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1.
BMC Urol ; 20(1): 173, 2020 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-33121461

RESUMO

BACKGROUND: The four most commonly-mutated genes in clear cell renal cell carcinoma (ccRCC) tumors are BAP1, PBRM1, SETD2 and VHL. And, there are currently 14 known RCC germline variants that have been reproducibly shown to be associated with RCC risk. However, the association of germline genetics with tumor genetics and clinical aggressiveness are unknown. METHODS: We analyzed 420 ccRCC patients from The Cancer Genome Atlas. Molecular subtype was determined based on acquired mutations in BAP1, PBRM1, SETD2 and VHL. Aggressive subtype was defined clinically using Mayo SSIGN score and molecularly using the ccA/ccB gene expression subtype. Publically-available Hi-C data were used to link germline risk variants with candidate target genes. RESULTS: The 8q24 variant rs35252396 was significantly associated with VHL mutation status (OR = 1.6, p = 0.0037) and SSIGN score (OR = 1.9, p = 0.00094), after adjusting for multiple comparisons. We observed that, while some germline variants have interactions with nearby genes, some variants demonstrate long-range interactions with target genes. CONCLUSIONS: These data further demonstrate the link between rs35252396, HIF pathway and ccRCC clinical aggressiveness, providing a more comprehensive picture of how germline genetics and tumor genetics interact with respect to tumor development and progression.

2.
Am J Hum Genet ; 106(5): 707-716, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32386537

RESUMO

Because polygenic risk scores (PRSs) for coronary heart disease (CHD) are derived from mainly European ancestry (EA) cohorts, their validity in African ancestry (AA) and Hispanic ethnicity (HE) individuals is unclear. We investigated associations of "restricted" and genome-wide PRSs with CHD in three major racial and ethnic groups in the U.S. The eMERGE cohort (mean age 48 ± 14 years, 58% female) included 45,645 EA, 7,597 AA, and 2,493 HE individuals. We assessed two restricted PRSs (PRSTikkanen and PRSTada; 28 and 50 variants, respectively) and two genome-wide PRSs (PRSmetaGRS and PRSLDPred; 1.7 M and 6.6 M variants, respectively) derived from EA cohorts. Over a median follow-up of 11.1 years, 2,652 incident CHD events occurred. Hazard and odds ratios for the association of PRSs with CHD were similar in EA and HE cohorts but lower in AA cohorts. Genome-wide PRSs were more strongly associated with CHD than restricted PRSs were. PRSmetaGRS, the best performing PRS, was associated with CHD in all three cohorts; hazard ratios (95% CI) per 1 SD increase were 1.53 (1.46-1.60), 1.53 (1.23-1.90), and 1.27 (1.13-1.43) for incident CHD in EA, HE, and AA individuals, respectively. The hazard ratios were comparable in the EA and HE cohorts (pinteraction = 0.77) but were significantly attenuated in AA individuals (pinteraction= 2.9 × 10-3). These results highlight the potential clinical utility of PRSs for CHD as well as the need to assemble diverse cohorts to generate ancestry- and ethnicity PRSs.


Assuntos
Afro-Americanos/genética , Doença das Coronárias/genética , Grupo com Ancestrais do Continente Europeu/genética , Predisposição Genética para Doença , Hispano-Americanos/genética , Herança Multifatorial/genética , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances
3.
JAMA Cardiol ; 2020 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-32374345

