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2.
Neuro Oncol ; 2019 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-31102405

RESUMO

BACKGROUND: Primary central nervous system lymphoma (PCNSL) is a rare form of extra-nodal non-Hodgkin lymphoma. PCNSL is a distinct subtype of non-Hodgkin lymphoma, with over 95% of tumors belonging to the diffuse large B-cell lymphoma (DLBCL) group. We have conducted a genome-wide association study (GWAS) on immunocompetent patients to address the possibility that common genetic variants influence the risk of developing PCNSL. METHODS: We performed a meta-analysis of two new genome-wide association studies of PCNSL totaling 475 cases and 1,134 controls of European ancestry. To increase genomic resolution, we imputed >10 million single-nucleotide polymorphisms (SNPs) using the 1000 Genomes Project combined with UK10K as reference. In addition we performed a transcription factor binding disruption analysis and investigated the patterns of local chromatin patterns by capture Hi-C data. RESULTS: We identified independent risk loci at 3p22.1 (rs41289586, ANO10, P = 2.17 x 10-8) and 6p25.3 near EXOC2 (rs116446171, P = 1.95 x 10-13). In contrast the lack of an association between rs41289586 and DLBCL, suggests distinct germline predisposition to PCNSL and DLBCL. We found looping chromatin interactions between non-coding regions at 6p25.3 (rs11646171) with the IRF4 promoter and at 8q24.21 (rs13254990) with the MYC promoter, both genes with strong relevance to B-cell tumorigenesis. CONCLUSION: To our knowledge this is the first study providing insight into the genetic predisposition to PCNSL. Our findings represent an important step in defining the contribution of common genetic variation to the risk of developing PCNSL.

3.
Cancer Res ; 79(8): 2065-2071, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30709929

RESUMO

Genome-wide association studies (GWAS) have so far identified 25 loci associated with glioma risk, with most showing specificity for either glioblastoma (GBM) or non-GBM tumors. The majority of these GWAS susceptibility variants reside in noncoding regions and the causal genes underlying the associations are largely unknown. Here we performed a transcriptome-wide association study to search for novel risk loci and candidate causal genes at known GWAS loci using Genotype-Tissue Expression Project (GTEx) data to predict cis-predicted gene expression in relation to GBM and non-GBM risk in conjunction with GWAS summary statistics on 12,488 glioma cases (6,183 GBM and 5,820 non-GBM) and 18,169 controls. Imposing a Bonferroni-corrected significance level of P < 5.69 × 10-6, we identified 31 genes, including GALNT6 at 12q13.33, as a candidate novel risk locus for GBM (mean Z = 4.43; P = 5.68 × 10-6). GALNT6 resides at least 55 Mb away from any previously identified glioma risk variant, while all other 30 significantly associated genes were located within 1 Mb of known GWAS-identified loci and were not significant after conditioning on the known GWAS-identified variants. These data identify a novel locus (GALNT6 at 12q13.33) and 30 genes at 12 known glioma risk loci associated with glioma risk, providing further insights into glioma tumorigenesis. SIGNIFICANCE: This study identifies new genes associated with glioma risk, increasing understanding of how these tumors develop.

4.
Br J Cancer ; 118(7): 1020-1027, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29531326

RESUMO

BACKGROUND: Obesity and related factors have been implicated as possible aetiological factors for the development of glioma in epidemiological observation studies. We used genetic markers in a Mendelian randomisation framework to examine whether obesity-related traits influence glioma risk. This methodology reduces bias from confounding and is not affected by reverse causation. METHODS: Genetic instruments were identified for 10 key obesity-related risk factors, and their association with glioma risk was evaluated using data from a genome-wide association study of 12,488 glioma patients and 18,169 controls. The estimated odds ratio of glioma associated with each of the genetically defined obesity-related traits was used to infer evidence for a causal relationship. RESULTS: No convincing association with glioma risk was seen for genetic instruments for body mass index, waist-to-hip ratio, lipids, type-2 diabetes, hyperglycaemia or insulin resistance. Similarly, we found no evidence to support a relationship between obesity-related traits with subtypes of glioma-glioblastoma (GBM) or non-GBM tumours. CONCLUSIONS: This study provides no evidence to implicate obesity-related factors as causes of glioma.

