RESUMEN
RTK/RAS/RAF pathway alterations (RPAs) are a hallmark of lung adenocarcinoma (LUAD). In this study, we use whole-genome sequencing (WGS) of 85 cases found to be RPA(-) by previous studies from The Cancer Genome Atlas (TCGA) to characterize the minority of LUADs lacking apparent alterations in this pathway. We show that WGS analysis uncovers RPA(+) in 28 (33%) of the 85 samples. Among the remaining 57 cases, we observe focal deletions targeting the promoter or transcription start site of STK11 (n = 7) or KEAP1 (n = 3), and promoter mutations associated with the increased expression of ILF2 (n = 6). We also identify complex structural variations associated with high-level copy number amplifications. Moreover, an enrichment of focal deletions is found in TP53 mutant cases. Our results indicate that RPA(-) cases demonstrate tumor suppressor deletions and genome instability, but lack unique or recurrent genetic lesions compensating for the lack of RPAs. Larger WGS studies of RPA(-) cases are required to understand this important LUAD subset.
Asunto(s)
Adenocarcinoma del Pulmón/genética , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Neoplasias Pulmonares/genética , Taquicininas/metabolismo , Secuenciación Completa del Genoma/métodos , HumanosRESUMEN
We evaluated ancestry effects on mutation rates, DNA methylation, and mRNA and miRNA expression among 10,678 patients across 33 cancer types from The Cancer Genome Atlas. We demonstrated that cancer subtypes and ancestry-related technical artifacts are important confounders that have been insufficiently accounted for. Once accounted for, ancestry-associated differences spanned all molecular features and hundreds of genes. Biologically significant differences were usually tissue specific but not specific to cancer. However, admixture and pathway analyses suggested some of these differences are causally related to cancer. Specific findings included increased FBXW7 mutations in patients of African origin, decreased VHL and PBRM1 mutations in renal cancer patients of African origin, and decreased immune activity in bladder cancer patients of East Asian origin.
Asunto(s)
Metilación de ADN , Etnicidad/genética , Predisposición Genética a la Enfermedad , MicroARNs/genética , Mutación , Proteínas de Neoplasias/genética , Neoplasias/genética , Proteínas de Unión al ADN/genética , Proteína 7 que Contiene Repeticiones F-Box-WD/genética , Regulación Neoplásica de la Expresión Génica , Genética de Población , Genoma Humano , Genómica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Neoplasias/etnología , Neoplasias/patología , Factores de Transcripción/genética , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genéticaRESUMEN
We present a systematic analysis of the effects of synchronizing a large-scale, deeply characterized, multi-omic dataset to the current human reference genome, using updated software, pipelines, and annotations. For each of 5 molecular data platforms in The Cancer Genome Atlas (TCGA)-mRNA and miRNA expression, single nucleotide variants, DNA methylation and copy number alterations-comprehensive sample, gene, and probe-level studies were performed, towards quantifying the degree of similarity between the 'legacy' GRCh37 (hg19) TCGA data and its GRCh38 (hg38) version as 'harmonized' by the Genomic Data Commons. We offer gene lists to elucidate differences that remained after controlling for confounders, and strategies to mitigate their impact on biological interpretation. Our results demonstrate that the hg19 and hg38 TCGA datasets are very highly concordant, promote informed use of either legacy or harmonized omics data, and provide a rubric that encourages similar comparisons as new data emerge and reference data evolve.
Asunto(s)
Genoma/genética , MicroARNs/genética , Neoplasias/genética , Programas Informáticos , Estudios Controlados Antes y Después , Conjuntos de Datos como Asunto , Perfilación de la Expresión Génica , Genoma Humano , Genómica , Intercambio de Información en Salud , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Anotación de Secuencia Molecular , Reproducibilidad de los ResultadosRESUMEN
We present the genome-wide chromatin accessibility profiles of 410 tumor samples spanning 23 cancer types from The Cancer Genome Atlas (TCGA). We identify 562,709 transposase-accessible DNA elements that substantially extend the compendium of known cis-regulatory elements. Integration of ATAC-seq (the assay for transposase-accessible chromatin using sequencing) with TCGA multi-omic data identifies a large number of putative distal enhancers that distinguish molecular subtypes of cancers, uncovers specific driving transcription factors via protein-DNA footprints, and nominates long-range gene-regulatory interactions in cancer. These data reveal genetic risk loci of cancer predisposition as active DNA regulatory elements in cancer, identify gene-regulatory interactions underlying cancer immune evasion, and pinpoint noncoding mutations that drive enhancer activation and may affect patient survival. These results suggest a systematic approach to understanding the noncoding genome in cancer to advance diagnosis and therapy.
