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Genomic analyses of gynaecologic carcinosarcomas reveal frequent mutations in chromatin remodelling genes.

ABSTRACT: Malignant mixed Müllerian tumours, also known as carcinosarcomas, are rare tumours of gynaecological origin. Here we perform whole-exome analyses of 22 tumours using massively parallel sequencing to determine the mutational landscape of this tumour type. On average, we identify 43 mutations per tumour, excluding four cases with a mutator phenotype that harboured inactivating mutations in mismatch repair genes. In addition to mutations in TP53 and KRAS, we identify genetic alterations in chromatin remodelling genes, ARID1A and ARID1B, in histone methyltransferase MLL3, in histone deacetylase modifier SPOP and in chromatin assembly factor BAZ1A, in nearly two thirds of cases. Alterations in genes with potential clinical utility are observed in more than three quarters of the cases and included members of the PI3-kinase and homologous DNA repair pathways. These findings highlight the importance of the dysregulation of chromatin remodelling in carcinosarcoma tumorigenesis and suggest new avenues for personalized therapy.

SUBMITTER: Jones S

PROVIDER: S-EPMC4354107 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Genomic analyses of gynecologic carcinosarcomas reveal frequent mutations in chromatin remodeling genes

Project description:Malignant Mixed Müllerian Tumors, also known as carcinosarcomas, are rare tumors of gynecological origin. Here we perform whole exome analyses of 22 tumors using massively parallel sequencing to determine the mutational landscape of this tumor type. On average, we identify 43 mutations per tumor, excluding four cases with a mutator phenotype that harbored inactivating mutations in mismatch repair genes. In addition to mutations in TP53 and KRAS, we identify genetic alterations in chromatin remodeling genes, ARID1A and ARID1B, in histone methyltransferase MLL3, in histone deacetylase modifier SPOP, and in chromatin assembly factor BAZ1A, in nearly two thirds of cases. Alterations in genes with potential clinical utility are observed in more than three quarters of the cases and included members of the PI 3-kinase and homologous DNA repair pathways. These findings highlight the importance of the dysregulation of chromatin remodeling in carcinosarcoma tumorigenesis and suggest new avenues for personalized therapy.

| EGAS00001000941 | EGA

Frequent mutations in chromatin-remodelling genes in pulmonary carcinoids.

Project description:Pulmonary carcinoids are rare neuroendocrine tumours of the lung. The molecular alterations underlying the pathogenesis of these tumours have not been systematically studied so far. Here we perform gene copy number analysis (n=54), genome/exome (n=44) and transcriptome (n=69) sequencing of pulmonary carcinoids and observe frequent mutations in chromatin-remodelling genes. Covalent histone modifiers and subunits of the SWI/SNF complex are mutated in 40 and 22.2% of the cases, respectively, with MEN1, PSIP1 and ARID1A being recurrently affected. In contrast to small-cell lung cancer and large-cell neuroendocrine lung tumours, TP53 and RB1 mutations are rare events, suggesting that pulmonary carcinoids are not early progenitor lesions of the highly aggressive lung neuroendocrine tumours but arise through independent cellular mechanisms. These data also suggest that inactivation of chromatin-remodelling genes is sufficient to drive transformation in pulmonary carcinoids.

| S-EPMC4132974 | biostudies-literature

Frequent mutations in chromatin-remodelling genes in pulmonary carcinoids

Project description:Pulmonary carcinoids are rare neuroendocrine tumours of the lung. The molecular alterations underlying the pathogenesis of these tumours have not been systematically studied so far. Here we perform gene copy number analysis (n¼54), genome/exome (n¼44) and transcriptome (n¼69) sequencing of pulmonary carcinoids and observe frequent mutations in chromatin-remodelling genes. Covalent histone modifiers and subunits of the SWI/SNF complex are mutated in 40 and 22.2% of the cases, respectively, with MEN1, PSIP1 and ARID1A being recurrently affected. In contrast to small-cell lung cancer and large-cell neuroendocrine tumours, TP53 and RB1 mutations are rare events, suggesting that pulmonary carcinoids are not early progenitor lesions of the highly aggressive lung neuroendocrine tumors but arise through independent cellular mechanisms. These data also suggest that inactivation of chromatinremodelling genes is sufficient to drive transformation in pulmonary carcinoids.

| EGAS00001000650 | EGA

Integrated genomic analyses reveal frequent <i>TERT</i> aberrations in acral melanoma.