RESUMO

Importance: Spontaneous coronary artery dissection (SCAD), an idiopathic disorder that predominantly affects young to middle-aged women, has emerged as an important cause of acute coronary syndrome, myocardial infarction, and sudden cardiac death. Objective: To identify common single-nucleotide variants (SNVs) associated with SCAD susceptibility. Design, Setting, and Participants: This single-center genome-wide association study examined approximately 5 million genotyped and imputed SNVs and subsequent SNV-targeted replication analysis results in individuals enrolled in the Mayo Clinic SCAD registry from August 30, 2011, to August 2, 2018. Data analysis was performed from June 21, 2017, to December 30, 2019. Main Outcomes and Measures: Genetic loci and positional candidate genes associated with SCAD. Results: This study included 484 white women with SCAD (mean [SD] age, 46.6 [9.2] years) and 1477 white female controls in the discovery cohort (mean [SD] age, 64.0 [14.5] years) and 183 white women with SCAD (mean [SD] age, 47.1 [9.9] years) and 340 white female controls in the replication cohort (mean [SD] age, 51.0 [15.3] years). Associations with SCAD risk reached genome-wide significance at 3 loci (1q21.3 [OR, 1.78; 95% CI, 1.51-2.09; P = 2.63 × 10-12], 6p24.1 [OR, 1.77; 95% CI, 1.51-2.09; P = 7.09 × 10-12], and 12q13.3 [OR, 1.67; 95% CI, 1.42-1.97; P = 3.62 × 10-10]), and 7 loci had evidence suggestive of an association (1q24.2 [OR, 2.10; 95% CI, 1.58-2.79; P = 2.88 × 10-7], 3q22.3 [OR, 1.47; 95% CI, 1.26-1.71; P = 6.65 × 10-7], 4q34.3 [OR, 1.84; 95% CI, 1.44-2.35; P = 9.80 × 10-7], 8q24.3 [OR, 2.57; 95% CI, 1.76-3.75; P = 9.65 × 10-7], 15q21.1 [OR, 1.75; 95% CI, 1.40-2.18; P = 7.23 × 10-7], 16q24.1 [OR, 1.91; 95% CI, 1.49-2.44; P = 2.56 × 10-7], and 21q22.11 [OR, 2.11; 95% CI, 1.59-2.82; P = 3.12 × 10-7]) after adjusting for the top 5 principal components. Associations were validated for 5 of the 10 risk alleles in the replication cohort. In a meta-analysis of the discovery and replication cohorts, associations for the 5 SNVs were significant, with relatively large effect sizes (1q21.3 [OR, 1.77; 95% CI, 1.54-2.03; P = 3.26 × 10-16], 6p24.1 [OR, 1.71; 95% CI, 1.49-1.97; P = 4.59 × 10-14], 12q13.3 [OR, 1.69; 95% CI, 1.47-1.94; P = 1.42 × 10-13], 15q21.1 [OR, 1.79; 95% CI, 1.48-2.17; P = 2.12 × 10-9], and 21q22.11 [OR, 2.18; 95% CI, 1.70-2.81; P = 1.09 × 10-9]). Each index SNV was within or near a gene highly expressed in arterial tissue and previously linked to SCAD (PHACTR1) and/or other vascular disorders (LRP1, LINC00310, and FBN1). Conclusions and Relevance: This study revealed 5 replicated risk loci and positional candidate genes for SCAD, most of which are associated with extracoronary arteriopathies. Moreover, the alternate alleles of 3 SNVs have been previously associated with atherosclerotic coronary artery disease, further implicating allelic susceptibility to coronary artery atherosclerosis vs dissection.

4.
PLoS Genet ; 16(3): e1008684, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32226016

RESUMO

Lipid levels are important markers for the development of cardio-metabolic diseases. Although hundreds of associated loci have been identified through genetic association studies, the contribution of genetic factors to variation in lipids is not fully understood, particularly in U.S. minority groups. We performed genome-wide association analyses for four lipid traits in over 45,000 ancestrally diverse participants from the Population Architecture using Genomics and Epidemiology (PAGE) Study, followed by a meta-analysis with several European ancestry studies. We identified nine novel lipid loci, five of which showed evidence of replication in independent studies. Furthermore, we discovered one novel gene in a PrediXcan analysis, minority-specific independent signals at eight previously reported loci, and potential functional variants at two known loci through fine-mapping. Systematic examination of known lipid loci revealed smaller effect estimates in African American and Hispanic ancestry populations than those in Europeans, and better performance of polygenic risk scores based on minority-specific effect estimates. Our findings provide new insight into the genetic architecture of lipid traits and highlight the importance of conducting genetic studies in diverse populations in the era of precision medicine.


