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1.
BMC Cancer ; 19(1): 190, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30823903

RESUMO

BACKGROUND: IDH1/2 mutated glioma has been associated with a germline risk variant, the rs55705857 G allele. The Utah Population Database (UPDB), a computerized genealogy of people in Utah, is a unique resource to evaluate cancer risk in related individuals. METHODS: One hundred and two individuals with IDH1/2 mutant or 1p/19q co-deleted glioma were genotyped and linked to the UPDB. DNA came from blood (21), tumor tissue (43), or both (38). We determined congruence between somatic and germline samples and estimated the relative risk for developing cancer to first and second-degree relatives of G and A allele carriers at rs55705857. RESULTS: Somatic (glioma) DNA had 85.7% sensitivity (CI 57.2-98.2%) and 95.8% specificity (CI 78.9-99.89%) for germline rs55705857 G allele. Forty-one patients were linked to pedigrees in the UPDB with at least three generations of data. First-degree relatives of rs55705857 G allele carriers were at significantly increased risk for developing cancer (RR = 1.72, p = 0.045, CI 1.02-2.94), and specifically for oligodendroglioma (RR = 57.61, p = 0.017, CI 2.96-320.98) or prostate cancer (RR = 4.10, p = 0.008, CI 1.62-9.58); relatives of individuals without the G allele were not at increased risk. Second-degree relatives of G allele carriers also had significantly increased risk for developing cancer (RR = 1.50, p = 0.007, CI 1.15-2.01). CONCLUSIONS: Tumor DNA may approximate genotype at the rs55705857 locus. We confirmed this locus confers an increased risk of all cancers and especially of oligodendroglioma. No increased cancer or brain tumor risk is seen in family members of individuals without the high-risk G allele.


Assuntos
Neoplasias Encefálicas/genética , Cromossomos Humanos Par 8/genética , Neoplasias Colorretais/genética , Mutação em Linhagem Germinativa/genética , Glioma/genética , Neoplasias da Próstata/genética , Neoplasias da Glândula Tireoide/genética , Alelos , Astrocitoma/genética , Bases de Dados Factuais , Família , Feminino , Predisposição Genética para Doença , Homozigoto , Humanos , Armazenamento e Recuperação da Informação , Isocitrato Desidrogenase/genética , Masculino , Mutação , Neoplasias/genética , Oligodendroglioma/genética , Utah
2.
N Engl J Med ; 372(26): 2499-508, 2015 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-26061753

RESUMO

BACKGROUND: The prediction of clinical behavior, response to therapy, and outcome of infiltrative glioma is challenging. On the basis of previous studies of tumor biology, we defined five glioma molecular groups with the use of three alterations: mutations in the TERT promoter, mutations in IDH, and codeletion of chromosome arms 1p and 19q (1p/19q codeletion). We tested the hypothesis that within groups based on these features, tumors would have similar clinical variables, acquired somatic alterations, and germline variants. METHODS: We scored tumors as negative or positive for each of these markers in 1087 gliomas and compared acquired alterations and patient characteristics among the five primary molecular groups. Using 11,590 controls, we assessed associations between these groups and known glioma germline variants. RESULTS: Among 615 grade II or III gliomas, 29% had all three alterations (i.e., were triple-positive), 5% had TERT and IDH mutations, 45% had only IDH mutations, 7% were triple-negative, and 10% had only TERT mutations; 5% had other combinations. Among 472 grade IV gliomas, less than 1% were triple-positive, 2% had TERT and IDH mutations, 7% had only IDH mutations, 17% were triple-negative, and 74% had only TERT mutations. The mean age at diagnosis was lowest (37 years) among patients who had gliomas with only IDH mutations and was highest (59 years) among patients who had gliomas with only TERT mutations. The molecular groups were independently associated with overall survival among patients with grade II or III gliomas but not among patients with grade IV gliomas. The molecular groups were associated with specific germline variants. CONCLUSIONS: Gliomas were classified into five principal groups on the basis of three tumor markers. The groups had different ages at onset, overall survival, and associations with germline variants, which implies that they are characterized by distinct mechanisms of pathogenesis. (Funded by the National Institutes of Health and others.).


