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Structural variation heavily influences the molecular landscape of cancer, in part by impacting DNA methylation-mediated transcriptional regulation. Here, using multi-omic datasets involving >2400 pediatric brain and central nervous system tumors of diverse histologies from the Children's Brain Tumor Network, we report hundreds of genes and associated CpG islands (CGIs) for which the nearby presence of somatic structural variant (SV) breakpoints is recurrently associated with altered expression or DNA methylation, respectively, including tumor suppressor genes ATRX and CDKN2A. Altered DNA methylation near enhancers associates with nearby somatic SV breakpoints, including MYC and MYCN. A subset of genes with SV-CGI methylation associations also have expression associations with patient survival, including BCOR, TERT, RCOR2, and PDLIM4. DNA methylation changes in recurrent or progressive tumors compared to the initial tumor within the same patient can predict survival in pediatric and adult cancers. Our comprehensive and pan-histology genomic analyses reveal mechanisms of noncoding alterations impacting cancer genes.
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Neoplasias Encefálicas , Ilhas de CpG , Metilação de DNA , Regulação Neoplásica da Expressão Gênica , Humanos , Metilação de DNA/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Ilhas de CpG/genética , Criança , Proteína Nuclear Ligada ao X/genética , Proteína Nuclear Ligada ao X/metabolismo , Epigenoma , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Proteína Proto-Oncogênica N-Myc/genética , Proteína Proto-Oncogênica N-Myc/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Masculino , Telomerase/genética , FemininoRESUMO
BACKGROUND: The differential gene expression profile of metastatic versus primary breast tumors represents an avenue for discovering new or underappreciated pathways underscoring processes of metastasis. However, as tumor biopsy samples are a mixture of cancer and non-cancer cells, most differentially expressed genes in metastases would represent confounders involving sample biopsy site rather than cancer cell biology. METHODS: By paired analysis, we defined a top set of differentially expressed genes in breast cancer metastasis versus primary tumors using an RNA-sequencing dataset of 152 patients from The Breast International Group Aiming to Understand the Molecular Aberrations dataset (BIG-AURORA). To filter the genes higher in metastasis for genes essential for breast cancer proliferation, we incorporated CRISPR-based data from breast cancer cell lines. RESULTS: A significant fraction of genes with higher expression in metastasis versus paired primary were essential by CRISPR. These 264 genes represented an essential signature of breast cancer metastasis. In contrast, nonessential metastasis genes largely involved tumor biopsy site. The essential signature predicted breast cancer patient outcome based on primary tumor expression patterns. Pathways underlying the essential signature included proteasome degradation, the electron transport chain, oxidative phosphorylation, and cancer metabolic reprogramming. Transcription factors MYC, MAX, HDAC3, and HCFC1 each bound significant fractions of essential genes. CONCLUSIONS: Associations involving the essential gene signature of breast cancer metastasis indicate true biological changes intrinsic to cancer cells, with important implications for applying existing therapies or developing alternate therapeutic approaches.
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Neoplasias da Mama , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Metástase Neoplásica , Transcriptoma , Humanos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Biomarcadores Tumorais/genética , Genes Essenciais/genética , Linhagem Celular Tumoral , Transdução de Sinais/genética , PrognósticoRESUMO
PURPOSE: To grade the pathological response of lymph nodes (LNs) to neoadjuvant chemotherapy (NAC) in patients with locally advanced gastric cancer (LAGC) and investigate its prognostic significance. METHODS: This retrospective study included 196 patients who underwent NAC, followed by radical gastrectomy for LAGC between January 2010 and October 2019. Pathological responses were evaluated based on the proportion of residual tumor cells within the tumor area in the primary tumor (PT) and LNs and included the following categories: 1a (0%), 1b (< 10%), 2 (10-50%), and 3 (> 50%). RESULTS: Among 166 patients with clinically node-positive disease, 38/27/39/62 were classified as having LN regression grade (LRG) 1a/1b/2/3, respectively. Compared to LN non-responders (LRG 2 or 3), LN responders (LRG 1a or 1b) had significantly higher 5-year overall survival (72.5% vs. 19.0%, P < 0.001) and recurrence-free survival rates (67.8% vs. 22.2%, P < 0.001), irrespective of PT response. Furthermore, a multivariate analysis revealed that the LN response was an independent risk factor for the overall survival (hazard ratio [HR] 0.417, 95% confidence interval [CI] 0.181-0.962, P = 0.040) and recurrence-free survival (HR 0.490, 95% CI 0.242-0.991, P = 0.047), but not the PT response (P > 0.05). CONCLUSIONS: The pathological LN response may be a reliable prognostic prediction tool in patients with LAGC who received NAC.