Assuntos
Grupos de Populações Continentais/genética , Lipídeos/sangue , Lipídeos/genética , Bases de Dados Genéticas , Feminino , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Lipídeos/análise , Masculino , Metagenômica/métodos , Grupos Minoritários , Herança Multifatorial/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Estados Unidos/epidemiologia
5.
JAMA Oncol ; 6(4): 495-503, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32027343

RESUMO

Importance: Per the World Health Organization 2016 integrative classification, newly diagnosed glioblastomas are separated into isocitrate dehydrogenase gene 1 or 2 (IDH)-wild-type and IDH-mutant subtypes, with median patient survival of 1.2 and 3.6 years, respectively. Although maximal resection of contrast-enhanced (CE) tumor is associated with longer survival, the prognostic importance of maximal resection within molecular subgroups and the potential importance of resection of non-contrast-enhanced (NCE) disease is poorly understood. Objective: To assess the association of resection of CE and NCE tumors in conjunction with molecular and clinical information to develop a new road map for cytoreductive surgery. Design, Setting, and Participants: This retrospective, multicenter cohort study included a development cohort from the University of California, San Francisco (761 patients diagnosed from January 1, 1997, through December 31, 2017, with 9.6 years of follow-up) and validation cohorts from the Mayo Clinic (107 patients diagnosed from January 1, 2004, through December 31, 2014, with 5.7 years of follow-up) and the Ohio Brain Tumor Study (99 patients with data collected from January 1, 2008, through December 31, 2011, with a median follow-up of 10.9 months). Image accessors were blinded to patient groupings. Eligible patients underwent surgical resection for newly diagnosed glioblastoma and had available survival, molecular, and clinical data and preoperative and postoperative magnetic resonance images. Data were analyzed from November 15, 2018, to March 15, 2019. Main Outcomes and Measures: Overall survival. Results: Among the 761 patients included in the development cohort (468 [61.5%] men; median age, 60 [interquartile range, 51.6-67.7] years), younger patients with IDH-wild-type tumors and aggressive resection of CE and NCE tumors had survival similar to that of patients with IDH-mutant tumors (median overall survival [OS], 37.3 [95% CI, 31.6-70.7] months). Younger patients with IDH-wild-type tumors and reduction of CE tumor but residual NCE tumors fared worse (median OS, 16.5 [95% CI, 14.7-18.3] months). Older patients with IDH-wild-type tumors benefited from reduction of CE tumor (median OS, 12.4 [95% CI, 11.4-14.0] months). The results were validated in the 2 external cohorts. The association between aggressive CE and NCE in patients with IDH-wild-type tumors was not attenuated by the methylation status of the promoter region of the DNA repair enzyme O6-methylguanine-DNA methyltransferase. Conclusions and Relevance: This study confirms an association between maximal resection of CE tumor and OS in patients with glioblastoma across all subgroups. In addition, maximal resection of NCE tumor was associated with longer OS in younger patients, regardless of IDH status, and among patients with IDH-wild-type glioblastoma regardless of the methylation status of the promoter region of the DNA repair enzyme O6-methylguanine-DNA methyltransferase. These conclusions may help reassess surgical strategies for individual patients with newly diagnosed glioblastoma.

