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
{"title":"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。","authors":"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","doi":"10.1158/1541-7786.MCR-25-0475","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.7000,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Cancer genomic alterations and microenvironmental features encode synergistic interactions with disease outcomes.\",\"authors\":\"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\",\"doi\":\"10.1158/1541-7786.MCR-25-0475\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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.</p>\",\"PeriodicalId\":19095,\"journal\":{\"name\":\"Molecular Cancer Research\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":4.7000,\"publicationDate\":\"2025-09-03\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Molecular Cancer Research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1158/1541-7786.MCR-25-0475\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Cancer Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1158/1541-7786.MCR-25-0475","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
Cancer genomic alterations and microenvironmental features encode synergistic interactions with disease outcomes.
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.
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.