5.
BMC Med ; 16(1): 42, 2018 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-29540232

RESUMO

BACKGROUND: An inverse relationship between allergies with glioma risk has been reported in several but not all epidemiological observational studies. We performed an analysis of genetic variants associated with atopy to assess the relationship with glioma risk using Mendelian randomisation (MR), an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations. METHODS: Two-sample MR was undertaken using genome-wide association study data. We used single nucleotide polymorphisms (SNPs) associated with atopic dermatitis, asthma and hay fever, IgE levels, and self-reported allergy as instrumental variables. We calculated MR estimates for the odds ratio (OR) for each risk factor with glioma using SNP-glioma estimates from 12,488 cases and 18,169 controls, using inverse-variance weighting (IVW), maximum likelihood estimation (MLE), weighted median estimate (WME) and mode-based estimate (MBE) methods. Violation of MR assumptions due to directional pleiotropy were sought using MR-Egger regression and HEIDI-outlier analysis. RESULTS: Under IVW, MLE, WME and MBE methods, associations between glioma risk with asthma and hay fever, self-reported allergy and IgE levels were non-significant. An inverse relationship between atopic dermatitis and glioma risk was found by IVW (OR 0.96, 95% confidence interval (CI) 0.93-1.00, P = 0.041) and MLE (OR 0.96, 95% CI 0.94-0.99, P = 0.003), but not by WME (OR 0.96, 95% CI 0.91-1.01, P = 0.114) or MBE (OR 0.97, 95% CI 0.92-1.02, P = 0.194). CONCLUSIONS: Our investigation does not provide strong evidence for relationship between atopy and the risk of developing glioma, but findings do not preclude a small effect in relation to atopic dermatitis. Our analysis also serves to illustrate the value of using several MR methods to derive robust conclusions.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Glioma/etiologia , Análise da Randomização Mendeliana/métodos , Genótipo , Glioma/patologia , Humanos , Fatores de Risco
6.
Neuro Oncol ; 20(8): 1092-1100, 2018 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-29432597

RESUMO

Background: Primary central nervous system lymphoma (PCNSL) represents a particular entity within non-Hodgkin lymphomas and is associated with poor outcome. The present study addresses the potential clinical relevance of chimeric transcripts in PCNSL discovered by using RNA sequencing (RNA-seq). Methods: Seventy-two immunocompetent and newly diagnosed PCNSL cases were included in the present study. Among them, 6 were analyzed by RNA-seq to detect new potential fusion transcripts. We confirmed the results in the remaining 66 PCNSL. The gene fusion was validated by fluorescence in situ hybridization (FISH) using formalin-fixed paraffin-embedded (FFPE) samples. We assessed the biological and clinical impact of one new gene fusion. Results: We identified a novel recurrent gene fusion, E26 transformation-specific translocation variant 6-immunoglobulin heavy chain (ETV6-IgH). Overall, ETV6-IgH was found in 13 out of 72 PCNSL (18%). No fusion conserved an intact functional domain of ETV6, and ETV6 was significantly underexpressed at gene level, suggesting an ETV6 haploinsufficiency mechanism. The presence of the gene fusion was also validated by FISH in FFPE samples. Finally, PCNSL samples harboring ETV6-IgH showed a better prognosis in multivariate analysis, P = 0.03, hazard ratio = 0.33, 95% CI = 0.12-0.88. The overall survival at 5 years was 69% for PCNSL harboring ETV6-IgH versus 29% for samples without this gene fusion. Conclusions: ETV6-IgH is a new potential surrogate marker of PCNSL with favorable prognosis with ETV6 haploinsufficiency as a possible mechanism. The potential clinical impact of ETV6-IgH should be validated in larger prospective studies.

7.
Sci Rep ; 8(1): 2339, 2018 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-29402980

RESUMO

To examine for a causal relationship between vitamin D and glioma risk we performed an analysis of genetic variants associated with serum 25-hydroxyvitamin D (25(OH)D) levels using Mendelian randomisation (MR), an approach unaffected by biases from confounding. Two-sample MR was undertaken using genome-wide association study data. Single nucleotide polymorphisms (SNPs) associated with 25(OH)D levels were used as instrumental variables (IVs). We calculated MR estimates for the odds ratio (OR) for 25(OH)D levels with glioma using SNP-glioma estimates from 12,488 cases and 18,169 controls, using inverse-variance weighted (IVW) and maximum likelihood estimation (MLE) methods. A non-significant association between 25(OH)D levels and glioma risk was shown using both the IVW (OR = 1.21, 95% confidence interval [CI] = 0.90-1.62, P = 0.201) and MLE (OR = 1.20, 95% CI = 0.98-1.48, P = 0.083) methods. In an exploratory analysis of tumour subtype, an inverse relationship between 25(OH)D levels and glioblastoma (GBM) risk was identified using the MLE method (OR = 0.62, 95% CI = 0.43-0.89, P = 0.010), but not the IVW method (OR = 0.62, 95% CI = 0.37-1.04, P = 0.070). No statistically significant association was shown between 25(OH)D levels and non-GBM glioma. Our results do not provide evidence for a causal relationship between 25(OH)D levels and all forms of glioma risk. More evidence is required to explore the relationship between 25(OH)D levels and risk of GBM.