6.
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
7.
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
8.
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
9.
Pharmacogenet Genomics ; 25(4): 157-63, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25714002

RESUMO

BACKGROUND: In tamoxifen-treated patients, breast cancer recurrence differs according to CYP2D6 genotype and endoxifen steady-state concentrations (Endx Css). The ¹³C-dextromethorphan breath test (DM-BT), labeled with ¹³C at the O-CH3 moiety, measures CYP2D6 enzyme activity. We sought to examine the ability of the DM-BT to identify known CYP2D6 genotypic poor metabolizers and examine the correlation between DM-BT and Endx Css. METHODS: DM-BT and tamoxifen pharmacokinetics were obtained at baseline, 3, and 6 months following tamoxifen initiation. Potent CYP2D6 inhibitors were prohibited. The correlation between baseline DM-BT with CYP2D6 genotype and Endx Css was determined. The association between baseline DM-BT (where values ≤0.9 is an indicator of poor in vivo CYP2D6 metabolism) and Endx Css (using values≤11.2 known to be associated with poorer recurrence free survival) was explored. RESULTS: A total of 91 patients were enrolled and 77 were eligible. CYP2D6 genotype was positively correlated with baseline, 3, and 6 months DM-BT (r ranging from 0.457-0. 60; P<0.001). Both CYP2D6 genotype (r=0.47, 0.56, P<0.0001), and baseline DM-BT (r=0.60, 0.54, P<0.001) were associated with 3 and 6 months Endx Css, respectively. Seven (78%) of nine patients with low (≤11.2 nmol/l) 3 month Endx Css also had low DM-BT (≤0.9) including 2/2 CYP2D6 PM/PM and 5/5 IM/PM. In contrast, one (2%) of 48 patients with a low DM-BT had Endx Css more than 11.2 nmol/l. CONCLUSION: In patients not taking potent CYP2D6 inhibitors, DM-BT was associated with CYP2D6 genotype and 3 and 6 months Endx Css but did not provide better discrimination of Endx Css compared with CYP2D6 genotype alone. Further studies are needed to identify additional factors which alter Endx Css.


Assuntos
Antineoplásicos Hormonais/farmacocinética , Antitussígenos , Neoplasias da Mama/tratamento farmacológico , Testes Respiratórios/métodos , Citocromo P-450 CYP2D6/genética , Dextrometorfano , Tamoxifeno/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Hormonais/administração & dosagem , Neoplasias da Mama/enzimologia , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Tamoxifeno/administração & dosagem , Resultado do Tratamento
10.
Nat Genet ; 46(7): 731-5, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24908248

RESUMO

Glioma, the most common central nervous system cancer in adults, has poor prognosis. Here we identify a new SNP associated with glioma risk, rs1920116 (near TERC), that reached genome-wide significance (Pcombined = 8.3 × 10(-9)) in a meta-analysis of genome-wide association studies (GWAS) of high-grade glioma and replication data (1,644 cases and 7,736 controls). This region has previously been associated with mean leukocyte telomere length (LTL). We therefore examined the relationship between LTL and both this new risk locus and other previously established risk loci for glioma using data from a recent GWAS of LTL (n = 37,684 individuals). Alleles associated with glioma risk near TERC and TERT were strongly associated with longer LTL (P = 5.5 × 10(-20) and 4.4 × 10(-19), respectively). In contrast, risk-associated alleles near RTEL1 were inconsistently associated with LTL, suggesting the presence of distinct causal alleles. No other risk loci for glioma were associated with LTL. The identification of risk alleles for glioma near TERC and TERT that also associate with telomere length implicates telomerase in gliomagenesis.


Assuntos
Glioma/genética , Polimorfismo de Nucleotídeo Único/genética , RNA/genética , Telomerase/genética , Telômero/genética , Adulto , Estudos de Casos e Controles , Estudo de Associação Genômica Ampla , Genótipo , Glioma/patologia , Humanos , Leucócitos/metabolismo , Leucócitos/patologia , Gradação de Tumores , Prognóstico , Fatores de Risco
11.
Neuro Oncol ; 15(8): 1041-7, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23733245

