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Integrative Genomic Analyses of 1,145 Patient Samples Reveal New Biomarkers in Esophageal Squamous Cell Carcinoma.

ABSTRACT: Due to the lack of effective diagnostic markers and therapeutic targets, esophageal squamous cell carcinoma (ESCC) shows a poor 5 years survival rate of less than 30%. To explore the potential therapeutic targets of ESCC, we integrated and reanalyzed the mutation data of WGS (whole genome sequencing) or WES (whole exome sequencing) from a total of 1,145 samples in 7 large ESCC cohorts, including 270 ESCC gene expression data. Two new mutation signatures and 20 driver genes were identified in our study. Among them, AP3S1, MUC16, and RPS15 were reported for the first time. We also discovered that the KMT2D was associated with the multiple clinical characteristics of ESCC, and KMT2D knockdown cells showed enhanced cell migration and cell invasion. Furthermore, a few neoantigens were shared between ESCC patients. For ESCC, compared to TMB, neoantigen might be treated as a better immunotherapy biomarker. Our research expands the understanding of ESCC mutations and helps the identification of ESCC biomarkers, especially for immunotherapy biomarkers.

SUBMITTER: Zou B

PROVIDER: S-EPMC8814608 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Integrative Genomic Analyses of 1,145 Patient Samples Reveal New Biomarkers in Esophageal Squamous Cell Carcinoma.

Zou Binbin B Guo Dinghe D Kong Pengzhou P Wang Yanqiang Y Cheng Xiaolong X Cui Yongping Y

Frontiers in molecular biosciences 20220121

Due to the lack of effective diagnostic markers and therapeutic targets, esophageal squamous cell carcinoma (ESCC) shows a poor 5 years survival rate of less than 30%. To explore the potential therapeutic targets of ESCC, we integrated and reanalyzed the mutation data of WGS (whole genome sequencing) or WES (whole exome sequencing) from a total of 1,145 samples in 7 large ESCC cohorts, including 270 ESCC gene expression data. Two new mutation signatures and 20 driver genes were identified in our ...[more]

PMID: 35127817

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Project description:BackgroundTraditionally, non-small cell lung cancer is treated as a single disease entity in terms of systemic therapy. Emerging evidence suggests the major subtypes--adenocarcinoma (AC) and squamous cell carcinoma (SqCC)--respond differently to therapy. Identification of the molecular differences between these tumor types will have a significant impact in designing novel therapies that can improve the treatment outcome.Methods and findingsWe used an integrative genomics approach, combing high-resolution comparative genomic hybridization and gene expression microarray profiles, to compare AC and SqCC tumors in order to uncover alterations at the DNA level, with corresponding gene transcription changes, which are selected for during development of lung cancer subtypes. Through the analysis of multiple independent cohorts of clinical tumor samples (>330), normal lung tissues and bronchial epithelial cells obtained by bronchial brushing in smokers without lung cancer, we identified the overexpression of BRF2, a gene on Chromosome 8p12, which is specific for development of SqCC of lung. Genetic activation of BRF2, which encodes a RNA polymerase III (Pol III) transcription initiation factor, was found to be associated with increased expression of small nuclear RNAs (snRNAs) that are involved in processes essential for cell growth, such as RNA splicing. Ectopic expression of BRF2 in human bronchial epithelial cells induced a transformed phenotype and demonstrates downstream oncogenic effects, whereas RNA interference (RNAi)-mediated knockdown suppressed growth and colony formation of SqCC cells overexpressing BRF2, but not AC cells. Frequent activation of BRF2 in >35% preinvasive bronchial carcinoma in situ, as well as in dysplastic lesions, provides evidence that BRF2 expression is an early event in cancer development of this cell lineage.ConclusionsThis is the first study, to our knowledge, to show that the focal amplification of a gene in Chromosome 8p12, plays a key role in squamous cell lineage specificity of the disease. Our data suggest that genetic activation of BRF2 represents a unique mechanism of SqCC lung tumorigenesis through the increase of Pol III-mediated transcription. It can serve as a marker for lung SqCC and may provide a novel target for therapy. Please see later in the article for the Editors' Summary.

Project description:Esophageal squamous cell carcinoma (ESCC) is a tumor composed of heterogeneous cells that easily become radioresistant, which leads to tumor recurrence. The most commonly used treatment for ESCC is fractionated irradiation (FIR) therapy that utilizes ionizing radiation to directly induce cytotoxic cell death. However, this treatment may not be able to eliminate all cancer cells due to high adaptive evolution. To determine whether the transcriptome dynamics during ESCC recurrence formation are associated with FIR response, an in vitro cell culture model for ESCC radioresistance that mimics the common radiotherapy process in patients with ESCC was established in the present study. High‑throughput sequencing analysis of in vitro cultured ESCC cells was performed using different cumulative irradiation doses, as well as tumor samples from FIR‑treated patients with ESCC before and after the development of radioresistance. Radioresistance‑associated genes and signaling pathways that were aberrantly expressed in radioresistant ESCC cells were identified, including autophagy‑related 9B (regulation of autophagy), DNA damage‑inducible transcript 4, myoglobin and plasminogen activator tissue type, which are associated with response to hypoxia, Bcl2‑binding component 3, tumor protein P63 and interferon γ‑inducible protein 16, which are associated with DNA damage response. The heterogeneity and dynamic gene expression of ESCC cells during acquired radioresistance were further studied in primary (41 single cells), 12 Gy FIR‑treated (87 single cells) and 30 Gy FIR‑treated (89 single cells) cancer cells using a single‑cell RNA sequencing approach. The results of the present study comprehensively characterized the transcriptome dynamics during acquired radioresistance in an in vitro model of ESCC and patient tumor samples at the population and single cell level. Single‑cell RNA sequencing revealed the heterogeneity of irradiated ESCC cells and an increase in the radioresistant ESCC cell subpopulation during acquired radioresistance. Overall, these results are of potential clinical relevance as they identify a number of signaling molecules associated with radioresistance, as well as opportunities for the development of novel therapeutic options for the treatment of ESCC.

Dataset Information

Integrative Genomic Analyses of 1,145 Patient Samples Reveal New Biomarkers in Esophageal Squamous Cell Carcinoma.

Publications

Integrative Genomic Analyses of 1,145 Patient Samples Reveal New Biomarkers in Esophageal Squamous Cell Carcinoma.

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