ahmad; Manoharan, Malini; Coral, Karunakaran; Murugan, Sakthivel; Gupta, Ravi; Gupta, Rohit; Khanna-Gupta, Arati; Chaudhuri, Amitabha; Kumar, Prashant; Nair, Bipin; Kumar, Rekha V.; Prasad, T. S. Keshava; Chatterjee, Aditi; Pandey, Akhilesh; Gowda, Harsha

doi:10.3389/fonc.2020.01457

Cited by 26 publications

(27 citation statements)

References 86 publications

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“…Such a strategy has previously been used to identify a mutational signature present in renal cell carcinomas which implicated an environmental exposure to aristolochic acid in a specific geographic location 12 . Whilst there have been previous studies which have provided a comprehensive overview of the ESCC genome, some including mutational signatures analysis, many of these are limited to whole exome sequencing or cases from high incidence regions only 13–20 . Furthermore, a comprehensive analysis of associations between mutational signatures and ESCC risk factors across multiple regions with varying incidence has not been described previously.…”

Section: Mainmentioning

confidence: 99%

Mutational signatures in esophageal squamous cell carcinoma from eight countries of varying incidence

Moody

Senkin

Islam

et al. 2021

Preprint

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Esophageal squamous cell carcinoma (ESCC) shows a remarkable variation in incidence which is not fully explained by known lifestyle and environmental risk factors. It has been speculated that an unknown exogenous exposure(s) could be responsible. Here we combine the fields of mutational signature analysis with cancer epidemiology to study 552 ESCC genomes from eight countries with varying incidence rates. The mutational profiles of ESCC were similar across all countries studied. Associations between specific mutational signatures and ESCC risk factors were identified for tobacco, alcohol, opium and germline variants, with modest impacts on mutation burden. We find no evidence of a mutational signature indicative of an exogenous exposure capable of explaining the differences in ESCC incidence. APOBEC associated mutational signatures SBS2 and SBS13 were present in 88% and 91% of cases respectively and accounted for a quarter of the mutation burden on average, indicating that activation of APOBEC is a crucial step in ESCC tumor development.

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Section: Mainmentioning

confidence: 99%

Mutational signatures in esophageal squamous cell carcinoma from eight countries of varying incidence

Moody

Senkin

Islam

et al. 2021

Preprint

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“…Our analysis illustrated that non-silent protein-coding mutation profiles distributed across ESCC cell lines and patient tissues are heterogeneous and diverse, with TP53, TTN, KMT2D, CSMD3, DNAH5, MUC16, and DST being the most frequently mutated genes. These observations are supported by recent research [39,40]; however, with the exception of TP53, the exact role of these mutated genes in ESCC has not been clearly elucidated. Further research is needed to confirm whether these mutated genes contribute to ESCC carcinogenesis.…”

Section: Tp53 Mutation Heterogeneity In Esccmentioning

confidence: 66%

Heterogeneity Analysis of Esophageal Squamous Cell Carcinoma in Cell Lines, Tumor Tissues and Patient-Derived Xenografts

Laster

Nie

et al. 2021

J. Cancer

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Esophageal Squamous Cell Carcinoma (ESCC) is the predominant type of Esophageal Cancer (EC), accounting for nearly 88% of EC incidents worldwide. Importantly, it is also a life-threatening cancer for patients diagnosed in advanced stages, with only a 20% 5-year survival rate due to a limited number of actionable targets and therapeutic options. Increasing evidence has shown that inter-tumor and intra-tumor heterogeneity are widely distributed across ESCC tumor tissues. In our work, multi-omics data from ESCC cell lines, tumor tissue, normal tissue and Patient-Derived Xenograft (PDX) tissues were analyzed to investigate the heterogeneity among ESCC samples at the DNA, RNA, and protein level. We identified enrichment of ECM-receptor interaction and Focal adhesion pathways from the subset of protein-coding genes with non-silent mutations in ESCC patients. We also found that TP53, TTN, KMT2D, CSMD3, DNAH5, MUC16 and DST are the most frequently mutated genes in ESCC patient samples. Out of the identified genes, TP53 is the most frequently mutated, with 84 distinct non-silent mutation variants. We observed that p.R248Q, p.R175G/H, and p.R273C/H are the most common TP53 mutation variants. The diversity of TP53 mutations reveal its importance in ESCC progression and may also provide promising targets for precision therapeutics. Additionally, we identified the Olfactory transduction as the top signaling pathway, enriched from genes uniquely expressed in The Cancer Genome Atlas (TCGA)-ESCC patient tumor tissues, which may provide implications for the exact roles of the corresponding genes in ESCC. Cyclic nucleotide-gated channel subunit beta 1(CNGB1), a gene belonging to the Olfactory transduction pathway, was found exclusively overexpressed in ESCC. Expression of CNGB1 could serve as a marker, indicating potential diagnostic or therapeutic value. Finally, we investigated heterogeneity in the context of the ESCC PDX model, which is an emerging tool used to predict drug response and recapitulate tumor behavior in vivo. We observed trans-species heterogeneity in as high as 75% of the identified proteins, indicating that the ambiguity of proteins should be addressed by specific strategies to avoid drawing false conclusions. The identification and characterization of gene mutation and expression heterogeneity across different ESCC datasets, including various novel TP53 mutations, ECM-receptor interaction, Focal adhesion, and Olfactory transduction pathways (CNGB1), provide researchers with evidence and implications for accurate research and precision therapeutic development.