RESUMO

BACKGROUND: Genome-wide association studies have implicated single nucleotide polymorphisms (SNPs) in 7 genes as glioma risk factors, including 2 (TERT, RTEL1) involved in telomerase structure/function. We examined associations of these 7 established glioma risk loci with age at diagnosis among patients with glioma. METHODS: SNP genotype data were available for 2286 Caucasian glioma patients from the University of California, San Francisco (n = 1434) and the Mayo Clinic (n = 852). Regression analyses were performed to test for associations between "number of risk alleles" and "age at diagnosis," adjusted for sex and study site and stratified by tumor grade/histology where appropriate. RESULTS: Four SNPs were significantly associated with age at diagnosis. Carrying a greater number of risk alleles at rs55705857 (CCDC26) and at rs498872 (PHLDB1) was associated with younger age at diagnosis (P = 1.4 × 10(-22) and P = 9.5 × 10(-7), respectively). These SNPs are stronger risk factors for oligodendroglial tumors, which tend to occur in younger patients, and their association with age at diagnosis varied across tumor subtypes. In contrast, carrying more risk alleles at rs2736100 (TERT) and at rs6010620 (RTEL1) was associated with older age at diagnosis (P = 6.2 × 10(-4) and P = 2.5 × 10(-4), respectively). These SNPs are risk factors for all glioma grades/histologies, and their association with age at diagnosis was consistent across tumor subgroups. CONCLUSIONS: Carrying a greater number of risk alleles might be expected to decrease age at diagnosis. However, glioma susceptibility conferred by variation in telomerase-related genes did not follow this pattern. This supports the hypothesis that telomerase-related mechanisms of telomere maintenance are more associated with gliomas that develop later in life than those utilizing telomerase-independent mechanisms (ie, alternative lengthening of telomeres).


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Encefálicas/patologia , DNA Helicases/genética , Glioma/patologia , Polimorfismo de Nucleotídeo Único/genética , Telomerase/genética , Adulto , Fatores Etários , Idoso , Neoplasias Encefálicas/genética , Estudos de Casos e Controles , Feminino , Seguimentos , Predisposição Genética para Doença , Genótipo , Glioma/genética , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Prognóstico , Fatores de Risco
12.
Clin Cancer Res ; 19(8): 2144-53, 2013 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-23468058

RESUMO

PURPOSE: Mammographic breast density (MBD) is decreased by tamoxifen, but the effect of aromatase inhibitors is less clear. EXPERIMENTAL DESIGN: We enrolled early-stage postmenopausal patients with breast cancer initiating adjuvant aromatase inhibitor therapy and ascertained mammograms before and at an average 10 months of aromatase inhibitor therapy. We matched cases to healthy postmenopausal women (controls) from a large mammography screening cohort on age, baseline body mass index, baseline MBD, and interval between mammograms. We estimated change in MBD using a computer-assisted thresholding program (Cumulus) and compared differences between cases and matched controls. RESULTS: In predominantly White women (96%), we found 14% of the 387 eligible cases had a MBD reduction of at least 5% after an average of 10 months of aromatase inhibitor therapy. MBD reductions were associated with higher baseline MBD, aromatase inhibitor use for more than 12 months, and prior postmenopausal hormone use. Comparing each case with her matched control, there was no evidence of an association of change in MBD with aromatase inhibitor therapy [median case-control difference among 369 pairs was -0.1% (10th and 90th percentile: -5.9%, 5.2%) P = 0.51]. Case-control differences were similar by type of aromatase inhibitor (P's 0.41 and 0.56); prior use of postmenopausal hormones (P = 0.85); baseline MBD (P = 0.55); and length of aromatase inhibitor therapy (P = 0.08). CONCLUSIONS: In postmenopausal women treated with aromatase inhibitors, 14% of cases had a MBD reduction of more than 5%, but these decreases did not differ from matched controls. These data suggest that MBD is not a clinically useful biomarker for predicting the value of aromatase inhibitor therapy in White postmenopausal women.


