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Immuno-stimultory/regulatory gene expression patterns in advanced ovarian cancer.

ABSTRACT: It has been established that a high degree of tumor-infiltrating T cells is associated with ovarian cancer prognosis. We hypothesized that tumors display an immune-related program of transcription that can act in a stimulatory or a regulatory manner. We analyzed transcriptome-wide gene expression data from 503 ovarian tumors from the Cancer Genome Atlas to identify genes that show differential prognoses when stratified by CD3 expression. Genes with immunological functions and tumor antigen genes were selected for analysis. We repeated our analysis in an independent validation study. Five genes showed stimulatory/regulatory patterns at a high level of confidence (Bonferroni p < 0.05). Three of these (MAGEA8, MPL, AMHR2) were validated and one (WT1) could not be evaluated. These patterns show specific prognostic effect only in conjunction with CD3 expression. When patients express multiple transcripts in poor prognosis directions, there is a dose response: increasingly regulatory type tumors are associated with higher stage, lower treatment response and shorter overall survival and progression free survival. The high-confidence set of transcripts (MAGEA8, MPL, AMHR2, WT1) and selected low-confidence hits (EPOR, TLR7) alone or in combination represent candidate prognosis markers for further investigation.

SUBMITTER: Eng KH

PROVIDER: S-EPMC4633167 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Immuno-stimultory/regulatory gene expression patterns in advanced ovarian cancer.

Eng Kevin H KH Weir Isabelle I Tsuji Takemasa T Odunsi Kunle K

Genes & cancer 20150901 9-10

It has been established that a high degree of tumor-infiltrating T cells is associated with ovarian cancer prognosis. We hypothesized that tumors display an immune-related program of transcription that can act in a stimulatory or a regulatory manner. We analyzed transcriptome-wide gene expression data from 503 ovarian tumors from the Cancer Genome Atlas to identify genes that show differential prognoses when stratified by CD3 expression. Genes with immunological functions and tumor antigen genes ...[more]

PMID: 26622942

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Project description:Introduction: In India, OVCa is women's third most common and lethal cancer type, accounting for 6.7% of observed cancer incidences. The contribution of somatic mutations, aberrant expression of gene and splice forms in determining the cell fate, gene networks, tumour-specific variants, and the role of immune fraction infiltration have been proven essential in understanding tumorigenesis. However, their interplay in OVCa in a histotype-specific manner remains unclear in the Indian context. In the present study, we aimed to unravel the Indian population histotype-specific exome variants, differentially expressed gene modules, splice events and immune profiles of OVCa samples. Methods: We analysed 10 tumour samples across 4 ovarian cancer histotypes along with 2 normal patient samples. This included BCFtool utilities and CNVkit for exome, WGCNA and DESeq2 for obtaining differential module hub genes and dysregulated miRNA targets, CIBERSORTx for individual immune profiles and rMATS for tumour specific splice variants. Result: We identified population-specific novel mutations in Cancer Gene Census Tier1 and Tier2 genes. MUC16, MUC4, CIITA, and NCOR2 were among the most mutated genes, along with TP53. Transcriptome analysis showed significant overexpression of mutated genes MUC16, MUC4, and CIITA, whereas NCOR2 was downregulated. WGCNA revealed histotype-specific gene hubs and networks. Among the significant pathways, alteration in the immune system was one of the pathways, and immune profiling using CIBERSORTx revealed histotype-specific immune cell fraction. miRNA analysis revealed miR-200 family, miR-200a and miR-429 were upregulated in HGSOCs.Splice factor abrasion caused splicing perturbations, with the most abundant alternative splice event being exon skipping and the most spliced gene, SNHG17. Pathway analysis of spliced genes revealed translational elongation and Base excision repair as the pathways altered in OVCa. Conclusion: Integrated exome, transcriptome, and splicing patterns revealed different population-specific molecular signatures of ovarian cancer histotypes in the Indian Cohort.

Dataset Information

Immuno-stimultory/regulatory gene expression patterns in advanced ovarian cancer.

Publications

Immuno-stimultory/regulatory gene expression patterns in advanced ovarian cancer.

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