Cancer genomic alterations and microenvironmental features encode synergistic interactions with disease outcomes.

IF 4.7 2区 医学 Q2 CELL BIOLOGY
Masroor Bayati, Zoe P Klein, Alexander T Bahcheli, Mykhaylo Slobodyanyuk, Jeffrey To, Kevin C L Cheng, Jigyansa Mishra, Diogo Pellegrina, Kissy Guevara-Hoyer, Chris McIntosh, Mamatha Bhat, Jüri Reimand
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Abstract

Oncogenesis, tumor progression and therapy response are shaped by somatic alterations in the cancer genome and features of the tumor immune microenvironment (TME). How interactions between these two systems influence tumor evolution and clinical outcomes remains incompletely understood. To address this challenge, we developed the multi-omics analysis framework PACIFIC that systematically integrates genetic cancer drivers and infiltration profiles of immune cells to find pairwise combinations of drivers and TME characteristics that jointly associate with clinical outcomes. By analyzing 8500 primary tumor samples of 26 cancer types, we report 34 immunogenomic interactions (IGXs) in 13 cancer types in which context-specific combinations of genomic alterations and immune cell levels were significantly correlated with patient survival. Subsets of tumor samples defined by some IGXs were characterized by tumor-intrinsic and microenvironmental metrics of immunogenicity and differential expression of immunotherapy target genes. In luminal-A breast cancer, an IGX involving MEN1 deletion combined with reduced levels of neutrophils associated with lower progression-free survival and deregulation of immune signaling pathways, as observed in two independent cancer genomics datasets. These results showcase the ability of PACIFIC to integrate complex multi-omics datasets with clinical information, enabling the identification of clinically relevant immunogenomic interactions. Such interactions provide a rich set of hypotheses for mechanistic studies and the development of biomarkers and therapeutic targets. Implications: Co-occurrence patterns of cancer drivers and TME characteristics highlight synergistic interactions with prognostic potential.

癌症基因组改变和微环境特征编码与疾病结果的协同相互作用。
肿瘤发生、肿瘤进展和治疗反应是由癌症基因组的体细胞改变和肿瘤免疫微环境(TME)的特征决定的。这两个系统之间的相互作用如何影响肿瘤的发展和临床结果仍然不完全清楚。为了应对这一挑战,我们开发了多组学分析框架PACIFIC,该框架系统地整合了遗传癌症驱动因素和免疫细胞浸润谱,以寻找驱动因素和TME特征的成对组合,这些特征与临床结果共同相关。通过分析26种癌症类型的8500例原发肿瘤样本,我们报告了13种癌症类型中的34种免疫基因组相互作用(IGXs),其中基因组改变和免疫细胞水平的上下文特异性组合与患者生存显著相关。由某些igx定义的肿瘤样本亚群通过免疫原性的肿瘤固有指标和微环境指标以及免疫治疗靶基因的差异表达来表征。在luminal-A乳腺癌中,两个独立的癌症基因组学数据集观察到,涉及MEN1缺失的IGX与中性粒细胞水平降低相关,与较低的无进展生存期和免疫信号通路的失调有关。这些结果表明,太平洋能够整合复杂的多组学数据集与临床信息,从而能够识别临床相关的免疫基因组相互作用。这种相互作用为机制研究和生物标志物和治疗靶点的开发提供了丰富的假设。意义:癌症驱动因素和TME特征的共同发生模式突出了与预后潜力的协同相互作用。
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来源期刊
Molecular Cancer Research
Molecular Cancer Research 医学-细胞生物学
CiteScore
9.90
自引率
0.00%
发文量
280
审稿时长
4-8 weeks
期刊介绍: Molecular Cancer Research publishes articles describing novel basic cancer research discoveries of broad interest to the field. Studies must be of demonstrated significance, and the journal prioritizes analyses performed at the molecular and cellular level that reveal novel mechanistic insight into pathways and processes linked to cancer risk, development, and/or progression. Areas of emphasis include all cancer-associated pathways (including cell-cycle regulation; cell death; chromatin regulation; DNA damage and repair; gene and RNA regulation; genomics; oncogenes and tumor suppressors; signal transduction; and tumor microenvironment), in addition to studies describing new molecular mechanisms and interactions that support cancer phenotypes. For full consideration, primary research submissions must provide significant novel insight into existing pathway functions or address new hypotheses associated with cancer-relevant biologic questions.
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