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Integrated DNA and RNA sequencing reveals early drivers involved in metastasis of gastric cancer.

ABSTRACT: Gastric cancer (GC) is the second cause of cancer-related death and metastasis is an important cause of death. Considering difficulties in searching for metastatic driver mutations, we tried a novel strategy here. We conducted an integrative genomic analysis on GC and identified early drivers lead to metastasis. Whole-exome sequencing (WES), transcriptomes sequencing and targeted-exome sequencing (TES) were performed on tumors and matched normal tissues from 432 Chinese GC patients, especially the comparative analysis between higher metastatic-potential (HMP) group with T1 stage and lymph-node metastasis, and lower metastatic-potential (LMP) group without lymph-nodes or distant metastasis. HMP group presented higher mutation load and heterogeneity, enrichment in immunosuppressive signaling, more immune cell infiltration than LMP group. An integrated mRNA-lncRNA signature based on differentially expressed genes was constructed and its prognostic value was better than traditional TNM stage. We identified 176 candidate prometastatic mutations by WES and selected 8 genes for following TES. Mutated TP53 and MADCAM1 were significantly associated with poor metastasis-free survival. We further demonstrated that mutated MADCAM1 could not only directly promote cancer cells migration, but also could trigger tumor metastasis by establishing immunosuppressive microenvironment, including promoting PD-L1-mediated immune escape and reprogramming tumor-associated macrophages by regulating CCL2 through Akt/mTOR axis. In conclusion, GCs with different metastatic-potential are distinguishable at the genetic level and we revealed a number of potential metastatic driver mutations. Driver mutations in early-onset metastatic GC could promote metastasis by establishing an immunosuppressive microenvironment. This study provided possibility for future target therapy of GC.

SUBMITTER: Zhang J

PROVIDER: S-EPMC9023472 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Integrated DNA and RNA sequencing reveals early drivers involved in metastasis of gastric cancer.

Zhang Jieyun J Liu Fatao F Yang Yanan Y Yu Nuoya N Weng Xiaoling X Yang Yue Y Gong Zhe Z Huang Shenglin S Gan Lu L Sun Sijie S Zhang Xiaowei X Gong Yiwei Y Liu Yun Y Guo Weijian W

Cell death & disease 20220421 4

Gastric cancer (GC) is the second cause of cancer-related death and metastasis is an important cause of death. Considering difficulties in searching for metastatic driver mutations, we tried a novel strategy here. We conducted an integrative genomic analysis on GC and identified early drivers lead to metastasis. Whole-exome sequencing (WES), transcriptomes sequencing and targeted-exome sequencing (TES) were performed on tumors and matched normal tissues from 432 Chinese GC patients, especially t ...[more]

PMID: 35449126

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Project description:PurposeATP-binding cassette A1 (ABCA1) is a potential prognostic marker for various tumor types. However, the biological effects and prognostic value of ABCA1 in gastric adenocarcinoma (GAC) remain unknown.MethodsGAC-associated single-cell RNA and bulk RNA-sequencing (bulk-seq) data were obtained from the Gene Expression Omnibus and The Cancer Genome Atlas databases, respectively. The differential expression of ABCA1 between GAC and normal gastric tissues was analyzed based on the bulk-seq data. Additionally, the relationship between ABCA1 expression and various clinicopathological features was explored. Furthermore, Kaplan-Meier survival and Cox regression analyses were performed to establish the prognostic value of ABCA1. The relationships between ABCA1 expression and anti-tumor drug sensitivity and immune checkpoints were also explored. Finally, the biological functions of ABCA1 were evaluated at the single-cell level, and in vitro studies were performed to assess the effects of ABCA1 on GAC cell proliferation and invasion.ResultsABCA1 expression is significantly elevated in GAC samples compared with that in normal gastric tissues. Clinical features and survival analysis revealed that high ABCA1 expression is associated with poor clinical phenotypes and prognosis, whereas Cox analysis identified ABCA1 as an independent risk factor for patients with GAC. Furthermore, high ABCA1 expression suppresses sensitivity to various chemotherapeutic drugs, including cisplatin and mitomycin, while upregulating immune checkpoints. ABCA1-overexpressing macrophages are associated with adverse clinical phenotypes in GAC and express unique ligand-receptor pairs that drive GAC progression. In vitro, ABCA1-knockdown GAC cells exhibit significantly inhibited proliferative and invasive properties.ConclusionHigh ABCA1 expression promotes an adverse immune microenvironment and low survival rates in patients with GAC. Furthermore, ABCA1 and ABCA1-producing macrophages may serve as novel molecular targets in GAC treatment.

Project description:The biological role and prognostic value of thrombospondin domain-containing 7A (THSD7A) in gastric cancer remain unclear. Our purpose was to determine the molecular mechanisms underlying the functioning of THSD7A and its prognostic value in gastric cancer. Gastric cancer-associated single cell and bulk RNA sequencing data obtained from two databases, were analyzed. We used bulk RNA sequencing to examine the differential expression of THSD7A in gastric cancer and normal gastric tissues and explored the relationship between THSD7A expression and clinicopathological characteristics. Kaplan-Meier survival and Cox analyses revealed the prognostic value of THSD7A. Gene set enrichment and immune infiltration analyses were used to determine the cancer-promoting mechanisms of THSD7A and its effect on the immune microenvironment. We explored the relationship between THSD7A expression and sensitivity of anti-tumor drugs and immune checkpoint levels. Biological functions of THSD7A were validated at single-cell and in vitro levels. THSD7A expression was significantly increased in gastric cancer samples. High THSD7A expression was associated with poor clinical phenotypes and prognoses. Cox analysis showed that THSD7A was an independent risk factor for patients with gastric cancer. Enrichment analysis suggested that epithelial-mesenchymal transition and inflammatory responses may be potential pro-cancer mechanisms of THSD7A. Upregulation of THSD7A promoted infiltration by M2 macrophages and regulatory T cells. High THSD7A expression suppressed the sensitivity of patients with gastric cancer to drugs, such as 5-fluorouracil, bleomycin, and cisplatin, and upregulated immune checkpoints, such as HAVCR2, PDCD1LG2, TIGIT, and CTLA4. At the single cell level, THSD7A was an endothelial cell-associated gene and endothelial cells overexpressing THSD7A showed unique pro-oncogenic effects. In vitro experiments confirmed that THSD7A was overexpressed in gastric cancer samples and cells, and that knocking out THSD7A significantly inhibited gastric cancer cell proliferation and invasion. THSD7A overexpression may be a unique prognostic marker and therapeutic target in gastric cancer. Therefore, our study provides a new perspective on the precise treatment of gastric cancer.

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Integrated DNA and RNA sequencing reveals early drivers involved in metastasis of gastric cancer.

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Integrated DNA and RNA sequencing reveals early drivers involved in metastasis of gastric cancer.

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