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Identification of immune-enhanced molecular subtype associated with BRCA1 mutations, immune checkpoints and clinical outcome in ovarian carcinoma.

ABSTRACT: Ovarian carcinoma has the highest mortality among the malignant tumours in gynaecology, and new treatment strategies are urgently needed to improve the clinical status of ovarian carcinoma patients. The Cancer Genome Atlas (TCGA) cohort were performed to explore the immune function of the internal environment of tumours and its clinical correlation with ovarian carcinoma. Finally, four molecular subtypes were obtained based on the global immune-related genes. The correlation analysis and clinical characteristics showed that four subtypes were all significantly related to clinical stage; the immune scoring results indicated that most immune signatures were upregulated in C3 subtype, and the majority of tumour-infiltrating immune cells were upregulated in both C3 and C4 subtypes. Compared with other subtypes, C3 subtype had a higher BRCA1 mutation, higher expression of immune checkpoints, and optimal survival prognosis. These findings of the immunological microenvironment in tumours may provide new ideas for developing immunotherapeutic strategies for ovarian carcinoma.

SUBMITTER: Zheng M

PROVIDER: S-EPMC7077593 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Identification of immune-enhanced molecular subtype associated with BRCA1 mutations, immune checkpoints and clinical outcome in ovarian carcinoma.

Zheng Mingjun M Hu Yuexin Y Gou Rui R Liu Ouxuan O Nie Xin X Li Xiao X Liu Qing Q Hao Yingying Y Liu Juanjuan J Lin Bei B

Journal of cellular and molecular medicine 20200129 5

Ovarian carcinoma has the highest mortality among the malignant tumours in gynaecology, and new treatment strategies are urgently needed to improve the clinical status of ovarian carcinoma patients. The Cancer Genome Atlas (TCGA) cohort were performed to explore the immune function of the internal environment of tumours and its clinical correlation with ovarian carcinoma. Finally, four molecular subtypes were obtained based on the global immune-related genes. The correlation analysis and clinica ...[more]

PMID: 31995855

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Project description:BACKGROUND: Increased number of single nucleotide substitutions is seen in breast and ovarian cancer genomes carrying disease-associated mutations in BRCA1 or BRCA2. The significance of these genome-wide mutations is unknown. We hypothesize genome-wide mutation burden mirrors deficiencies in DNA repair and is associated with treatment outcome in ovarian cancer. METHODS AND RESULTS: The total number of synonymous and non-synonymous exome mutations (Nmut), and the presence of germline or somatic mutation in BRCA1 or BRCA2 (mBRCA) were extracted from whole-exome sequences of high-grade serous ovarian cancers from The Cancer Genome Atlas (TCGA). Cox regression and Kaplan-Meier methods were used to correlate Nmut with chemotherapy response and outcome. Higher Nmut correlated with a better response to chemotherapy after surgery. In patients with mBRCA-associated cancer, low Nmut was associated with shorter progression-free survival (PFS) and overall survival (OS), independent of other prognostic factors in multivariate analysis. Patients with mBRCA-associated cancers and a high Nmut had remarkably favorable PFS and OS. The association with survival was similar in cancers with either BRCA1 or BRCA2 mutations. In cancers with wild-type BRCA, tumor Nmut was associated with treatment response in patients with no residual disease after surgery. CONCLUSIONS: Tumor Nmut was associated with treatment response and with both PFS and OS in patients with high-grade serous ovarian cancer carrying BRCA1 or BRCA2 mutations. In the TCGA cohort, low Nmut predicted resistance to chemotherapy, and for shorter PFS and OS, while high Nmut forecasts a remarkably favorable outcome in mBRCA-associated ovarian cancer. Our observations suggest that the total mutation burden coupled with BRCA1 or BRCA2 mutations in ovarian cancer is a genomic marker of prognosis and predictor of treatment response. This marker may reflect the degree of deficiency in BRCA-mediated pathways, or the extent of compensation for the deficiency by alternative mechanisms.

