RESUMEN
Germline genetic variants modulate human immune response. We present analytical pipelines for assessing the contribution of hosts' genetic background to the immune landscape of solid tumors using harmonized data from more than 9,000 patients in The Cancer Genome Atlas (TCGA). These include protocols for heritability, genome-wide association studies (GWAS), colocalization, and rare variant analyses. These workflows are developed around the structure of TCGA but can be adapted to explore other repositories or in the context of cancer immunotherapy. For complete details on the use and execution of this protocol, please refer to Sayaman et al. (2021).
Asunto(s)
Estudio de Asociación del Genoma Completo , Neoplasias , Humanos , Estudio de Asociación del Genoma Completo/métodos , Neoplasias/genética , Neoplasias/terapia , Genoma , Inmunidad , Células GerminativasRESUMEN
Understanding the contribution of the host's genetic background to cancer immunity may lead to improved stratification for immunotherapy and to the identification of novel therapeutic targets. We investigated the effect of common and rare germline variants on 139 well-defined immune traits in â¼9000 cancer patients enrolled in TCGA. High heritability was observed for estimates of NK cell and T cell subset infiltration and for interferon signaling. Common variants of IFIH1, TMEM173 (STING1), and TMEM108 were associated with differential interferon signaling and variants mapping to RBL1 correlated with T cell subset abundance. Pathogenic or likely pathogenic variants in BRCA1 and in genes involved in telomere stabilization and Wnt-ß-catenin also acted as immune modulators. Our findings provide evidence for the impact of germline genetics on the composition and functional orientation of the tumor immune microenvironment. The curated datasets, variants, and genes identified provide a resource toward further understanding of tumor-immune interactions.
Asunto(s)
Mutación de Línea Germinal/genética , Inmunoterapia/métodos , Células Asesinas Naturales/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Neoplasias/inmunología , Linfocitos T/inmunología , Bases de Datos Genéticas , Femenino , Regulación Neoplásica de la Expresión Génica , Genes BRCA1 , Estudio de Asociación del Genoma Completo , Humanos , Interferones/metabolismo , Masculino , Persona de Mediana Edad , Neoplasias/genética , Carácter Cuantitativo Heredable , Proteína p107 Similar a la del Retinoblastoma/genética , Transducción de Señal/genética , Proteínas Wnt/genética , Proteínas Wnt/metabolismo , beta Catenina/genética , beta Catenina/metabolismoRESUMEN
The Cancer Research Institute (CRI) iAtlas is an interactive web platform for data exploration and discovery in the context of tumors and their interactions with the immune microenvironment. iAtlas allows researchers to study immune response characterizations and patterns for individual tumor types, tumor subtypes, and immune subtypes. iAtlas supports computation and visualization of correlations and statistics among features related to the tumor microenvironment, cell composition, immune expression signatures, tumor mutation burden, cancer driver mutations, adaptive cell clonality, patient survival, expression of key immunomodulators, and tumor infiltrating lymphocyte (TIL) spatial maps. iAtlas was launched to accompany the release of the TCGA PanCancer Atlas and has since been expanded to include new capabilities such as (1) user-defined loading of sample cohorts, (2) a tool for classifying expression data into immune subtypes, and (3) integration of TIL mapping from digital pathology images. We expect that the CRI iAtlas will accelerate discovery and improve patient outcomes by providing researchers access to standardized immunogenomics data to better understand the tumor immune microenvironment and its impact on patient responses to immunotherapy.
