RESUMO
Myxofibrosarcoma (MFS) is a common adult soft tissue sarcoma characterized by an infiltrative growth pattern and a high local recurrence rate. Here we report the genetic and epigenetic landscape of MFS based on the results of whole-exome sequencing (N = 41), RNA sequencing (N = 29), and methylation analysis (N = 41), using 41 MFSs as a discovery set, and subsequent targeted sequencing of 140 genes in the entire cohort of 99 MFSs and 17 MFSs' data from TCGA. Fourteen driver genes are identified, including potentially actionable therapeutic targets seen in 37% of cases. There are frequent alterations in p53 signaling (51%) and cell cycle checkpoint genes (43%). Other conceivably actionable driver genes including ATRX, JAK1, NF1, NTRK1, and novel oncogenic BRAF fusion gene are identified. Methylation patterns cluster into three subtypes associated with unique combinations of driver mutations, clinical outcomes, and immune cell compositions. Our results provide a valuable genomic resource to enable the design of precision medicine for MFS.
Assuntos
Epigênese Genética , Fibroma/genética , Fibrossarcoma/genética , Regulação Neoplásica da Expressão Gênica , Genes cdc , Proteínas de Fusão Oncogênica/genética , Animais , Estudos de Coortes , Fibroma/metabolismo , Fibroma/mortalidade , Fibroma/patologia , Fibrossarcoma/metabolismo , Fibrossarcoma/mortalidade , Fibrossarcoma/patologia , Xenoenxertos , Humanos , Janus Quinase 1/genética , Janus Quinase 1/metabolismo , Camundongos , Camundongos Nus , Proteínas de Transporte de Monossacarídeos/genética , Proteínas de Transporte de Monossacarídeos/metabolismo , Mutação , Neurofibromina 1/genética , Neurofibromina 1/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Receptor trkA/genética , Receptor trkA/metabolismo , Análise de Sobrevida , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Sequenciamento do Exoma , Proteína Nuclear Ligada ao X/genética , Proteína Nuclear Ligada ao X/metabolismoRESUMO
The accumulations of different types of genetic alterations such as nucleotide substitutions, structural rearrangements and viral genome integrations and epigenetic alterations contribute to carcinogenesis. Here, we report correlation between the occurrence of epigenetic features and genetic aberrations by whole-genome bisulfite, whole-genome shotgun, long-read, and virus capture sequencing of 373 liver cancers. Somatic substitutions and rearrangement breakpoints are enriched in tumor-specific hypo-methylated regions with inactive chromatin marks and actively transcribed highly methylated regions in the cancer genome. Individual mutation signatures depend on chromatin status, especially, signatures with a higher transcriptional strand bias occur within active chromatic areas. Hepatitis B virus (HBV) integration sites are frequently detected within inactive chromatin regions in cancer cells, as a consequence of negative selection for integrations in active chromatin regions. Ultra-high structural instability and preserved unmethylation of integrated HBV genomes are observed. We conclude that both precancerous and somatic epigenetic features contribute to the cancer genome architecture.
Assuntos
Genoma Humano , Neoplasias Hepáticas/genética , Adulto , Idoso , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/virologia , Cromatina/genética , Cromatina/metabolismo , Metilação de DNA , Epigenômica , Feminino , Genoma Viral , Vírus da Hepatite B/genética , Vírus da Hepatite B/fisiologia , Humanos , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Mutação , Integração ViralRESUMO
AIMS: Approximately 60-70% of high-grade round-cell sarcomas that lack the Ewing sarcoma breakpoint region 1 (EWSR1) rearrangement harbour a rearrangement of the CIC gene, most commonly CIC-DUX4. Recent studies have established that CIC-rearranged sarcomas constitute a distinct group characterized by recognizable histology and immunoprofiles, such as positivity for ETV4 and WT1 and negativity for NKX2.2. Although these sarcomas are diagnosed increasingly in practice by fluorescence in-situ hybridization (FISH) with CIC break-apart probes, the optimal modality to diagnose these sarcomas has not been determined. In this study, we describe four round-cell sarcomas that showed false-negative results by CIC break-apart FISH assays. METHODS AND RESULTS: These sarcomas showed characteristic histology of CIC-rearranged sarcomas, and all were immunohistochemically positive for ETV4 and WT1 and negative for NKX2.2. Although FISH showed non-atypical negative signals for CIC rearrangement, high-throughput RNA sequencing identified CIC-DUX4 and its fusion breakpoint in all cases. Their clinical and histological findings, as well as fusion points determined by RNA sequencing, did not differ significantly from those of nine FISH-positive CIC-DUX4 sarcoma cases. We estimated that the FISH false-negative rate for CIC-rearranged sarcomas was 14%. Although neither histology nor immunoprofiles (e.g. ETV4 and WT1) are entirely sensitive or specific for CIC-rearranged sarcomas, the observation that these four cases were identified successfully by such phenotypes suggested their practical utility. CONCLUSIONS: CIC break-apart FISH assays missed a significant minority of CIC-DUX4 sarcomas, and full awareness of typical morphology and judicious immunohistochemical work-ups, including analyses of ETV4 and WT1, should complement diagnostic assessment.