Assuntos
Cromossomos Humanos Par 19 , Cromossomos Humanos Par 1 , Glioma/genética , Isocitrato Desidrogenase/genética , Mutação , Telomerase/genética , Adulto , Idade de Início , Biomarcadores Tumorais , Análise Mutacional de DNA , DNA de Neoplasias/análise , Feminino , Mutação em Linhagem Germinativa , Glioma/classificação , Glioma/mortalidade , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Regiões Promotoras Genéticas , Modelos de Riscos Proporcionais
3.
Acta Neuropathol ; 133(6): 1001-1016, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28255664

RESUMO

The "integrated diagnosis" for infiltrating gliomas in the 2016 revised World Health Organization (WHO) classification of tumors of the central nervous system requires assessment of the tumor for IDH mutations and 1p/19q codeletion. Since TERT promoter mutations and ATRX alterations have been shown to be associated with prognosis, we analyzed whether these tumor markers provide additional prognostic information within each of the five WHO 2016 categories. We used data for 1206 patients from the UCSF Adult Glioma Study, the Mayo Clinic and The Cancer Genome Atlas (TCGA) with infiltrative glioma, grades II-IV for whom tumor status for IDH, 1p/19q codeletion, ATRX, and TERT had been determined. All cases were assigned to one of 5 groups following the WHO 2016 diagnostic criteria based on their morphologic features, and IDH and 1p/19q codeletion status. These groups are: (1) Oligodendroglioma, IDH-mutant and 1p/19q-codeleted; (2) Astrocytoma, IDH-mutant; (3) Glioblastoma, IDH-mutant; (4) Glioblastoma, IDH-wildtype; and (5) Astrocytoma, IDH-wildtype. Within each group, we used univariate and multivariate Cox proportional hazards models to assess associations of overall survival with patient age at diagnosis, grade, and ATRX alteration status and/or TERT promoter mutation status. Among Group 1 IDH-mutant 1p/19q-codeleted oligodendrogliomas, the TERT-WT group had significantly worse overall survival than the TERT-MUT group (HR: 2.72, 95% CI 1.05-7.04, p = 0.04). In both Group 2, IDH-mutant astrocytomas and Group 3, IDH-mutant glioblastomas, neither TERT mutations nor ATRX alterations were significantly associated with survival. Among Group 4, IDH-wildtype glioblastomas, ATRX alterations were associated with favorable outcomes (HR: 0.36, 95% CI 0.17-0.81, p = 0.01). Among Group 5, IDH-wildtype astrocytomas, the TERT-WT group had significantly better overall survival than the TERT-MUT group (HR: 0.48, 95% CI 0.27-0.87), p = 0.02). Thus, we present evidence that in certain WHO 2016 diagnostic groups, testing for TERT promoter mutations or ATRX alterations may provide additional useful prognostic information.


Assuntos
Neoplasias do Sistema Nervoso Central/genética , Glioma/genética , Telomerase/genética , Proteína Nuclear Ligada ao X/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Neoplasias do Sistema Nervoso Central/patologia , Feminino , Glioma/patologia , Humanos , Isocitrato Desidrogenase/genética , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mutação , Gradação de Tumores , Prognóstico , Organização Mundial da Saúde , Adulto Jovem
4.
CRISPR J ; 6(2): 176-182, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-37071670

RESUMO

The CRISPR-Cas9 system has enabled researchers to precisely modify/edit the sequence of a genome. A typical editing experiment consists of two steps: (1) editing cultured cells; (2) cell cloning and selection of clones with and without intended edit, presumed to be isogenic. The application of CRISPR-Cas9 system may result in off-target edits, whereas cloning will reveal culture-acquired mutations. We analyzed the extent of the former and the latter by whole genome sequencing in three experiments involving separate genomic loci and conducted by three independent laboratories. In all experiments we hardly found any off-target edits, whereas detecting hundreds to thousands of single nucleotide mutations unique to each clone after relatively short culture of 10-20 passages. Notably, clones also differed in copy number alterations (CNAs) that were several kb to several mb in size and represented the largest source of genomic divergence among clones. We suggest that screening of clones for mutations and CNAs acquired in culture is a necessary step to allow correct interpretation of DNA editing experiments. Furthermore, since culture associated mutations are inevitable, we propose that experiments involving derivation of clonal lines should compare a mix of multiple unedited lines and a mix of multiple edited lines.