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Cancer cells exhibit heightened secretory states that drive tumor progression. Here, we identify a chromosome 3q amplicon that serves as a platform for secretory regulation in cancer. The 3q amplicon encodes multiple Golgi-resident proteins, including the scaffold Golgi integral membrane protein 4 (GOLIM4) and the ion channel ATPase Secretory Pathway Ca2+ Transporting 1 (ATP2C1). We show that GOLIM4 recruits ATP2C1 and Golgi phosphoprotein 3 (GOLPH3) to coordinate calcium-dependent cargo loading and Golgi membrane bending and vesicle scission. GOLIM4 depletion disrupts the protein complex, resulting in a secretory blockade that inhibits the progression of 3q-amplified malignancies. In addition to its role as a scaffold, GOLIM4 maintains intracellular manganese (Mn) homeostasis by binding excess Mn in the Golgi lumen, which initiates the routing of Mn-bound GOLIM4 to lysosomes for degradation. We show that Mn treatment inhibits the progression of multiple types of 3q-amplified malignancies by degrading GOLIM4, resulting in a secretory blockade that interrupts pro-survival autocrine loops and attenuates pro-metastatic processes in the tumor microenvironment. Potentially underlying the selective activity of Mn against 3q-amplified malignancies, ATP2C1 co-amplification increases Mn influx into the Golgi lumen, resulting in a more rapid degradation of GOLIM4. These findings show that functional cooperativity between co-amplified genes underlies heightened secretion and a targetable secretory addiction in 3q-amplified malignancies.
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Germline variation and somatic alterations contribute to the molecular profile of cancers. We combine RNA with whole genome sequencing across 1,218 cancer patients to determine the extent germline structural variants (SVs) impact expression of nearby genes. For hundreds of genes, recurrent and common germline SV breakpoints within 100 kb associate with increased or decreased expression in tumors spanning various tissues of origin. A significant fraction of germline SV expression associations involves duplication of intergenic enhancers or 3' UTR disruption. Genes altered by both somatic and germline SVs include ATRX and CEBPA. Genes essential in cancer cell lines include BARD1 and IRS2. Genes with both expression and germline SV breakpoint patterns associated with patient survival include GCLM. Our results capture a class of phenotypic variation at work in the disease setting, including genes with cancer roles. Specific germline SVs represent potential cancer risk variants for genetic testing, including those involving genes with targeting implications.
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Neoplasias , Transcriptoma , Humanos , Transcriptoma/genética , Neoplasias/genética , RNA , Células GerminativasRESUMO
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignant cancer type worldwide. Although the therapeutic modalities currently used for patients with HNSCC improved in recent decades, HNSCC prognosis is still poor. Therefore, it is an urgent necessity to understand the pathogenesis of HNSCC, to develop novel and effective treatment strategies, and to characterize and identify the oncogenes that are responsible for an aggressive HNSCC phenotype. In this study, we aimed to better understand the roles of miR-1825 in the pathogenesis of HNSCC. We examined the impacts of miR-1825 deregulation on the cancer-associated phenotypes using in vitro tests evaluating cell viability, clonogenicity, cell migration, invasion, apoptosis, and stem cell characteristics. In addition, we investigated the effects of miR-1825 overexpression on the tumor formation capacity of head and neck cancer cells in vivo using nude mice. We searched for potential targets of miR-1825 using microarray analysis and luciferase assay. We found that miR-1825 expression is upregulated in head and neck cells and clinical tumor samples in comparison to corresponding controls, where it potentially acts as an oncogene. We, then, showed that ectopic miR-1825 overexpression promotes cellular phenotypes related to head and neck cancer progression in vitro and has a stimulating potential on cancer formation in vivo. We also identified FREM1 as a direct target of miR-1825 and demonstrated its reduced expression in HNSCC samples using immunohistochemistry analysis. Collectively, we suggest that the miR-1825/FREM1 axis serves as an important mediator of HNSCC development, where miR-1825 acts as an oncogene.