Project description:Background: Recent data demonstrated efficacy of immune checkpoint inhibitors in advanced OCCC, but little is known about the immune microenvironment of these tumours and its impact on outcomes. We studied the expression of a panel of immune response genes in OCCC to identify the presence and prognostic relevance of irGES in these tumours. Methods: Immune response gene profiling was performed on 96 FFPE OCCC tumour samples with matched clinical outcomes, collected from the National University Hospital, Singapore between 2003 – 2016, using the nanoString nCounter PanCancer Immune Profiling Panel. Unsupervised hierarchical clustering analysis was performed to stratify OCCCs to derive the irGES profiles. Upregulation of specific genes of interest at the protein level and the status of mismatch repair (MMR) and ARID1A were validated using immunohistochemistry (IHC). Results: Total of 74/84 samples were successfully profiled. Median age at diagnosis was 53 yrs. 41 (55.4%) were stage 1, 7 (9.5%) stage 2, 24 (32.4%) Stage3, 2 (2.7%) stage 4. 64/74 (86.5%) of patients received adjuvant chemotherapy post debulking surgery with 38% recurrence rate (median PFS 27 months). Median follow up was 36 months. Based on irGES, 4 distinct molecular subgroups of OCCCs were identified. G1 was hallmarked by NK cell markers and PD-1 expression (PD-1 high), G2 by increased CTLA-4 expression, G3 by upregulation of genes associated with immunogenicity and antigen presentation, and G4 by increased levels of pro - angiogenic genes. The PD-1 high group was observed to have significantly poorer PFS (median PFS 20 months vs 68 months, p= 0.011) and a trend towards poorer OS when compared with G2/3/4 (median OS 38.8 months vs undefined, p = 0.0501). The pro - angiogenic (G4) carried the best prognosis (median PFS 108 months vs 26 months, p= 0.0515; median OS undefined, p= 0.0726). This difference in OS and PFS was consistently observed between stage 1 and non-stage 1 pts (hazard ratio 5.856 and 5.659, p < 0.0001, respectively). Significant correlation was observed between gene and protein expression of tumour PD-1, tumour and stromal PD-L1, and tumour IL-6 using IHC (p < 0.0001 for all comparisons). 6 (8.1%) pts were MMR deficient and there was no significant association between ARID1A and MMR expression across each irGES groups. Conclusion: OCCCs are heterogeneous and can be classified into 4 molecular subgroups based on their irGES profiles representing distinct clinicopathological characteristics and prognostic outcomes. If validated in larger datasets, these signatures may serve to guide clinical trial design and personalized treatment for OCCC pts.

Project description:PurposeFatty acid metabolism (FAM) affects the immune phenotype in a metabolically dynamic tumor microenvironment (TME), but the use of FAM-related genes (FAMGs) to predict the prognosis and immunotherapy response of cutaneous melanoma (CM) patients has not been investigated. In this study, we aimed to construct FAM molecular subtypes and identify key prognostic biomarkers in CM.MethodsWe used a CM dataset in The Cancer Genome Atlas (TCGA) to construct FAM molecular subtypes. We performed Kaplan-Meier (K-M) analysis, gene set enrichment analysis (GSEA), and TME analysis to assess differences in the prognosis and immune phenotype between subtypes. We used weighted gene co-expression network analysis (WGCNA) to identify key biomarkers that regulate tumor metabolism and immunity between the subtypes. We compared overall survival (OS), progression-free survival (PFS), and disease-specific survival (DSS) between CM patients with high or low biomarker expression. We applied univariable and multivariable Cox analyses to verify the independent prognostic value of the FAM biomarkers. We used GSEA and TME analysis to investigate the immune-related regulation mechanism of the FAM subtype biomarker. We evaluated the immune checkpoint inhibition (ICI) response and chemotherapy sensitivity between CM patients with high or low biomarker expression. We performed real-time fluorescent quantitative PCR (qRT-PCR) and semi-quantitative analysis of the immunohistochemical (IHC) data from the Human Protein Atlas to evaluate the mRNA and protein expression levels of the FAM biomarkers in CM.ResultsWe identified 2 FAM molecular subtypes (cluster 1 and cluster 2). K-M analysis showed that cluster 2 had better OS and PFS than cluster 1 did. GSEA showed that, compared with cluster 1, cluster 2 had significantly upregulated immune response pathways. The TME analysis indicated that immune cell subpopulations and immune functions were highly enriched in cluster 2 as compared with cluster 1. WGCNA identified 6 hub genes (ACSL5, ALOX5AP, CD1D, CD74, IL4I1, and TBXAS1) as FAM biomarkers. CM patients with high expression levels of the six biomarkers had better OS, PFS, and DSS than those with low expression levels of the biomarkers. The Cox regression analyses verified that the 6 FAM biomarkers can be independent prognostic factors for CM patients. The single-gene GSEA showed that the high expression levels of the 6 genes were mainly enriched in T-cell antigen presentation, the PD-1 signaling pathway, and tumor escape. The TME analysis confirmed that the FAM subtype biomarkers were not only related to immune infiltration but also highly correlated with immune checkpoints such as PD-1, PD-L1, and CTLA-4. TIDE scores confirmed that patients with high expression levels of the 6 biomarkers had worse immunotherapy responses. The 6 genes conveyed significant sensitivity to some chemotherapy drugs. qRT-PCR and IHC analyses verified the expression levels of the 6 biomarkers in CM cells.ConclusionOur FAM subtypes verify that different FAM reprogramming affects the function and phenotype of infiltrating immune cells in the CM TME. The FAM molecular subtype biomarkers can be independent predictors of prognosis and immunotherapy response in CM patients.

Dataset Information

Identification of immune-enhanced molecular subtype associated with BRCA1 mutations, immune checkpoints and clinical outcome in ovarian carcinoma.

Publications

Identification of immune-enhanced molecular subtype associated with BRCA1 mutations, immune checkpoints and clinical outcome in ovarian carcinoma.

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