Assuntos
Sistemas CRISPR-Cas , Edição de Genes , Sistemas CRISPR-Cas/genética , Mutação , DNA
5.
Cell Rep Med ; 4(6): 101082, 2023 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-37343523

RESUMO

Genetic alterations help predict the clinical behavior of diffuse gliomas, but some variability remains uncorrelated. Here, we demonstrate that haploinsufficient deletions of chromatin-bound tumor suppressor NFKB inhibitor alpha (NFKBIA) display distinct patterns of occurrence in relation to other genetic markers and are disproportionately present at recurrence. NFKBIA haploinsufficiency is associated with unfavorable patient outcomes, independent of genetic and clinicopathologic predictors. NFKBIA deletions reshape the DNA and histone methylome antipodal to the IDH mutation and induce a transcriptome landscape partly reminiscent of H3K27M mutant pediatric gliomas. In IDH mutant gliomas, NFKBIA deletions are common in tumors with a clinical course similar to that of IDH wild-type tumors. An externally validated nomogram model for estimating individual patient survival in IDH mutant gliomas confirms that NFKBIA deletions predict comparatively brief survival. Thus, NFKBIA haploinsufficiency aligns with distinct epigenome changes, portends a poor prognosis, and should be incorporated into models predicting the disease fate of diffuse gliomas.


Assuntos
Neoplasias Encefálicas , Glioma , Criança , Humanos , Neoplasias Encefálicas/genética , Epigenoma , Glioma/genética , Glioma/patologia , Haploinsuficiência/genética , Mutação/genética , Inibidor de NF-kappaB alfa/genética , Isocitrato Desidrogenase
7.
Neurooncol Pract ; 9(4): 259-270, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35859544

RESUMO

Knowledge about inherited and acquired genetics of adult diffuse glioma has expanded significantly over the past decade. Genomewide association studies (GWAS) stratified by histologic subtype identified six germline variants that were associated specifically with glioblastoma (GBM) and 12 that were associated with lower grade glioma. A GWAS performed using the 2016 WHO criteria, stratifying patients by IDH mutation and 1p/19q codeletion (as well as TERT promoter mutation), discovered that many of the known variants are associated with specific WHO glioma subtypes. In addition, the GWAS stratified by molecular group identified two additional novel regions: variants in D2HGDH that were associated with tumors that had an IDH mutation and a variant near FAM20C that was associated with tumors that had both IDH mutation and 1p/19q codeletion. The results of these germline associations have been used to calculate polygenic risk scores, from which to estimate relative and absolute risk of overall glioma and risk of specific glioma subtypes. We will review the concept of polygenic risk models and their potential clinical utility, as well as discuss the published adult diffuse glioma polygenic risk models. To date, these prior genetic studies have been done on European populations. Using the published glioma polygenic risk model, we show that the genetic associations published to date do not generalize across genetic ancestries, demonstrating that genetic studies need to be done on more diverse populations.

8.
Science ; 378(6615): 68-78, 2022 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-36201590

RESUMO

Establishing causal links between inherited polymorphisms and cancer risk is challenging. Here, we focus on the single-nucleotide polymorphism rs55705857, which confers a sixfold greater risk of isocitrate dehydrogenase (IDH)-mutant low-grade glioma (LGG). We reveal that rs55705857 itself is the causal variant and is associated with molecular pathways that drive LGG. Mechanistically, we show that rs55705857 resides within a brain-specific enhancer, where the risk allele disrupts OCT2/4 binding, allowing increased interaction with the Myc promoter and increased Myc expression. Mutating the orthologous mouse rs55705857 locus accelerated tumor development in an Idh1R132H-driven LGG mouse model from 472 to 172 days and increased penetrance from 30% to 75%. Our work reveals mechanisms of the heritable predisposition to lethal glioma in ~40% of LGG patients.


Assuntos
Neoplasias Encefálicas , Cromossomos Humanos Par 8 , Glioma , Isocitrato Desidrogenase , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Cromossomos Humanos Par 8/genética , Glioma/genética , Glioma/patologia , Humanos , Isocitrato Desidrogenase/genética , Camundongos , Mutação , Polimorfismo de Nucleotídeo Único
9.
Am J Epidemiol ; 174(5): 574-81, 2011 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-21742680