Assuntos
Hibridização in Situ Fluorescente , Proteínas de Fusão Oncogênica/análise , Sarcoma de Células Pequenas/genética , Neoplasias de Tecidos Moles/genética , Adulto , Reações Falso-Negativas , Feminino , Rearranjo Gênico , Proteína Homeobox Nkx-2.2 , Proteínas de Homeodomínio , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares , Fatores de Transcrição , Adulto JovemRESUMO
CIC-rearranged sarcoma is a new entity of undifferentiated small round cell sarcoma characterized by chimeric fusions with CIC rearrangement. We report a NUTM2A-CIC fusion sarcoma in a 43-year-old woman who died of rapidly progressive disease. Histologic analysis revealed multinodular proliferation of small round tumor cells with mild nuclear pleomorphism. The sclerotic fibrous septa separated the tumor into multiple nodules. Immunohistochemistry showed that the tumor cells were diffusely positive for vimentin, focally positive for cytokeratin, and negative for CD99 and NKX2.2. Tumor cells were also negative for ETV4, which was recently identified as a specific marker for CIC-rearranged sarcoma. High-throughput RNA sequencing of a formalin-fixed, paraffin-embedded clinical sample unveiled a novel NUTM2A-CIC fusion between NUTM2A exon 7 and CIC exon 12, and fluorescence in situ hybridization identified CIC and NUTM2A split signals. This case shared several clinicopathological findings with previously reported CIC-rearranged cases. We recognized the tumor as a genetically distinct variant of CIC-rearranged sarcomas with a novel NUTM2A-CIC fusion.
Assuntos
Biomarcadores Tumorais/genética , Fusão Gênica , Rearranjo Gênico , Proteínas de Fusão Oncogênica/genética , Proteínas Repressoras/genética , Sarcoma/genética , Adulto , Biomarcadores Tumorais/análise , Proliferação de Células , Progressão da Doença , Éxons , Evolução Fatal , Feminino , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Proteína Homeobox Nkx-2.2 , Proteínas de Homeodomínio , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Proteínas Nucleares , Fenótipo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sarcoma/química , Sarcoma/patologia , Fatores de Transcrição , Carga TumoralRESUMO
Recent advances in DNA microarray technology have enabled the identification of small alterations throughout the genome. We used standard karyotype analysis, followed by DNA microarray analysis and PCR to precisely map the chromosomal 4p deletion and determine the deletion breakpoints in the genome of an epileptic patient. The karyotype of the patient was 46,XY,del(4)(p15.2p15.3) as determined by G-banding analysis. We used a high-density oligonucleotide genotyping array to estimate the size of the deletion (4.5 Mb) and to locate the breakpoints within a 9-kb region on one side of the deletion and a 100-kb region on the other side. We amplified by PCR and sequenced the genomic region encompassing the breakpoints, and mapped the deletion to regions extending from 21648457 to 26164287 and from 26164505 to 26167493, respectively (chromosome 4 of NCBI Homo sapiens Genome Build 35.1). The deletion involves 18 genes, one of which (CCKAR) is partially deleted.