8.
Acta Neuropathol ; 135(5): 743-755, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29460007

RESUMO

Recent genome-wide association studies of glioma have led to the discovery of single nucleotide polymorphisms (SNPs) at 25 loci influencing risk. Gliomas are heterogeneous, hence to investigate the relationship between risk SNPs and glioma subtype we analysed 1659 tumours profiled for IDH mutation, TERT promoter mutation and 1p/19q co-deletion. These data allowed definition of five molecular subgroups of glioma: triple-positive (IDH mutated, 1p/19q co-deletion, TERT promoter mutated); TERT-IDH (IDH mutated, TERT promoter mutated, 1p/19q-wild-type); IDH-only (IDH mutated, 1p/19q wild-type, TERT promoter wild-type); triple-negative (IDH wild-type, 1p/19q wild-type, TERT promoter wild-type) and TERT-only (TERT promoter mutated, IDH wild-type, 1p/19q wild-type). Most glioma risk loci showed subtype specificity: (1) the 8q24.21 SNP for triple-positive glioma; (2) 5p15.33, 9p21.3, 17p13.1 and 20q13.33 SNPs for TERT-only glioma; (3) 1q44, 2q33.3, 3p14.1, 11q21, 11q23.3, 14q12, and 15q24.2 SNPs for IDH mutated glioma. To link risk SNPs to target candidate genes we analysed Hi-C and gene expression data, highlighting the potential role of IDH1 at 2q33.3, MYC at 8q24.21 and STMN3 at 20q13.33. Our observations provide further insight into the nature of susceptibility to glioma.

9.
Acta Neuropathol ; 134(5): 691-703, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28638988

RESUMO

Molecular classification of cancer has entered clinical routine to inform diagnosis, prognosis, and treatment decisions. At the same time, new tumor entities have been identified that cannot be defined histologically. For central nervous system tumors, the current World Health Organization classification explicitly demands molecular testing, e.g., for 1p/19q-codeletion or IDH mutations, to make an integrated histomolecular diagnosis. However, a plethora of sophisticated technologies is currently needed to assess different genomic and epigenomic alterations and turnaround times are in the range of weeks, which makes standardized and widespread implementation difficult and hinders timely decision making. Here, we explored the potential of a pocket-size nanopore sequencing device for multimodal and rapid molecular diagnostics of cancer. Low-pass whole genome sequencing was used to simultaneously generate copy number (CN) and methylation profiles from native tumor DNA in the same sequencing run. Single nucleotide variants in IDH1, IDH2, TP53, H3F3A, and the TERT promoter region were identified using deep amplicon sequencing. Nanopore sequencing yielded ~0.1X genome coverage within 6 h and resulting CN and epigenetic profiles correlated well with matched microarray data. Diagnostically relevant alterations, such as 1p/19q codeletion, and focal amplifications could be recapitulated. Using ad hoc random forests, we could perform supervised pan-cancer classification to distinguish gliomas, medulloblastomas, and brain metastases of different primary sites. Single nucleotide variants in IDH1, IDH2, and H3F3A were identified using deep amplicon sequencing within minutes of sequencing. Detection of TP53 and TERT promoter mutations shows that sequencing of entire genes and GC-rich regions is feasible. Nanopore sequencing allows same-day detection of structural variants, point mutations, and methylation profiling using a single device with negligible capital cost. It outperforms hybridization-based and current sequencing technologies with respect to time to diagnosis and required laboratory equipment and expertise, aiming to make precision medicine possible for every cancer patient, even in resource-restricted settings.