RESUMO

Glioma risk has consistently been inversely associated with allergy history but not with smoking history despite putative biologic plausibility. Data from 855 high-grade glioma cases and 1,160 controls from 4 geographic regions of the United States during 1997-2008 were analyzed for interactions between allergy and smoking histories and inherited variants in 5 established glioma risk regions: 5p15.3 (TERT), 8q24.21 (CCDC26/MLZE), 9p21.3 (CDKN2B), 11q23.3 (PHLDB1/DDX6), and 20q13.3 (RTEL1). The inverse relation between allergy and glioma was stronger among those who did not (odds ratio(allergy-glioma) = 0.40, 95% confidence interval: 0.28, 0.58) versus those who did (odds ratio(allergy-glioma) = 0.76, 95% confidence interval: 0.59, 0.97; P(interaction) = 0.02) carry the 9p21.3 risk allele. However, the inverse association with allergy was stronger among those who carried (odds ratio(allergy-glioma) = 0.44, 95% confidence interval: 0.29, 0.68) versus those who did not carry (odds ratio(allergy-glioma) = 0.68, 95% confidence interval: 0.54, 0.86) the 20q13.3 glioma risk allele, but this interaction was not statistically significant (P = 0.14). No relation was observed between glioma risk and smoking (odds ratio = 0.92, 95% confidence interval: 0.77, 1.10; P = 0.37), and there were no interactions for glioma risk of smoking history with any of the risk alleles. The authors' observations are consistent with a recent report that the inherited glioma risk variants in chromosome regions 9p21.3 and 20q13.3 may modify the inverse association of allergy and glioma.


Assuntos
Alelos , Astrocitoma/genética , Neoplasias Encefálicas/genética , Predisposição Genética para Doença/genética , Glioblastoma/genética , Hipersensibilidade/complicações , Polimorfismo de Nucleotídeo Único , Fumar/efeitos adversos , Astrocitoma/etiologia , Neoplasias Encefálicas/etiologia , Estudos de Casos e Controles , Feminino , Glioblastoma/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
10.
Neuro Oncol ; 23(4): 638-649, 2021 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-33130899

RESUMO

BACKGROUND: Large-scale genome-wide association studies (GWAS) have implicated thousands of germline genetic variants in modulating individuals' risk to various diseases, including cancer. At least 25 risk loci have been identified for low-grade gliomas (LGGs), but their molecular functions remain largely unknown. METHODS: We hypothesized that GWAS loci contain causal single nucleotide polymorphisms (SNPs) that reside in accessible open chromatin regions and modulate the expression of target genes by perturbing the binding affinity of transcription factors (TFs). We performed an integrative analysis of genomic and epigenomic data from The Cancer Genome Atlas and other public repositories to identify candidate causal SNPs within linkage disequilibrium blocks of LGG GWAS loci. We assessed their potential regulatory role via in silico TF binding sequence perturbations, convolutional neural network trained on TF binding data, and simulated annealing-based interpretation methods. RESULTS: We built an interactive website (http://education.knoweng.org/alg3/) summarizing the functional footprinting of 280 variants in 25 LGG GWAS regions, providing rich information for further computational and experimental scrutiny. We identified as case studies PHLDB1 and SLC25A26 as candidate target genes of rs12803321 and rs11706832, respectively, and predicted the GWAS variant rs648044 to be the causal SNP modulating ZBTB16, a known tumor suppressor in multiple cancers. We showed that rs648044 likely perturbed the binding affinity of the TF MAFF, as supported by RNA interference and in vitro MAFF binding experiments. CONCLUSIONS: The identified candidate (causal SNP, target gene, TF) triplets and the accompanying resource will help accelerate our understanding of the molecular mechanisms underlying genetic risk factors for gliomas.


Assuntos
Estudo de Associação Genômica Ampla , Glioma , Sistemas de Transporte de Aminoácidos , Proteínas de Ligação ao Cálcio , Predisposição Genética para Doença , Glioma/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas do Tecido Nervoso , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
11.
J Neuropathol Exp Neurol ; 80(9): 821-829, 2021 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-34363682