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“…In addition, cumulative evidences suggest that changes in SYNE1 expression levels, somatic mutations, promoter methylation level, and single-nucleotide polymorphisms are related to the occurrence and development of lung cancer (20), oral cancer (21), hepatocellular carcinoma (22), and gastric cancer (23). Furthermore, SYNE1 was found to be frequently mutated in an Indian ESCC cohort (24). In the present study, we reported SYNE1 mutations associated with worse prognosis in patients with ESCC, which is consistent with a previous report of patients with clear cell renal cell carcinoma showing that SYNE1 mutations correlate with a higher tumor mutation burden and poorer outcomes (25).…”

Section: Discussionmentioning

confidence: 99%

Combination of 35-Gene Mutation Profile and Radiotherapy Dosimetry Predicts the Therapeutic Outcome of Definitive Chemoradiation in Patients With Esophageal Squamous Cell Carcinoma

et al. 2021

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Esophageal cancer is a common malignancy worldwide and a leading cause of cancer-related mortality. Definitive concurrent chemoradiotherapy (CCRT) has been widely used to treat locally advanced esophageal squamous cell carcinoma (ESCC). In this study, we evaluated the predictive power of a 35-gene mutation profile and radiation parameters in patients with ESCC. Data from 44 patients with ESCC who underwent definitive CCRT were retrospectively reviewed. A 35-gene mutation profile, derived from reported ESCC-specific next-generation sequencing results, and radiation dosimetry parameters were examined using the Kaplan–Meier curve and Cox proportional hazards model. All patients were native Chinese and underwent CCRT with a median follow-up time of 22.0 months. Significant prognostic factors affecting progression-free survival in the multivariable Cox regression model were clinical nodal staging ≥2 (hazard ratio, HR: 2.52, 95% CI: 1.15–5.54, p = 0.022), ≥10% lung volume receiving ≥30 Gy (V30) (HR: 2.36, 95% CI: 1.08–5.17, p = 0.032), and mutation of fibrous sheath interacting protein 2 (FSIP2) (HR: 0.08, 95% CI: 0.01–0.58, p = 0.013). For overall survival, significant prognostic factors in the multivariable Cox regression model were lung V30 ≥10% (HR: 3.71, 95% CI: 1.48–9.35, p = 0.005) and mutation of spectrin repeat containing nuclear envelope protein 1 (SYNE1) (HR: 2.95, 95% CI: 1.25–6.97, p = 0.014). Our cohort showed higher MUC17 (79.5% vs. 5.7%), FSIP2 (18.2% vs. 6.2%), and SYNE1 (38.6% vs. 11.0%) mutation rates and lower TP53 (38.6% vs. 68.7%) mutation rates than the ESCC cohorts from The Cancer Genome Atlas. In conclusion, by using a combination of a 35-gene mutation profile and radiotherapy dosimetry, mutations in FSIP2 and SYNE1 as well as lung V30 were identified as potential predictors for developing a prediction model for clinical outcomes in patients with ESCC administered definitive CCRT.

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Mutational Landscape of Esophageal Squamous Cell Carcinoma in an Indian Cohort

Cited by 26 publications

References 86 publications

Mutational signatures in esophageal squamous cell carcinoma from eight countries of varying incidence

Mutational signatures in esophageal squamous cell carcinoma from eight countries of varying incidence

Heterogeneity Analysis of Esophageal Squamous Cell Carcinoma in Cell Lines, Tumor Tissues and Patient-Derived Xenografts

Combination of 35-Gene Mutation Profile and Radiotherapy Dosimetry Predicts the Therapeutic Outcome of Definitive Chemoradiation in Patients With Esophageal Squamous Cell Carcinoma

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