Project description:Genomic analyses of cutaneous melanoma (CM) have yielded biological and therapeutic insights, but understanding of non-ultraviolet (UV)-derived CMs remains limited. Deeper analysis of acral lentiginous melanoma (ALM), a rare sun-shielded melanoma subtype associated with worse survival than CM, is needed to delineate non-UV oncogenic mechanisms. We thus performed comprehensive genomic and transcriptomic analysis of 34 ALM patients. Unlike CM, somatic alterations were dominated by structural variation and absence of UV-derived mutation signatures. Only 38% of patients demonstrated driver BRAF/NRAS/NF1 mutations. In contrast with CM, we observed PAK1 copy gains in 15% of patients, and somatic TERT translocations, copy gains, and missense and promoter mutations, or germline events, in 41% of patients. We further show that in vitro TERT inhibition has cytotoxic effects on primary ALM cells. These findings provide insight into the role of TERT in ALM tumorigenesis and reveal preliminary evidence that TERT inhibition represents a potential therapeutic strategy in ALM.

| S-EPMC5378171 | biostudies-literature

Frequent driver mutations in histone H3.3 and chromatin remodeling genes in paediatric glioblastoma

Project description:Whole exome sequencing identified frequent driver mutations in a series of paediatric glioblastomas We used microarray-based profiling to investigate differences in gene expression according to mutational status of driver genes RNA from 27 primary tumor samples was subject to QC by Agilent BioAnalyser analysis and then hybridised to an Affymetrix U133 Plus2 gene expression array

| S-ECPF-GEOD-34824 | biostudies-other

Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder.

Project description:Transitional cell carcinoma (TCC) is the most common type of bladder cancer. Here we sequenced the exomes of nine individuals with TCC and screened all the somatically mutated genes in a prevalence set of 88 additional individuals with TCC with different tumor stages and grades. In our study, we discovered a variety of genes previously unknown to be mutated in TCC. Notably, we identified genetic aberrations of the chromatin remodeling genes (UTX, MLL-MLL3, CREBBP-EP300, NCOR1, ARID1A and CHD6) in 59% of our 97 subjects with TCC. Of these genes, we showed UTX to be altered substantially more frequently in tumors of low stages and grades, highlighting its potential role in the classification and diagnosis of bladder cancer. Our results provide an overview of the genetic basis of TCC and suggest that aberration of chromatin regulation might be a hallmark of bladder cancer.

| S-EPMC5373841 | biostudies-literature

Genomic Analyses of Metaplastic or Sarcomatoid Carcinomas From Different Organs Revealed Frequent Mutations in KMT2D.

Project description:Background: Metaplastic or sarcomatoid carcinomas (MSCs) are rare epithelial malignancies with heterologous histological differentiation that can occur in different organs. The objective of the current study was to identify novel somatically mutated genes in MSCs from different organs. Methods: Whole-exome sequencing was performed in 16 paired MSCs originating from the breast (n = 10), esophagus (n = 3), lung (n = 2), and kidney (n = 1). In addition, we collected data on KMT2D mutations from eight independent cohorts (n = 195) diagnosed with MSCs derived from the breast (n = 83), liver (n = 8), esophagus (n = 15), lung (n = 10), and uterus or ovary (n = 79). The expression of KMT2D and its clinical significance were evaluated in our cohort. Results: The most frequently mutated genes were TP53 (13/16, 81%) and KMT2D (5/16,31%). We identified seven somatic KMT2D mutations in the exploratory cohort (n = 16 tumors), including three nonsense mutations, two frameshift indels, one missense mutation, and one splice site mutation. Interestingly, two patients showed double hits on KMT2D with nonsense mutations and frameshift indels. In the eight validation cohorts (n = 195), the average mutation rates for TP53 and KMT2D were 78% (152/195) and 13% (25/195), respectively. Two or more hits on KMT2D were also present in three validation cohorts. Furthermore, KMT2D mutations were associated with low expression of KMT2D, large tumor size and unfavorable prognosis. Conclusions: These findings provide clues for understanding the genetic basis of MSCs originating from different organs and implicate KMT2D alteration as a frequent pathogenic mutation, allowing provision of appropriate treatment for this rare malignant disease in the future.