RESUMO

Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a recently described epileptogenic tumor characterized by oligodendroglioma-like components, aberrant CD34 expression, and frequent mitogen-activated protein kinase (MAPK) pathway activation. We molecularly profiled 13 cases with diagnostic histopathological features of PLNTY (10 female; median age, 16 years; range, 5-52). Patients frequently presented with seizures (9 of 12 with available history) and temporal lobe tumors (9 of 13). MAPK pathway activating alterations were identified in all 13 cases. Fusions were present in the 7 youngest patients: FGFR2-CTNNA3 (n = 2), FGFR2-KIAA1598 (FGFR2-SHTN1) (n = 1), FGFR2-INA (n = 1), FGFR2-MPRIP (n = 1), QKI-NTRK2 (n = 1), and KIAA1549-BRAF (n = 1). BRAF V600E mutation was present in 6 patients (17 years or older). Two fusion-positive cases additionally harbored TP53/RB1 abnormalities suggesting biallelic inactivation. Copy number changes predominantly involving whole chromosomes were observed in all 10 evaluated cases, with losses of chromosome 10q occurring with FGFR2-KIAA1598 (SHTN1)/CTNNA3 fusions. The KIAA1549-BRAF and QKI-NTRK2 fusions were associated respectively with a 7q34 deletion and 9q21 duplication. This study shows that despite its name, PLNTY also occurs in older adults, who frequently show BRAF V600E mutation. It also expands the spectrum of the MAPK pathway activating alterations associated with PLNTY and demonstrates recurrent chromosomal copy number changes consistent with chromosomal instability.


Assuntos
Glicoproteínas de Membrana/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Neoplasias Neuroepiteliomatosas/metabolismo , Receptor trkB/metabolismo , Convulsões/metabolismo , Adulto , Aneuploidia , Cromossomos Humanos Par 9/metabolismo , Feminino , Fusão Gênica/fisiologia , Humanos , Recidiva , Convulsões/genética , Fatores de Transcrição/metabolismo
12.
Genes Chromosomes Cancer ; 48(10): 854-64, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19544381

RESUMO

Nearly 10% of human gliomas are oligodendrogliomas. Deletion of chromosome arm 19q, often in conjunction with deletion of 1p, has been observed in 65-80% of these tumors. This has suggested the presence of a tumor suppressor gene located on the 19q arm. Chromosome 19 deletion is also of interest due to the better prognosis of patients with deletion, including longer survival and better response to chemotherapy, compared with patients without deletion. Two glioma cell lines with deletion of 19q were used for chromosome 19 microcell-mediated transfer, to assess the effect of replacing the deleted segment. Complementation with chromosome 19 significantly reduced the growth rate of the hybrid cells compared with the parental cell lines. Affymetrix U133 Plus 2.0 Gene Chip analysis was performed to measure and compare the expression of the chromosome 19 genes in the chromosome 19 hybrid cell lines to the parental cell line. Probes were considered significantly different when a P value <0.01 was seen in all of the cell line comparisons. Of 345 probes within the commonly deleted 19q region, seven genes (APOE, RCN3, FLJ10781, SAE1, STRN4, CCDC8, and BCL2L12) were identified as potential candidate genes. RT-PCR analysis of primary tumor specimens showed that several genes had significant differences when stratified by tumor morphology or deletion status. This suggests that one or more of these candidates may play a role in glioma formation or progression.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 19 , Glioma/genética , Processos de Crescimento Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Forma Celular/genética , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Técnicas Genéticas , Glioma/metabolismo , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , Reprodutibilidade dos Testes , Reação em Cadeia da Polimerase Via Transcriptase Reversa
13.
Neurooncol Adv ; 2(1): vdaa109, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33205043

RESUMO

BACKGROUND: Oligodendroglioma is genetically defined by concomitant IDH (IDH1/IDH2) mutation and whole-arm 1p/19q codeletion. Codeletion of 1p/19q traditionally evaluated by fluorescence in situ hybridization (FISH) cannot distinguish partial from whole-arm 1p/19q codeletion. Partial 1p/19q codeletion called positive by FISH is diagnostically a "false-positive" result. Chromosomal microarray (CMA) discriminates partial from whole-arm 1p/19q codeletion. Herein, we aimed to estimate the frequency of partial 1p/19q codeletion that would lead to a false-positive FISH result. METHODS: FISH 1p/19q codeletion test probe coordinates were mapped onto Oncoscan CMA data to determine the rate of partial 1p/19q codeletion predicted to be positive by FISH. Diffuse astrocytic gliomas with available CMA data (2015-2018) were evaluated and classified based on IDH1-R132H/ATRX/p53 immunohistochemistry, IDH/TERT promoter targeted sequencing, and/or CMA according to classification updates. Predicted false-positive cases were verified by FISH whenever possible. RESULTS: The overall estimated false-positive FISH 1p/19q codeletion rate was 3.6% (8/223). Predicted false positives were verified by FISH in 6 (of 8) cases. False-positive rates did not differ significantly (P = .49) between IDH-mutant (4.6%; 4/86) and IDH-wildtype (2.9%; 4/137) tumors. IDH-wildtype false positives were all WHO grade IV, whereas IDH-mutant false positives spanned WHO grades II-IV. Testing for 1p/19q codeletion would not have been indicated for most false positives based on current classification recommendations. CONCLUSION: Selective 1p/19q codeletion testing and cautious interpretation for conflicting FISH and histopathological findings are recommended to avoid potential misdiagnosis.

