Dataset Information

Comprehensive genomic analysis of Oesophageal Squamous Cell Carcinoma reveals clinical relevance.

ABSTRACT: Oesophageal carcinoma is the fourth leading cause of cancer-related death in China, and more than 90% of these tumours are oesophageal squamous cell carcinoma (ESCC). Although several ESCC genomic sequencing studies have identified mutated somatic genes, the number of samples in each study was relatively small, and the molecular basis of ESCC has not been fully elucidated. Here, we performed an integrated analysis of 490 tumours by combining the genomic data from 7 previous ESCC projects. We identified 18 significantly mutated genes (SMGs). PTEN, DCDC1 and CUL3 were first reported as SMGs in ESCC. Notably, the AJUBA mutations and mutational signature4 were significantly correlated with a poorer survival in patients with ESCC. Hierarchical clustering analysis of the copy number alteration (CNA) of cancer gene census (CGC) genes in ESCC patients revealed three subtypes, and subtype3 exhibited more CNAs and marked for worse prognosis compared with subtype2. Moreover, database annotation suggested that two significantly differential CNA genes (PIK3CA and FBXW7) between subtype3 and subtype2 may serve as therapeutic drug targets. This study has extended our knowledge of the genetic basis of ESCC and shed some light into the clinical relevance, which would help improve the therapy and prognosis of ESCC patients.

SUBMITTER: Du P

PROVIDER: S-EPMC5681595 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Comprehensive genomic analysis of Oesophageal Squamous Cell Carcinoma reveals clinical relevance.

Du Peina P Huang Peide P Huang Xuanlin X Li Xiangchun X Feng Zhimin Z Li Fengyu F Liang Shaoguang S Song Yongmei Y Stenvang Jan J Brünner Nils N Yang Huanming H Ou Yunwei Y Gao Qiang Q Li Lin L

Scientific reports 20171110 1

Oesophageal carcinoma is the fourth leading cause of cancer-related death in China, and more than 90% of these tumours are oesophageal squamous cell carcinoma (ESCC). Although several ESCC genomic sequencing studies have identified mutated somatic genes, the number of samples in each study was relatively small, and the molecular basis of ESCC has not been fully elucidated. Here, we performed an integrated analysis of 490 tumours by combining the genomic data from 7 previous ESCC projects. We ide ...[more]

PMID: 29127303

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Project description:BackgroundTumour immune microenvironment is related with carcinogenesis and efficacy of immunotherapy. B cells play major roles in humoral immunity, but detailed functions of tumour-infiltrating B lymphocytes (TIL-Bs) are unknown. Therefore, our aim was to investigate the functional heterogeneity of TIL-Bs in oesophageal squamous cell carcinoma (ESCC) and lymph nodes (LNs) during chemotherapy.MethodsSingle-cell transcriptome analysis was performed on 23 specimens. We also performed immunohistochemical analysis of immunoglobulin κ C (IGKC), an antibody-secreting cell (ASC) marker, in 166 ESCC samples and evaluated the implication of IGKC in 2-year recurrence free survival (RFS) and 3-year overall survival (OS).ResultsA total of 81,246 cells were grouped into 24 clusters. We extracted B cell clusters based on canonical markers and identified 12 TIL-B subtypes in ESCC. We found that several functions, such as co-stimulation and CD40 signalling, were enhanced in TIL-Bs after chemotherapy. The proportion of naive B cells (NBCs) decreased and B cell activation genes were up-regulated in NBCs after chemotherapy. The proportion of ASCs in tumours increased with the loss of migratory abilities and antibody production in ASCs was promoted after chemotherapy. Differentially expressed genes up-regulated with chemotherapy in ASCs correlated with prolonged survival with oesophageal cancer (p = .028). In a metastatic LN, the ASC proportion increased and B cell differentiation was enhanced. In immunohistochemical analysis, RFS and OS of high IGKC expression cases were significantly better than those of low IGKC expression cases (RFS: p < .0001, OS: p < .0001). And in multivariable analysis, the expression of IGKC was an independent favourable prognostic factor for RFS (hazard ratio (HR): 0.23, 95% confidence interval (CI): 0.12-0.45, p < .0001) and OS (HR: 0.20, 95% CI: 0.086-0.47, p = .0002) in ESCC.ConclusionsOur findings provide novel insights for the heterogeneity of TIL-Bs during chemotherapy and will be useful to understand the clinical importance of TIL-Bs.

Project description:Metastatic cutaneous squamous cell carcinoma (CSCC) is a highly morbid disease requiring radical surgery and adjuvant therapy, which is associated with a poor prognosis. Yet, compared to other advanced malignancies, relatively little is known of the genomic landscape of metastatic CSCC. We have previously reported the mutational signatures and mutational patterns of CCCTC-binding factor (CTCF) regions in metastatic CSCC. However, many other genomic components (indel signatures, non-coding drivers, and structural variants) of metastatic CSCC have not been reported. To this end, we performed whole genome sequencing on lymph node metastases and blood DNA from 25 CSCC patients with regional metastases of the head and neck. We designed a multifaceted computational analysis at the whole genome level to provide a more comprehensive perspective of the genomic landscape of metastatic CSCC. In the non-coding genome, 3' untranslated region (3'UTR) regions of EVC (48% of specimens), PPP1R1A (48% of specimens), and ABCA4 (20% of specimens) along with the tumor-suppressing long non-coding RNA (lncRNA) LINC01003 (64% of specimens) were significantly functionally altered (Q-value < 0.05) and represent potential non-coding biomarkers of CSCC. Recurrent copy number loss in the tumor suppressor gene PTPRD was observed. Gene amplification was much less frequent, and few genes were recurrently amplified. Single nucleotide variants driver analyses from three tools confirmed TP53 and CDKN2A as recurrently mutated genes but also identified C9 as a potential novel driver in this disease. Furthermore, indel signature analysis highlighted the dominance of ID signature 13 (ID13) followed by ID8 and ID9. ID9 has previously been shown to have no association with skin melanoma, unlike ID13 and ID8, suggesting a novel pattern of indel variation in metastatic CSCC. The enrichment analysis of various genetically altered candidates shows enrichment of "TGF-beta regulation of extracellular matrix" and "cell cycle G1 to S check points." These enriched terms are associated with genetic instability, cell proliferation, and migration as mechanisms of genomic drivers of metastatic CSCC.

Dataset Information

Comprehensive genomic analysis of Oesophageal Squamous Cell Carcinoma reveals clinical relevance.

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Comprehensive genomic analysis of Oesophageal Squamous Cell Carcinoma reveals clinical relevance.

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