| S-EPMC8319738 | biostudies-literature

Genomic and transcriptomic analyses reveal a tandem amplification unit of 11 genes and mutations in mismatch repair genes in methotrexate-resistant HT-29 cells.

Project description:DHFR gene amplification is commonly present in methotrexate (MTX)-resistant colon cancer cells and acute lymphoblastic leukemia. In this study, we proposed an integrative framework to characterize the amplified region by using a combination of single-molecule real-time sequencing, next-generation optical mapping, and chromosome conformation capture (Hi-C). We identified an amplification unit spanning 11 genes, from the DHFR gene to the ATP6AP1L gene position, with high adjusted interaction frequencies on chromosome 5 (~2.2 Mbp) and a twenty-fold tandemly amplified region, and novel inversions at the start and end positions of the amplified region as well as frameshift insertions in most of the MSH and MLH genes were detected. These mutations might stimulate chromosomal breakage and cause the dysregulation of mismatch repair. Characterizing the tandem gene-amplified unit may be critical for identifying the mechanisms that trigger genomic rearrangements. These findings may provide new insight into the mechanisms underlying the amplification process and the evolution of drug resistance.

| S-EPMC8492700 | biostudies-literature

Frequent alterations in cytoskeleton remodelling genes in primary and metastatic lung adenocarcinomas.

Project description:The landscape of genetic alterations in lung adenocarcinoma derived from Asian patients is largely uncharacterized. Here we present an integrated genomic and transcriptomic analysis of 335 primary lung adenocarcinomas and 35 corresponding lymph node metastases from Chinese patients. Altogether 13 significantly mutated genes are identified, including the most commonly mutated gene TP53 and novel mutation targets such as RHPN2, GLI3 and MRC2. TP53 mutations are furthermore significantly enriched in tumours from patients harbouring metastases. Genes regulating cytoskeleton remodelling processes are also frequently altered, especially in metastatic samples, of which the high expression level of IQGAP3 is identified as a marker for poor prognosis. Our study represents the first large-scale sequencing effort on lung adenocarcinoma in Asian patients and provides a comprehensive mutational landscape for both primary and metastatic tumours. This may thus form a basis for personalized medical care and shed light on the molecular pathogenesis of metastatic lung adenocarcinoma.

| S-EPMC4682110 | biostudies-literature

Structural analyses of the chromatin remodelling enzymes INO80-C and SWR-C.

Project description:INO80-C and SWR-C are conserved members of a subfamily of ATP-dependent chromatin remodelling enzymes that function in transcription and genome-maintenance pathways. A crucial role for these enzymes is to control chromosomal distribution of the H2A.Z histone variant. Here we use electron microscopy (EM) and two-dimensional class averaging to demonstrate that these remodelling enzymes have similar overall architectures. Each enzyme is characterized by a dynamic 'tail' domain and a compact 'head' that contains Rvb1/Rvb2 subunits organized as hexameric rings. EM class averages and mass spectrometry support the existence of single heterohexameric rings in both SWR-C and INO80-C. EM studies define the position of the Arp8/Arp4/Act1 module within INO80-C, and we find that this module enhances nucleosome-binding affinity but is largely dispensable for remodelling activities. In contrast, the Ies6/Arp5 module is essential for INO80-C remodelling, and furthermore this module controls conformational changes that may couple nucleosome binding to remodelling.

| S-EPMC4431590 | biostudies-literature

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