14.
Neuro Oncol ; 22(11): 1602-1613, 2020 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-32386320

RESUMO

BACKGROUND: Twenty-five germline variants are associated with adult diffuse glioma, and some of these variants have been shown to be associated with particular subtypes of glioma. We hypothesized that additional germline variants could be identified if a genome-wide association study (GWAS) were performed by molecular subtype. METHODS: A total of 1320 glioma cases and 1889 controls were used in the discovery set and 799 glioma cases and 808 controls in the validation set. Glioma cases were classified into molecular subtypes based on combinations of isocitrate dehydrogenase (IDH) mutation, telomerase reverse transcriptase (TERT) promoter mutation, and 1p/19q codeletion. Logistic regression was applied to the discovery and validation sets to test for associations of variants with each of the subtypes. A meta-analysis was subsequently performed using a genome-wide P-value threshold of 5 × 10-8. RESULTS: Nine variants in or near D-2-hydroxyglutarate dehydrogenase (D2HGDH) on chromosome 2 were genome-wide significant in IDH-mutated glioma (most significant was rs5839764, meta P = 2.82 × 10-10). Further stratifying by 1p/19q codeletion status, one variant in D2HGDH was genome-wide significant in IDH-mutated non-codeleted glioma (rs1106639, meta P = 4.96 × 10-8). Further stratifying by TERT mutation, one variant near FAM20C (family with sequence similarity 20, member C) on chromosome 7 was genome-wide significant in gliomas that have IDH mutation, TERT mutation, and 1p/19q codeletion (rs111976262, meta P = 9.56 × 10-9). Thirty-six variants in or near GMEB2 on chromosome 20 near regulator of telomere elongation helicase 1 (RTEL1) were genome-wide significant in IDH wild-type glioma (most significant was rs4809313, meta P = 2.60 × 10-10). CONCLUSIONS: Performing a GWAS by molecular subtype identified 2 new regions and a candidate independent region near RTEL1, which were associated with specific glioma molecular subtypes.


Assuntos
Oxirredutases do Álcool/genética , Neoplasias Encefálicas , Caseína Quinase I/genética , Proteínas da Matriz Extracelular/genética , Glioma , Adulto , Neoplasias Encefálicas/genética , Feminino , Estudo de Associação Genômica Ampla , Glioma/genética , Humanos , Isocitrato Desidrogenase/genética , Masculino , Pessoa de Meia-Idade , Mutação , Telomerase/genética
15.
Clin Cancer Res ; 26(5): 1094-1104, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31852831

RESUMO

PURPOSE: Glioblastoma is the most frequent and lethal primary brain tumor. Development of novel therapies relies on the availability of relevant preclinical models. We have established a panel of 96 glioblastoma patient-derived xenografts (PDX) and undertaken its genomic and phenotypic characterization. EXPERIMENTAL DESIGN: PDXs were established from glioblastoma, IDH-wildtype (n = 93), glioblastoma, IDH-mutant (n = 2), diffuse midline glioma, H3 K27M-mutant (n = 1), and both primary (n = 60) and recurrent (n = 34) tumors. Tumor growth rates, histopathology, and treatment response were characterized. Integrated molecular profiling was performed by whole-exome sequencing (WES, n = 83), RNA-sequencing (n = 68), and genome-wide methylation profiling (n = 76). WES data from 24 patient tumors was compared with derivative models. RESULTS: PDXs recapitulate many key phenotypic and molecular features of patient tumors. Orthotopic PDXs show characteristic tumor morphology and invasion patterns, but largely lack microvascular proliferation and necrosis. PDXs capture common and rare molecular drivers, including alterations of TERT, EGFR, PTEN, TP53, BRAF, and IDH1, most at frequencies comparable with human glioblastoma. However, PDGFRA amplification was absent. RNA-sequencing and genome-wide methylation profiling demonstrated broad representation of glioblastoma molecular subtypes. MGMT promoter methylation correlated with increased survival in response to temozolomide. WES of 24 matched patient tumors showed preservation of most genetic driver alterations, including EGFR amplification. However, in four patient-PDX pairs, driver alterations were gained or lost on engraftment, consistent with clonal selection. CONCLUSIONS: Our PDX panel captures the molecular heterogeneity of glioblastoma and recapitulates many salient genetic and phenotypic features. All models and genomic data are openly available to investigators.