Assuntos
Neoplasias Encefálicas/diagnóstico , Epigenômica/métodos , Genômica/métodos , Glioma/diagnóstico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Variações do Número de Cópias de DNA , Metilação de DNA , Glioma/genética , Glioma/patologia , Humanos , Nanoporos , Regiões Promotoras Genéticas
10.
Nat Genet ; 49(5): 789-794, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28346443

RESUMO

Genome-wide association studies (GWAS) have transformed our understanding of glioma susceptibility, but individual studies have had limited power to identify risk loci. We performed a meta-analysis of existing GWAS and two new GWAS, which totaled 12,496 cases and 18,190 controls. We identified five new loci for glioblastoma (GBM) at 1p31.3 (rs12752552; P = 2.04 × 10-9, odds ratio (OR) = 1.22), 11q14.1 (rs11233250; P = 9.95 × 10-10, OR = 1.24), 16p13.3 (rs2562152; P = 1.93 × 10-8, OR = 1.21), 16q12.1 (rs10852606; P = 1.29 × 10-11, OR = 1.18) and 22q13.1 (rs2235573; P = 1.76 × 10-10, OR = 1.15), as well as eight loci for non-GBM tumors at 1q32.1 (rs4252707; P = 3.34 × 10-9, OR = 1.19), 1q44 (rs12076373; P = 2.63 × 10-10, OR = 1.23), 2q33.3 (rs7572263; P = 2.18 × 10-10, OR = 1.20), 3p14.1 (rs11706832; P = 7.66 × 10-9, OR = 1.15), 10q24.33 (rs11598018; P = 3.39 × 10-8, OR = 1.14), 11q21 (rs7107785; P = 3.87 × 10-10, OR = 1.16), 14q12 (rs10131032; P = 5.07 × 10-11, OR = 1.33) and 16p13.3 (rs3751667; P = 2.61 × 10-9, OR = 1.18). These data substantiate that genetic susceptibility to GBM and non-GBM tumors are highly distinct, which likely reflects different etiology.


Assuntos
Neoplasias Encefálicas/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Glioblastoma/genética , Glioma/genética , Alelos , Neoplasias Encefálicas/classificação , Regulação Neoplásica da Expressão Gênica , Genótipo , Glioblastoma/classificação , Glioma/classificação , Humanos , Metanálise como Assunto , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/genética
11.
Oncologist ; 21(9): 1131-5, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27401888

RESUMO

BACKGROUND: The 1p19q non-codeleted gliomas with IDH mutation, defined as "molecular astrocytomas," display frequent TP53 mutations and have an intermediate prognosis. We investigated the prognostic impact of copy number-neutral loss of heterozygosity (CNLOH) in 17p in this population. METHODS: We analyzed 793 gliomas (206 grade II, 377 grade III, and 210 grade IV) by single nucleotide polymorphism array and for TP53 mutations. RESULTS: Homodisomy revealed by CNLOH was observed in 156 cases (19.7%). It was more frequent in astrocytomas and oligoastrocytomas (98/256, 38%) than oligodendrogliomas (28/327, 8.6%; p < .0001) or glioblastoma multiforme (30/210, 14.3%; p < .0001), tightly associated with TP53 mutation (69/71 vs. 20/79; p = 2 × 10(-16)), and mutually exclusive with 1p19q codeletion (1/156 vs. 249/556; p < .0001). In the group of IDH-mutated 1p19q non-codeleted gliomas, CNLOH 17p was associated with longer survival (86.3 vs. 46.2 months; p = .004), particularly in grade III gliomas (overall survival >100 vs. 37.9 months; p = .007). These data were confirmed in an independent dataset from the Cancer Genome Atlas. CONCLUSION: CNLOH 17p is a prognostic marker and further refines the molecular classification of gliomas. IMPLICATIONS FOR PRACTICE: Homodisomy of chromosome 17p (CNLOH 17p) is a frequent feature in IDH-mutated 1p19q non-codeleted gliomas (group 2). It is constantly associated with TP53 mutation. It was found, within this specific molecular group of gliomas (corresponding to molecular astrocytomas), that CNLOH 17p is associated with a much better outcome and may therefore represent an additional prognostic marker to refine the prognostic classification of gliomas.