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Both proteome and transcriptome data can help assess the relevance of non-coding somatic mutations in cancer. Here, we combine mass spectrometry-based proteomics data with whole genome sequencing data across 1307 human tumors spanning various tissues to determine the extent somatic structural variant (SV) breakpoint patterns impact protein expression of nearby genes. We find that about 25% of the hundreds of genes with SV-associated cis-regulatory alterations at the mRNA level are similarly associated at the protein level. SVs associated with enhancer hijacking, retrotransposon translocation, altered DNA methylation, or fusion transcripts are implicated in protein over-expression. SVs combined with altered protein levels considerably extend the numbers of patients with tumors somatically altered for critical pathways. We catalog both SV breakpoint patterns involving patient survival and genes with nearby SV breakpoints associated with increased cell dependency in cancer cell lines. Pan-cancer proteogenomics identifies targetable non-coding alterations, by virtue of the associated deregulated genes.
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Neoplasias , Proteoma , Humanos , Proteoma/genética , Neoplasias/genética , Linhagem Celular , Metilação de DNA/genética , Espectrometria de MassasRESUMO
Intestinal stem cells (ISC) encounter inflammatory insults in immune mediated gastro-intestinal (GI) diseases. It remains unknown whether, and how, they adapt, and if the adaptation leaves scars on the ISCs that affects their subsequent regeneration capacity. We investigated the consequences of inflammation on Lgr5+ISCs in well-defined clinically relevant models of gastro-intestinal acute graft-versus-host disease (GI GVHD). Utilizing single cell transcriptomics, organoid, metabolic, epigenomic and in vivo models we found that Lgr5+ISCs undergo metabolic changes that lead to accumulation of succinate, which reprograms its epigenome. These changes reduced the ability of ISCs to differentiate and regenerate ex vivo in serial organoid cultures demonstrating the persistence of the maladaptive impact of an in vivo inflammatory encounter by the ISCs. Thus, inflammation from GI GVHD leaves a memory of its effects on ISCs that persist and are likely to affect their sensitivity to adapt to future stress or challenges.
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The regenerative potential of the endometrium is attributed to endometrial stem cells; however, the signaling pathways controlling its regenerative potential remain obscure. In this study, genetic mouse models and endometrial organoids are used to demonstrate that SMAD2/3 signaling controls endometrial regeneration and differentiation. Mice with conditional deletion of SMAD2/3 in the uterine epithelium using Lactoferrin-iCre develop endometrial hyperplasia at 12-weeks and metastatic uterine tumors by 9-months of age. Mechanistic studies in endometrial organoids determine that genetic or pharmacological inhibition of SMAD2/3 signaling disrupts organoid morphology, increases the glandular and secretory cell markers, FOXA2 and MUC1, and alters the genome-wide distribution of SMAD4. Transcriptomic profiling of the organoids reveals elevated pathways involved in stem cell regeneration and differentiation such as the bone morphogenetic protein (BMP) and retinoic acid signaling (RA) pathways. Therefore, TGFß family signaling via SMAD2/3 controls signaling networks which are integral for endometrial cell regeneration and differentiation.
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Endométrio , Proteínas Smad , Útero , Animais , Feminino , Camundongos , Diferenciação Celular , Endométrio/metabolismo , Epitélio , Homeostase , Proteínas Smad/metabolismoRESUMO
Molecular mechanisms underlying cancer metastasis span diverse tissues of origin. Here, we synthesize and collate the transcriptomes of patient-derived xenografts and patient tumor metastases, and these data collectively represent 38 studies and over 3,000 patients and 4,000 tumors. We identify four expression-based subtypes of metastasis transcending tumor lineage. The first subtype has extensive copy alterations, higher expression of MYC transcriptional targets and DNA repair genes, and bromodomain inhibitor response association. The second subtype has higher expression of genes involving metabolism and prostaglandin synthesis and regulation. The third subtype has evidence of neuronal differentiation, higher expression of DNA and histone methylation genes and EZH2 transcriptional targets, and BCL2 inhibitor response association. The fourth subtype has higher expression of immune checkpoint and Notch pathway genes. The metastasis subtypes reflect expression differences from paired primaries, with subtype switching being common. These subtypes facilitate understanding of the molecular underpinnings of metastases beyond tissue-oriented domains, with therapeutic implications.
