ABSTRACT
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.
Subject(s)
Adenocarcinoma of Lung/genetics , Kelch-Like ECH-Associated Protein 1/metabolism , Lung Neoplasms/genetics , Tachykinins/metabolism , Whole Genome Sequencing/methods , HumansABSTRACT
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.
Subject(s)
DNA Methylation , Ethnicity/genetics , Genetic Predisposition to Disease , MicroRNAs/genetics , Mutation , Neoplasm Proteins/genetics , Neoplasms/genetics , DNA-Binding Proteins/genetics , F-Box-WD Repeat-Containing Protein 7/genetics , Gene Expression Regulation, Neoplastic , Genetics, Population , Genome, Human , Genomics , High-Throughput Nucleotide Sequencing , Humans , Neoplasms/ethnology , Neoplasms/pathology , Transcription Factors/genetics , Von Hippel-Lindau Tumor Suppressor Protein/geneticsABSTRACT
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.
Subject(s)
Genome/genetics , MicroRNAs/genetics , Neoplasms/genetics , Software , Controlled Before-After Studies , Datasets as Topic , Gene Expression Profiling , Genome, Human , Genomics , Health Information Exchange , High-Throughput Nucleotide Sequencing , Humans , Molecular Sequence Annotation , Reproducibility of ResultsABSTRACT
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.
Subject(s)
Biomarkers, Tumor/genetics , Lung Neoplasms/genetics , Mesothelioma/genetics , Mutation , Pleural Neoplasms/genetics , Aged , Female , Histone-Lysine N-Methyltransferase , Humans , Kaplan-Meier Estimate , Lung Neoplasms/pathology , Lung Neoplasms/therapy , Male , Mesothelioma/pathology , Mesothelioma/therapy , Middle Aged , Pleural Neoplasms/pathology , Pleural Neoplasms/therapy , Prognosis , Protein Methyltransferases/genetics , Tumor Suppressor Proteins/genetics , Ubiquitin Thiolesterase/geneticsABSTRACT
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.
Subject(s)
Chromatin/metabolism , Gene Expression Regulation, Neoplastic , Genetic Predisposition to Disease , Neoplasms/genetics , Neoplasms/metabolism , Regulatory Sequences, Nucleic Acid , Chromatin/genetics , DNA Footprinting , Enhancer Elements, Genetic , Genetic Loci , Humans , Immunity/genetics , Transcription Factors/metabolism , Transposases/metabolismABSTRACT
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.
Subject(s)
Neoplasms, Germ Cell and Embryonal/pathology , Testicular Neoplasms/pathology , DNA Copy Number Variations , DNA Methylation , Gene Expression Regulation, Neoplastic , Humans , Male , MicroRNAs/metabolism , Neoplasms, Germ Cell and Embryonal/classification , Neoplasms, Germ Cell and Embryonal/metabolism , Proto-Oncogene Proteins c-kit/genetics , Proto-Oncogene Proteins c-kit/metabolism , Seminoma/metabolism , Seminoma/pathology , Testicular Neoplasms/classification , Testicular Neoplasms/metabolism , ras Proteins/genetics , ras Proteins/metabolismABSTRACT
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.
Subject(s)
Mutation/genetics , Neoplasms, Glandular and Epithelial/genetics , Thymoma/genetics , Thymus Neoplasms/genetics , Transcription Factors, TFII/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Female , Genomics , Humans , Male , Middle Aged , Young AdultABSTRACT
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.