Assuntos
Glioma/genética , Isocitrato Desidrogenase/genética , Perda de Heterozigosidade/genética , Proteína Supressora de Tumor p53/genética , Adulto , Idoso , Biomarcadores Tumorais/genética , Cromossomos Humanos Par 17/genética , Intervalo Livre de Doença , Feminino , Glioma/epidemiologia , Glioma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico
12.
Nat Commun ; 6: 7207, 2015 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-26068201

RESUMO

Anaplastic oligodendroglioma (AO) are rare primary brain tumours that are generally incurable, with heterogeneous prognosis and few treatment targets identified. Most oligodendrogliomas have chromosomes 1p/19q co-deletion and an IDH mutation. Here we analysed 51 AO by whole-exome sequencing, identifying previously reported frequent somatic mutations in CIC and FUBP1. We also identified recurrent mutations in TCF12 and in an additional series of 83 AO. Overall, 7.5% of AO are mutated for TCF12, which encodes an oligodendrocyte-related transcription factor. Eighty percent of TCF12 mutations identified were in either the bHLH domain, which is important for TCF12 function as a transcription factor, or were frameshift mutations leading to TCF12 truncated for this domain. We show that these mutations compromise TCF12 transcriptional activity and are associated with a more aggressive tumour type. Our analysis provides further insights into the unique and shared pathways driving AO.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Neoplasias Encefálicas/genética , Mutação , Oligodendroglioma/genética , Regulação para Baixo , Humanos , Ativação Transcricional/genética
13.
Nat Commun ; 6: 5973, 2015 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-25609015

RESUMO

Testicular germ cell tumours (TGCTs) are the most common cancer in young men. Here we perform whole-exome sequencing (WES) of 42 TGCTs to comprehensively study the cancer's mutational profile. The mutation rate is uniformly low in all of the tumours (mean 0.5 mutations per Mb) as compared with common cancers, consistent with the embryological origin of TGCT. In addition to expected copy number gain of chromosome 12p and mutation of KIT, we identify recurrent mutations in the tumour suppressor gene CDC27 (11.9%). Copy number analysis reveals recurring amplification of the spermatocyte development gene FSIP2 (15.3%) and a 0.4 Mb region at Xq28 (15.3%). Two treatment-refractory patients are shown to harbour XRCC2 mutations, a gene strongly implicated in defining cisplatin resistance. Our findings provide further insights into genes involved in the development and progression of TGCT.


Assuntos
Análise Mutacional de DNA/métodos , Exoma , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Testiculares/genética , Adulto , Aberrações Cromossômicas , Cromossomos Humanos Par 12 , Cisplatino/química , Estudos de Coortes , Proteínas de Ligação a DNA/metabolismo , Progressão da Doença , Dosagem de Genes , Genes Supressores de Tumor , Humanos , Interleucinas/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasias Embrionárias de Células Germinativas/cirurgia , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas c-kit/genética , Seminoma/genética , Espermatócitos/citologia , Neoplasias Testiculares/cirurgia
14.
Oncotarget ; 5(13): 5065-75, 2014 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-24970810

RESUMO

Little is known about the genomic basis of primary central nervous system lymphoma (PCNSL) tumorigenesis. To investigate the mutational profile of PCNSL, we analyzed nine paired tumor and germline DNA samples from PCNSL patients by high throughput exome sequencing. Eight genes of interest have been further investigated by focused resequencing in 28 additional PCNSL tumors to better estimate their incidence. Our study identified recurrent somatic mutations in 37 genes, some involved in key signaling pathways such as NFKB, B cell differentiation and cell cycle control. Focused resequencing in the larger cohort revealed high mutation rates for genes already described as mutated in PCNSL such as MYD88 (38%), CD79B (30%), PIM1 (22%) and TBL1XR1 (19%) and for genes not previously reported to be involved in PCNSL tumorigenesis such as ETV6 (16%), IRF4 (14%), IRF2BP2 (11%) and EBF1 (11%). Of note, only 3 somatically acquired SNVs were annotated in the COSMIC database. Our results demonstrate a high genetic heterogeneity of PCNSL and mutational pattern similarities with extracerebral diffuse large B cell lymphomas, particularly of the activated B-cell (ABC) subtype, suggesting shared underlying biological mechanisms. The present study provides new insights into the mutational profile of PCNSL and potential targets for therapeutic strategies.


Assuntos
Neoplasias do Sistema Nervoso Central/genética , Exoma/genética , Predisposição Genética para Doença/genética , Linfoma Difuso de Grandes Células B/genética , Mutação , Linfócitos B/metabolismo , Linfócitos B/patologia , Análise Mutacional de DNA/métodos , Humanos , Mutação INDEL , Polimorfismo de Nucleotídeo Único
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