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Antineoplásicos , Neoplasias , Humanos , Neoplasias/tratamento farmacológico , Antineoplásicos/uso terapêutico , TranscriptomaRESUMO
One of the mechanisms by which cancer cells acquire hyperinvasive and migratory properties with progressive loss of epithelial markers is the epithelial-to-mesenchymal transition (EMT). We have previously reported that in different cancer types, including nonsmall cell lung cancer (NSCLC), the microRNA-183/96/182 cluster (m96cl) is highly repressed in cells that have undergone EMT. In the present study, we used a novel conditional m96cl mouse to establish that loss of m96cl accelerated the growth of Kras mutant autochthonous lung adenocarcinomas. In contrast, ectopic expression of the m96cl in NSCLC cells results in a robust suppression of migration and invasion in vitro, and tumor growth and metastasis in vivo. Detailed immune profiling of the tumors revealed a significant enrichment of activated CD8+ cytotoxic T lymphocytes (CD8+ CTLs) in m96cl-expressing tumors, and m96cl-mediated suppression of tumor growth and metastasis was CD8+ CTL-dependent. Using coculture assays with naïve immune cells, we show that m96cl expression drives paracrine stimulation of CD8+ CTL proliferation and function. Using tumor microenvironment-associated gene expression profiling, we identified that m96cl elevates the interleukin-2 (IL2) signaling pathway and results in increased IL2-mediated paracrine stimulation of CD8+ CTLs. Furthermore, we identified that the m96cl modulates the expression of IL2 in cancer cells by regulating the expression of transcriptional repressors Foxf2 and Zeb1, and thereby alters the levels of secreted IL2 in the tumor microenvironment. Last, we show that in vivo depletion of IL2 abrogates m96cl-mediated activation of CD8+ CTLs and results in loss of metastatic suppression. Therefore, we have identified a novel mechanistic role of the m96cl in the suppression of lung cancer growth and metastasis by inducing an IL2-mediated systemic CD8+ CTL immune response.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , MicroRNAs , Animais , Linfócitos T CD8-Positivos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Interleucina-2/genética , Interleucina-2/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Linfócitos T Citotóxicos , Microambiente TumoralRESUMO
Mass-spectrometry-based proteomic data on human tumors-combined with corresponding multi-omics data-present opportunities for systematic and pan-cancer proteogenomic analyses. Here, we assemble a compendium dataset of proteomics data of 2002 primary tumors from 14 cancer types and 17 studies. Protein expression of genes broadly correlates with corresponding mRNA levels or copy number alterations (CNAs) across tumors, but with notable exceptions. Based on unsupervised clustering, tumors separate into 11 distinct proteome-based subtypes spanning multiple tissue-based cancer types. Two subtypes are enriched for brain tumors, one subtype associating with MYC, Wnt, and Hippo pathways and high CNA burden, and another subtype associating with metabolic pathways and low CNA burden. Somatic alteration of genes in a pathway associates with higher pathway activity as inferred by proteome or transcriptome data. A substantial fraction of cancers shows high MYC pathway activity without MYC copy gain but with mutations in genes with noncanonical roles in MYC. Our proteogenomics survey reveals the interplay between genome and proteome across tumor lineages.
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Neoplasias , Proteogenômica , Variações do Número de Cópias de DNA , Humanos , Neoplasias/genética , Proteoma/genética , ProteômicaRESUMO
BACKGROUND: We aimed to identify molecular changes in recurrent or progressive pediatric brain tumors, as compared to the corresponding initial tumors from the same patients, using genomic, transcriptomic, and proteomic data from a unique and large cohort of 55 patients and 63 recurrent or progressive tumors from the Children's Brain Tumor Tissue Consortium, representing various histologic types. METHODS: We carried out paired analyses for each gene between recurrent/progressive and initial tumor groups, using RNA-sequencing and mass spectrometry-based proteomic data. By whole-genome sequencing (WGS) analysis, we also examined somatic DNA events for a set of cancer-associated genes. RESULTS: Of 44 patients examined by WGS, 35 involved at least one cancer-associated gene with a somatic alteration event in a recurrent or progressive tumor that was not present in the initial tumor, including genes NF1, CDKN2A, CCND2, EGFR, and MYCN. By paired analysis, 68 mRNA transcripts were differentially expressed in recurrent/progressive tumors with p<0.001, and these genes could predict patient outcomes in an independent set of pediatric brain tumors. Gene transcript-level associations with recurrence or progression were enriched for protein-level associations. There was a significant overlap in results from pediatric brain tumors and results from adult brain tumors from The Cancer Genome Atlas. Unsupervised analysis defined five subsets of recurrent or progressive tumors, with differences in gene expression and overall patient survival. CONCLUSIONS: Our study uncovers genes showing consistent expression differences in recurrent or progressive tumors. These genes may provide molecular clues as to processes or pathways underlying more aggressive pediatric brain tumors.