Assuntos
Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/tratamento farmacológico , Mamografia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Quimioterapia Adjuvante , Feminino , Humanos , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Pós-Menopausa , Saúde da Mulher/estatística & dados numéricos
13.
Neuro Oncol ; 15(5): 535-41, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23361564

RESUMO

INTRODUCTION: Recent discoveries of inherited glioma risk loci and acquired IDH mutations are providing new insights into glioma etiology. IDH mutations are common in lower grade gliomas and secondary glioblastomas and uncommon in primary glioblastomas. Because the inherited variant in 11q23 has been associated with risk of lower grade glioma and not with glioblastomas, we hypothesized that this variant increases susceptibility to IDH-mutated gliomas, but not to IDH-wild-type gliomas. METHODS: We tested this hypothesis in patients with glioma and controls from the San Francisco Adult Glioma Study, the Mayo Clinic, and Illumina controls (1102 total patients, 5299 total controls). Case-control additive associations of 11q23 risk alleles (rs498872, T allele) were calculated using logistic regression, stratified by tumor IDH status (mutated or wild-type) and by histology and grade. We also adjusted for the recently discovered 8q24 glioma risk locus rs55705857 G allele. RESULTS: The 11q23 glioma risk locus was associated with increased risk of IDH-mutated gliomas of all histologies and grades (odds ratio [OR] = 1.50; 95% confidence interval [CI] = 1.29-1.74; P = 1.3X10(-7)) but not with IDH-wild-type gliomas of any histology or grade (OR = 0.91; 95% CI = 0.81-1.03; P = 0.14). The associations were independent of the rs55705857 G allele. CONCLUSION: A variant at the 11q23 locus increases risk for IDH-mutated but not IDH-wild-type gliomas, regardless of grade or histology.


Assuntos
Neoplasias Encefálicas/genética , Cromossomos Humanos Par 11/genética , Predisposição Genética para Doença , Glioma/genética , Isocitrato Desidrogenase/genética , Mutação/genética , Adulto , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/patologia , Estudos de Casos e Controles , Cromossomos Humanos Par 8/genética , Feminino , Glioma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Polimorfismo de Nucleotídeo Único/genética , Prognóstico
14.
Cancer ; 119(3): 586-92, 2013 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-22915053

RESUMO

BACKGROUND: Increasing evidence shows chemotherapy in combination with vascular endothelial growth factor (VEGF) inhibition is a clinically active therapy for patients with metastatic melanoma (MM). METHODS: A phase 2 trial was conducted in chemotherapy-naive patients with unresectable stage IV MM who were randomized to temozolomide (200 mg/m(2) on days 1 through 5) and bevacizumab (10 mg/kg intravenously on days 1 and 15) every 28 days (Regimen TB) or nab-paclitaxel (100 mg/m(2) , or 80 mg/m(2) post-addendum 5 secondary to toxicity, on days 1, 8, and 15), bevacizumab (10 mg/kg on days 1 and 15), and carboplatin (area under the curve [AUC] 6 on day 1, or AUC 5 post-addendum 5) every 28 days (Regimen ABC). Accrual goal was 41 patients per regimen. The primary aim of this study was to estimate progression-free survival rate at 6 months (PFS6) in each regimen. A regimen would be considered promising if its PFS6 rate was > 60%. RESULTS: Ninety-three eligible patients (42 TB and 51 ABC) were enrolled. The majority of patients had M1c disease (20 TB and 26 ABC). The median PFS and overall survival times with ABC were 6.7 months and 13.9 months, respectively. Median PFS time and median overall survival with TB were 3.8 months and 12.3 months, respectively. The most common severe toxicities (≥ grade 3) in both regimens were cytopenias, fatigue, and thrombosis. Among the first 41 patients enrolled onto each regimen, PFS6 rate was 32.8% (95% confidence interval: 21.1%-51.2%) for TB and 56.1% (90% confidence interval: 44.7%-70.4%) for ABC. CONCLUSIONS: The addition of bevacizumab to nab-paclitaxel and carboplatin shows promising activity despite tolerability issues.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Albuminas/administração & dosagem , Albuminas/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Dacarbazina/administração & dosagem , Dacarbazina/efeitos adversos , Dacarbazina/análogos & derivados , Feminino , Humanos , Masculino , Melanoma/mortalidade , Melanoma/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Análise de Sobrevida , Temozolomida , Resultado do Tratamento , Adulto Jovem
15.
Nat Genet ; 44(10): 1122-5, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22922872