Assuntos
Biomarcadores Tumorais/genética , Sequenciamento do Exoma/métodos , Genótipo , Glioblastoma/classificação , Glioblastoma/genética , Mutação , Fenótipo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antineoplásicos Alquilantes/farmacologia , Neoplasias Encefálicas/classificação , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Metilação de DNA , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Receptores ErbB/genética , Feminino , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Humanos , Isocitrato Desidrogenase/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Regiões Promotoras Genéticas , Taxa de Sobrevida , Temozolomida/farmacologia , Proteínas Supressoras de Tumor/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto Jovem
16.
Neuro Oncol ; 21(11): 1458-1469, 2019 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-31346613

RESUMO

BACKGROUND: Glioblastoma (GBM) represents an aggressive cancer type with a median survival of only 14 months. With fewer than 5% of patients surviving 5 years, comprehensive profiling of these rare patients could elucidate prognostic biomarkers that may confer better patient outcomes. We utilized multiple molecular approaches to characterize the largest patient cohort of isocitrate dehydrogenase (IDH)-wildtype GBM long-term survivors (LTS) to date. METHODS: Retrospective analysis was performed on 49 archived formalin-fixed paraffin embedded tumor specimens from patients diagnosed with GBM at the Mayo Clinic between December 1995 and September 2013. These patient samples were subdivided into 2 groups based on survival (12 LTS, 37 short-term survivors [STS]) and subsequently examined by mutation sequencing, copy number analysis, methylation profiling, and gene expression. RESULTS: Of the 49 patients analyzed in this study, LTS were younger at diagnosis (P = 0.016), more likely to be female (P = 0.048), and MGMT promoter methylated (UniD, P = 0.01). IDH-wildtype STS and LTS demonstrated classic GBM mutations and copy number changes. Pathway analysis of differentially expressed genes showed LTS enrichment for sphingomyelin metabolism, which has been linked to decreased GBM growth, invasion, and angiogenesis. STS were enriched for DNA repair and cell cycle control networks. CONCLUSIONS: While our findings largely report remarkable similarity between these LTS and more typical STS, unique attributes were observed in regard to altered gene expression and pathway enrichment. These attributes may be valuable prognostic markers and are worth further examination. Importantly, this study also underscores the limitations of existing biomarkers and classification methods in predicting patient prognosis.


Assuntos
Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Isocitrato Desidrogenase/genética , Mutação , Sobreviventes/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Metilação de DNA , Epigênese Genética , Feminino , Seguimentos , Perfilação da Expressão Gênica , Glioblastoma/patologia , Glioblastoma/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Transcriptoma , Adulto Jovem
17.
Neuro Oncol ; 21(4): 451-461, 2019 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-30624711

RESUMO

BACKGROUND: Twenty-five single nucleotide polymorphisms (SNPs) are associated with adult diffuse glioma risk. We hypothesized that the inclusion of these 25 SNPs with age at diagnosis and sex could estimate risk of glioma as well as identify glioma subtypes. METHODS: Case-control design and multinomial logistic regression were used to develop models to estimate the risk of glioma development while accounting for histologic and molecular subtypes. Case-case design and logistic regression were used to develop models to predict isocitrate dehydrogenase (IDH) mutation status. A total of 1273 glioma cases and 443 controls from Mayo Clinic were used in the discovery set, and 852 glioma cases and 231 controls from UCSF were used in the validation set. All samples were genotyped using a custom Illumina OncoArray. RESULTS: Patients in the highest 5% of the risk score had more than a 14-fold increase in relative risk of developing an IDH mutant glioma. Large differences in lifetime absolute risk were observed at the extremes of the risk score percentile. For both IDH mutant 1p/19q non-codeleted glioma and IDH mutant 1p/19q codeleted glioma, the lifetime risk increased from almost null to 2.3% and almost null to 1.7%, respectively. The SNP-based model that predicted IDH mutation status had a validation concordance index of 0.85. CONCLUSIONS: These results suggest that germline genotyping can provide new tools for the initial management of newly discovered brain lesions. Given the low lifetime risk of glioma, risk scores will not be useful for population screening; however, they may be useful in certain clinically defined high-risk groups.