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Biomarcadores Tumorais , Neoplasias Encefálicas/etiologia , Neoplasias Encefálicas/patologia , Suscetibilidade a Doenças , Neoplasias Encefálicas/mortalidade , Criança , Biologia Computacional/métodos , Bases de Dados Genéticas , Progressão da Doença , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Humanos , Mutação , Recidiva , Transcriptoma , Sequenciamento do ExomaRESUMO
The global impact of somatic structural variants (SVs) on gene regulation in advanced tumors with complex treatment histories has been mostly uncharacterized. Here, using whole-genome and RNA sequencing from 570 recurrent or metastatic tumors, we report the altered expression of hundreds of genes in association with nearby SV breakpoints, including oncogenes and G-protein-coupled receptor-related genes such as PLEKHG2. A significant fraction of genes with SV-expression associations correlate with worse patient survival in primary and advanced cancers, including SRD5A1. In many instances, SV-expression associations involve retrotransposons being translocated near genes. High overall SV burden is associated with treatment with DNA alkylating agents or taxanes and altered expression of metabolism-associated genes. SV-expression associations within tumors from topoisomerase I inhibitor-treated patients include chromatin-related genes. Within anthracycline-treated tumors, SV breakpoints near chromosome 1p genes include PDE4B. Patient treatment and history can help understand the widespread SV-mediated cis-regulatory alterations found in cancer.
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Regulação Neoplásica da Expressão Gênica/genética , Variação Estrutural do Genoma/genética , Recidiva Local de Neoplasia/genética , Aberrações Cromossômicas , Variações do Número de Cópias de DNA/genética , Bases de Dados Genéticas , Rearranjo Gênico/genética , Genoma Humano , Genômica , Humanos , Oncogenes , Análise de Sequência de RNA/métodos , Translocação Genética/genética , Sequenciamento do Exoma/métodos , Sequenciamento Completo do Genoma/métodosRESUMO
During early pregnancy in the mouse, nidatory estrogen (E2) stimulates endometrial receptivity by activating a network of signaling pathways that is not yet fully characterized. Here, we report that bone morphogenetic proteins (BMPs) control endometrial receptivity via a conserved activin receptor type 2 A (ACVR2A) and SMAD1/5 signaling pathway. Mice were generated to contain single or double conditional deletion of SMAD1/5 and ACVR2A/ACVR2B receptors using progesterone receptor (PR)-cre. Female mice with SMAD1/5 deletion display endometrial defects that result in the development of cystic endometrial glands, a hyperproliferative endometrial epithelium during the window of implantation, and impaired apicobasal transformation that prevents embryo implantation and leads to infertility. Analysis of Acvr2a-PRcre and Acvr2b-PRcre pregnant mice determined that BMP signaling occurs via ACVR2A and that ACVR2B is dispensable during embryo implantation. Therefore, BMPs signal through a conserved endometrial ACVR2A/SMAD1/5 pathway that promotes endometrial receptivity during embryo implantation.