Asunto(s)
Cromatina/metabolismo , Regulación Neoplásica de la Expresión Génica , Predisposición Genética a la Enfermedad , Neoplasias/genética , Neoplasias/metabolismo , Secuencias Reguladoras de Ácidos Nucleicos , Cromatina/genética , Huella de ADN , Elementos de Facilitación Genéticos , Sitios Genéticos , Humanos , Inmunidad/genética , Factores de Transcripción/metabolismo , Transposasas/metabolismoRESUMEN
Malignant pleural mesothelioma (MPM) is a highly lethal cancer of the lining of the chest cavity. To expand our understanding of MPM, we conducted a comprehensive integrated genomic study, including the most detailed analysis of BAP1 alterations to date. We identified histology-independent molecular prognostic subsets, and defined a novel genomic subtype with TP53 and SETDB1 mutations and extensive loss of heterozygosity. We also report strong expression of the immune-checkpoint gene VISTA in epithelioid MPM, strikingly higher than in other solid cancers, with implications for the immune response to MPM and for its immunotherapy. Our findings highlight new avenues for further investigation of MPM biology and novel therapeutic options. SIGNIFICANCE: Through a comprehensive integrated genomic study of 74 MPMs, we provide a deeper understanding of histology-independent determinants of aggressive behavior, define a novel genomic subtype with TP53 and SETDB1 mutations and extensive loss of heterozygosity, and discovered strong expression of the immune-checkpoint gene VISTA in epithelioid MPM.See related commentary by Aggarwal and Albelda, p. 1508.This article is highlighted in the In This Issue feature, p. 1494.
Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias Pulmonares/genética , Mesotelioma/genética , Mutación , Neoplasias Pleurales/genética , Anciano , Femenino , N-Metiltransferasa de Histona-Lisina , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/terapia , Masculino , Mesotelioma/patología , Mesotelioma/terapia , Persona de Mediana Edad , Neoplasias Pleurales/patología , Neoplasias Pleurales/terapia , Pronóstico , Proteína Metiltransferasas/genética , Proteínas Supresoras de Tumor/genética , Ubiquitina Tiolesterasa/genéticaRESUMEN
Thymic epithelial tumors (TETs) are one of the rarest adult malignancies. Among TETs, thymoma is the most predominant, characterized by a unique association with autoimmune diseases, followed by thymic carcinoma, which is less common but more clinically aggressive. Using multi-platform omics analyses on 117 TETs, we define four subtypes of these tumors defined by genomic hallmarks and an association with survival and World Health Organization histological subtype. We further demonstrate a marked prevalence of a thymoma-specific mutated oncogene, GTF2I, and explore its biological effects on multi-platform analysis. We further observe enrichment of mutations in HRAS, NRAS, and TP53. Last, we identify a molecular link between thymoma and the autoimmune disease myasthenia gravis, characterized by tumoral overexpression of muscle autoantigens, and increased aneuploidy.
Asunto(s)
Mutación/genética , Neoplasias Glandulares y Epiteliales/genética , Timoma/genética , Neoplasias del Timo/genética , Factores de Transcripción TFII/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Genómica , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
We studied 137 primary testicular germ cell tumors (TGCTs) using high-dimensional assays of genomic, epigenomic, transcriptomic, and proteomic features. These tumors exhibited high aneuploidy and a paucity of somatic mutations. Somatic mutation of only three genes achieved significance-KIT, KRAS, and NRAS-exclusively in samples with seminoma components. Integrated analyses identified distinct molecular patterns that characterized the major recognized histologic subtypes of TGCT: seminoma, embryonal carcinoma, yolk sac tumor, and teratoma. Striking differences in global DNA methylation and microRNA expression between histology subtypes highlight a likely role of epigenomic processes in determining histologic fates in TGCTs. We also identified a subset of pure seminomas defined by KIT mutations, increased immune infiltration, globally demethylated DNA, and decreased KRAS copy number. We report potential biomarkers for risk stratification, such as miRNA specifically expressed in teratoma, and others with molecular diagnostic potential, such as CpH (CpA/CpC/CpT) methylation identifying embryonal carcinomas.
Asunto(s)
Neoplasias de Células Germinales y Embrionarias/patología , Neoplasias Testiculares/patología , Variaciones en el Número de Copia de ADN , Metilación de ADN , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , MicroARNs/metabolismo , Neoplasias de Células Germinales y Embrionarias/clasificación , Neoplasias de Células Germinales y Embrionarias/metabolismo , Proteínas Proto-Oncogénicas c-kit/genética , Proteínas Proto-Oncogénicas c-kit/metabolismo , Seminoma/metabolismo , Seminoma/patología , Neoplasias Testiculares/clasificación , Neoplasias Testiculares/metabolismo , Proteínas ras/genética , Proteínas ras/metabolismoRESUMEN
Comprehensive multiplatform analysis of 80 uveal melanomas (UM) identifies four molecularly distinct, clinically relevant subtypes: two associated with poor-prognosis monosomy 3 (M3) and two with better-prognosis disomy 3 (D3). We show that BAP1 loss follows M3 occurrence and correlates with a global DNA methylation state that is distinct from D3-UM. Poor-prognosis M3-UM divide into subsets with divergent genomic aberrations, transcriptional features, and clinical outcomes. We report change-of-function SRSF2 mutations. Within D3-UM, EIF1AX- and SRSF2/SF3B1-mutant tumors have distinct somatic copy number alterations and DNA methylation profiles, providing insight into the biology of these low- versus intermediate-risk clinical mutation subtypes.