RESUMO

Variants at 8q24.21 have been shown to be associated with glioma development. By means of tag SNP genotyping and imputation, pooled next-generation sequencing using long-range PCR and subsequent validation SNP genotyping, we identified seven low-frequency SNPs at 8q24.21 that were strongly associated with glioma risk (P=1×10(-25) to 1×10(-14)). The most strongly associated SNP, rs55705857, remained highly significant after individual adjustment for the other top six SNPs and two previously published SNPs. After stratifying by histological and tumor genetic subtype, the most significant associations of rs55705857 were with oligodendroglial tumors and gliomas with mutant IDH1 or IDH2 (odds ratio (OR)=5.1, P=1.1×10(-31) and OR=4.8, P=6.6×10(-22), respectively). Strong associations were observed for astrocytomas with mutated IDH1 or IDH2 (grades 2-4) (OR=5.16-6.66, P=4.7×10(-12) to 2.2×10(-8)) but not for astrocytomas with wild-type IDH1 and IDH2 (smallest P=0.26). The conserved sequence block that includes rs55705857 is consistently modeled as a microRNA.


Assuntos
Astrocitoma/genética , Cromossomos Humanos Par 8 , Predisposição Genética para Doença , Isocitrato Desidrogenase/genética , Oligodendroglioma/genética , Adulto , Idoso , Astrocitoma/enzimologia , Estudos de Casos e Controles , Feminino , Frequência do Gene , Estudos de Associação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Pessoa de Meia-Idade , Oligodendroglioma/enzimologia , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Análise de Sequência de DNA
16.
Clin Cancer Res ; 18(11): 3154-62, 2012 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-22472174

RESUMO

PURPOSE: Glioblastoma is a devastating, incurable disease with few known prognostic factors. Here, we present the first genome-wide survival and validation study for glioblastoma. EXPERIMENTAL DESIGN: Cox regressions for survival with 314,635 inherited autosomal single-nucleotide polymorphisms (SNP) among 315 San Francisco Adult Glioma Study patients for discovery and three independent validation data sets [87 Mayo Clinic, 232 glioma patients recruited from several medical centers in Southeastern United States (GliomaSE), and 115 The Cancer Genome Atlas patients] were used to identify SNPs associated with overall survival for Caucasian glioblastoma patients treated with the current standard of care, resection, radiation, and temozolomide (total n = 749). Tumor expression of the gene that contained the identified prognostic SNP was examined in three separate data sets (total n = 619). Genotype imputation was used to estimate hazard ratios (HR) for SNPs that had not been directly genotyped. RESULTS: From the discovery and validation analyses, we identified a variant in single-stranded DNA-binding protein 2 (SSBP2) on 5q14.1 associated with overall survival in combined analyses (HR, 1.64; P = 1.3 × 10(-6)). Expression of SSBP2 in tumors from three independent data sets also was significantly related to patient survival (P = 5.3 × 10(-4)). Using genotype imputation, the SSBP2 SNP rs17296479 had the strongest statistically significant genome-wide association with poorer overall patient survival (HR, 1.79; 95% CI, 1.45-2.22; P = 1.0 × 10(-7)). CONCLUSION: The minor allele of SSBP2 SNP rs17296479 and the increased tumor expression of SSBP2 were statistically significantly associated with poorer overall survival among glioblastoma patients. With further confirmation, previously unrecognized inherited variations influencing survival may warrant inclusion in clinical trials to improve randomization. Unaccounted for genetic influence on survival could produce unwanted bias in such studies.