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Proteínas Morfogenéticas Ósseas/metabolismo , Implantação do Embrião , Infertilidade Feminina/genética , Receptores de Activinas Tipo II/genética , Receptores de Activinas Tipo II/metabolismo , Animais , Biópsia , Modelos Animais de Doenças , Endométrio/metabolismo , Endométrio/patologia , Estrogênios/metabolismo , Feminino , Humanos , Camundongos , Camundongos Knockout , Gravidez , Transdução de Sinais/fisiologia , Proteína Smad1/análise , Proteína Smad1/genética , Proteína Smad1/metabolismo , Proteína Smad5/análise , Proteína Smad5/genética , Proteína Smad5/metabolismoRESUMO
BACKGROUND: Combined whole-genome sequencing (WGS) and RNA sequencing of cancers offer the opportunity to identify genes with altered expression due to genomic rearrangements. Somatic structural variants (SVs), as identified by WGS, can involve altered gene cis-regulation, gene fusions, copy number alterations, or gene disruption. The absence of computational tools to streamline integrative analysis steps may represent a barrier in identifying genes recurrently altered by genomic rearrangement. RESULTS: Here, we introduce SVExpress, a set of tools for carrying out integrative analysis of SV and gene expression data. SVExpress enables systematic cataloging of genes that consistently show increased or decreased expression in conjunction with the presence of nearby SV breakpoints. SVExpress can evaluate breakpoints in proximity to genes for potential enhancer translocation events or disruption of topologically associated domains, two mechanisms by which SVs may deregulate genes. The output from any commonly used SV calling algorithm may be easily adapted for use with SVExpress. SVExpress can readily analyze genomic datasets involving hundreds of cancer sample profiles. Here, we used SVExpress to analyze SV and expression data across 327 cancer cell lines with combined SV and expression data in the Cancer Cell Line Encyclopedia (CCLE). In the CCLE dataset, hundreds of genes showed altered gene expression in relation to nearby SV breakpoints. Altered genes involved TAD disruption, enhancer hijacking, and gene fusions. When comparing the top set of SV-altered genes from cancer cell lines with the top SV-altered genes previously reported for human tumors from The Cancer Genome Atlas and the Pan-Cancer Analysis of Whole Genomes datasets, a significant number of genes overlapped in the same direction for both cell lines and tumors, while some genes were significant for cell lines but not for human tumors and vice versa. CONCLUSION: Our SVExpress tools allow computational biologists with a working knowledge of R to integrate gene expression with SV breakpoint data to identify recurrently altered genes. SVExpress is freely available for academic or commercial use at https://github.com/chadcreighton/SVExpress . SVExpress is implemented as a set of Excel macros and R code. All source code (R and Visual Basic for Applications) is available.
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Variações do Número de Cópias de DNA , Variação Estrutural do Genoma , Sequenciamento Completo do Genoma , Genoma , Genoma Humano , Genômica , HumanosRESUMO
Whole-genome sequencing combined with transcriptomics can reveal impactful non-coding single nucleotide variants (SNVs) in cancer. Here, we developed an integrative analytical approach that, as a first step, identifies genes altered in expression or DNA methylation in association with nearby somatic SNVs, in contrast to alternative approaches that first identify mutational hotspots. Using genomic datasets from the Pan-Cancer Analysis of Whole Genomes (PCAWG) consortium and the Children's Brain Tumor Tissue Consortium (CBTTC), we identified hundreds of genes and associated CpG islands for which the nearby presence of a non-coding somatic SNV recurrently associated with altered expression or DNA methylation, respectively. Genomic regions upstream or downstream of genes, gene introns and gene untranslated regions were all involved. The PCAWG adult cancer cohort yielded different significant SNV-expression associations from the CBTTC pediatric brain tumor cohort. The SNV-expression associations involved a wide range of cancer types and histologies, as well as potential gain or loss of transcription factor binding sites. Notable genes with SNV-associated increased expression include TERT, COPS3, POLE2 and HDAC2-involving multiple cancer types-MYC, BCL2, PIM1 and IGLL5-involving lymphomas-and CYHR1-involving pediatric low-grade gliomas. Non-coding somatic SNVs show a major role in shaping the cancer transcriptome, not limited to mutational hotspots.
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The global impact of somatic structural variants (SSVs) on gene expression in pediatric brain tumors has not been thoroughly characterised. Here, using whole-genome and RNA sequencing from 854 tumors of more than 30 different types from the Children's Brain Tumor Tissue Consortium, we report the altered expression of hundreds of genes in association with the presence of nearby SSV breakpoints. SSV-mediated expression changes involve gene fusions, altered cis-regulation, or gene disruption. SSVs considerably extend the numbers of patients with tumors somatically altered for critical pathways, including receptor tyrosine kinases (KRAS, MET, EGFR, NF1), Rb pathway (CDK4), TERT, MYC family (MYC, MYCN, MYB), and HIPPO (NF2). Compared to initial tumors, progressive or recurrent tumors involve a distinct set of SSV-gene associations. High overall SSV burden associates with TP53 mutations, histone H3.3 gene H3F3C mutations, and the transcription of DNA damage response genes. Compared to adult cancers, pediatric brain tumors would involve a different set of genes with SSV-altered cis-regulation. Our comprehensive and pan-histology genomic analyses reveal SSVs to play a major role in shaping the transcriptome of pediatric brain tumors.