Assuntos
Neoplasias Encefálicas/genética , Glioma/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/classificação , Neoplasias Encefálicas/patologia , Estudos de Casos e Controles , Feminino , Genótipo , Glioma/classificação , Glioma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Adulto Jovem
18.
Neuro Oncol ; 20(6): 810-817, 2018 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-29040662

RESUMO

Background: Single-gene mutation syndromes account for some familial glioma (FG); however, they make up only a small fraction of glioma families. Gliomas can be classified into 3 major molecular subtypes based on isocitrate dehydrogenase (IDH) mutation and 1p/19q codeletion. We hypothesized that the prevalence of molecular subtypes might differ in familial versus sporadic gliomas and that tumors in the same family should have the same molecular subtype. Methods: Participants in the FG study (Gliogene) provided samples for germline DNA analysis. Formalin-fixed, paraffin-embedded tumors were obtained from a subset of FG cases, and DNA was extracted. We analyzed tissue from 75 families, including 10 families containing a second affected family member. Copy number variation data were obtained using a first-generation Affymetrix molecular inversion probe (MIP) array. Results: Samples from 62 of 75 (83%) FG cases could be classified into the 3 subtypes. The prevalence of the molecular subtypes was: 30 (48%) IDH-wildtype, 21 (34%) IDH-mutant non-codeleted, and 11 (19%) IDH-mutant and 1p/19q codeleted. This distribution of molecular subtypes was not statistically different from that of sporadic gliomas (P = 0.54). Of 10 paired FG samples, molecular subtypes were concordant for 7 (κ = 0.59): 3 IDH-mutant non-codeleted, 2 IDH-wildtype, and 2 IDH-mutant and 1p/19q codeleted gliomas. Conclusions: Our data suggest that within individual families, patients develop gliomas of the same molecular subtype. However, we did not observe differences in the prevalence of the molecular subtypes in FG compared with sporadic gliomas. These observations provide further insight into the distribution of molecular subtypes in FG.


Assuntos
Variações do Número de Cópias de DNA , Predisposição Genética para Doença , Glioma/classificação , Glioma/patologia , Isocitrato Desidrogenase/genética , Mutação , Neoplasias Encefálicas/classificação , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Aberrações Cromossômicas , Feminino , Glioma/genética , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Linhagem , Prognóstico
19.
Oncotarget ; 8(22): 35523-35531, 2017 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-28388591

RESUMO

BACKGROUND: The NRG Oncology RTOG 9402 trial showed significant survival benefit in patients with 1p/19q co-deleted anaplastic oligodendrogliomas (AO) who received both radiation (RT) and chemotherapy (PCV regimen) versus RT alone. Substantial separation of the survival curves was only seen after 7.3 years. We aimed to determine whether there are specific genetic alterations that distinguish co-deleted AO patients who benefit from the addition of PCV from those who do not. METHODS: We performed whole exome sequencing on matched tumor and normal DNA from all available short-term (STS) and long-term survivors (LTS) who received RT+PCV. hTERT status and rs55705857 genotypes (G-allele) were analyzed in both cohorts. RESULTS: Six STS (survival of <7.3y) and 7 LTS (survival of ≥7.3y and no progression) had sufficient material for analysis. There was no significant difference between the groups regarding age, performance status and extent of resection. On average, STS had 7 and LTS 4 mutations. Most common mutations in STS vs. LTS were: IDH1 (67 vs. 86%), CIC (50 vs. 71%) and FUBP1 (17 vs. 71%). The hTERT promoter was mutated in 83% STS and 86% LTS. Genotyping of rs55705857 showed a higher prevalence of G allele carriers in LTS than STS (43 vs. 17%). CONCLUSIONS: These findings confirm that IDH, CIC, FUBP1 mutations and rs55705857 genotype are common in AO. No distinct genetic signature was identified to differentiate STS and LTS.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Variação Genética , Oligodendroglioma/genética , Oligodendroglioma/patologia , Adulto , Idoso , Alelos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/mortalidade , Aberrações Cromossômicas , Cromossomos Humanos Par 1 , Cromossomos Humanos Par 19 , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Gradação de Tumores , Oligodendroglioma/tratamento farmacológico , Oligodendroglioma/mortalidade , Prognóstico , Resultado do Tratamento
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