对印度卵巢癌队列的多组学分析揭示了组织学类型特异性的突变和基因表达模式。

Multi-omics analysis of the Indian ovarian cancer cohort revealed histotype-specific mutation and gene expression patterns.

作者信息

Mhatre Anisha, Koroth Jinsha, Manjunath Meghana, Kumar S Sandeep, Gawari Ramesh, Choudhary Bibha

机构信息

Department of Biotechnology and Bioinformatics, Institute of Bioinformatics and Applied Biotechnology, Bangalore, Karnataka, India.

Graduate Student Registered Under Manipal Academy of Higher Education, Manipal, Karnataka, India.

出版信息

Front Genet. 2023 Apr 6;14:1102114. doi: 10.3389/fgene.2023.1102114. eCollection 2023.

DOI:10.3389/fgene.2023.1102114

PMID:37091785

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10117685/

Abstract

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. 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. 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. Integrated exome, transcriptome, and splicing patterns revealed different population-specific molecular signatures of ovarian cancer histotypes in the Indian Cohort.

摘要

在印度，卵巢癌是女性第三大常见且致命的癌症类型，占观察到的癌症发病率的6.7%。体细胞突变、基因及其剪接形式的异常表达在决定细胞命运、基因网络、肿瘤特异性变体以及免疫分数浸润的作用等方面，已被证明对理解肿瘤发生至关重要。然而，在印度背景下，它们在卵巢癌中以组织学类型特异性方式的相互作用仍不清楚。在本研究中，我们旨在揭示印度人群卵巢癌样本的组织学类型特异性外显子变体、差异表达的基因模块、剪接事件和免疫图谱。我们分析了4种卵巢癌组织学类型的10个肿瘤样本以及2个正常患者样本。这包括用于外显子分析的BCFtool实用程序和CNVkit，用于获取差异模块中心基因和失调的miRNA靶点的WGCNA和DESeq2，用于个体免疫图谱分析的CIBERSORTx以及用于肿瘤特异性剪接变体分析的rMATS。我们在癌症基因普查一级和二级基因中鉴定出了人群特异性的新突变。MUC16、MUC4、CIITA和NCOR2是与TP53一起突变最多的基因。转录组分析显示，突变基因MUC16、MUC4和CIITA显著过表达，而NCOR2则下调。WGCNA揭示了组织学类型特异性的基因中心和网络。在显著的通路中，免疫系统的改变是其中一条通路，使用CIBERSORTx进行的免疫图谱分析揭示了组织学类型特异性的免疫细胞分数。miRNA分析显示，miR - 200家族、miR - 200a和miR - 429在高级别浆液性卵巢癌（HGSOCs）中上调。剪接因子缺失导致剪接扰动，最丰富的可变剪接事件是外显子跳跃，剪接最多的基因是SNHG17。对剪接基因的通路分析显示，翻译延伸和碱基切除修复是卵巢癌中发生改变的通路。综合外显子组、转录组和剪接模式揭示了印度队列中卵巢癌组织学类型不同的人群特异性分子特征。