Assuntos
Neoplasias Encefálicas/genética , Proteínas de Ligação a DNA/genética , Glioblastoma/genética , Polimorfismo de Nucleotídeo Único , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/terapia , Dacarbazina/análogos & derivados , Dacarbazina/uso terapêutico , Feminino , Estudo de Associação Genômica Ampla , Glioblastoma/mortalidade , Glioblastoma/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Temozolomida
17.
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
18.
Cancer Genet ; 204(1): 13-8, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21356187

RESUMO

Two recent genome-wide association studies reported that single nucleotide polymorphisms (SNPs) in (or near) TERT (5p15), CCDC26 (8q24), CDKN2A/B (9p21), PHLDB1 (11q23), and RTEL1 (20q13) are associated with infiltrating glioma. From these reports, it was not clear whether the single nucleotide polymorphism associations predispose to glioma in general or whether they are specific to certain glioma grades or morphologic subtypes. To identify hypothesized associations between susceptibility loci and tumor subtype, we genotyped two case-control groups composed of the spectrum of infiltrating glioma subtypes and stratified the analyses by type. We report that specific germ line polymorphisms are associated with different glioma subtypes. CCDC26 (8q24) region polymorphisms are strongly associated with oligodendroglial tumor risk (rs4295627, odds ratio [OR] = 2.05, P = 8.3 × 10(-11)) but not glioblastoma risk. The opposite is true of RTEL (20q13) region polymorphisms, which are significantly associated with glioblastoma (rs2297440, OR = 0.56, P = 4.6 × 10(-10)) but not oligodendroglial tumor. The SNPs in or near CCDC26 (8q24) are associated with oligodendroglial tumors regardless of combined 1p and 19q deletion status; however, the association is greatest for those with combined deletion (rs4295627, OR = 2.77, P = 2.6 × 10(-9)). These observations generate hypotheses concerning the possible mechanisms by which specific SNPs (or alterations in linkage disequilibrium with such SNPs) are associated with glioma development.


Assuntos
Neoplasias Encefálicas/genética , Glioma/genética , Polimorfismo Genético , Adulto , Alelos , Estudos de Casos e Controles , Deleção Cromossômica , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 19/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Genótipo , Glioblastoma/genética , Humanos , Masculino , Razão de Chances
19.
Carcinogenesis ; 31(10): 1770-7, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20668009

RESUMO

To determine whether inherited variations in immune function single-nucleotide polymorphisms (SNPs), genes or pathways affect glioblastoma risk, we analyzed data from recent genome-wide association studies in conjunction with predefined immune function genes and pathways. Gene and pathway analyses were conducted on two independent data sets using 6629 SNPs in 911 genes on 17 immune pathways from 525 glioblastoma cases and 602 controls from the University of California, San Francisco (UCSF) and a subset of 6029 SNPs in 893 genes from 531 cases and 1782 controls from MD Anderson (MDA). To further assess consistency of SNP-level associations, we also compared data from the UK (266 cases and 2482 controls) and the Mayo Clinic (114 cases and 111 controls). Although three correlated epidermal growth factor receptor (EGFR) SNPs were consistently associated with glioblastoma in all four data sets (Mantel-Haenzel P values = 1 × 10⁻5 to 4 × 10⁻³), independent replication is required as genome-wide significance was not attained. In gene-level analyses, eight immune function genes were significantly (minP < 0.05) associated with glioblastoma; the IL-2RA (CD25) cytokine gene had the smallest minP values in both UCSF (minP = 0.01) and MDA (minP = 0.001) data sets. The IL-2RA receptor is found on the surface of regulatory T cells potentially contributing to immunosuppression characteristic of the glioblastoma microenvironment. In pathway correlation analyses, cytokine signaling and adhesion-extravasation-migration pathways showed similar associations with glioblastoma risk in both MDA and UCSF data sets. Our findings represent the first systematic description of immune genes and pathways that characterize glioblastoma risk.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/imunologia , Glioblastoma/genética , Glioblastoma/imunologia , Polimorfismo de Nucleotídeo Único , Adulto , Neoplasias Encefálicas/etiologia , Citocinas/genética , Feminino , Estudo de Associação Genômica Ampla , Glioblastoma/etiologia , Humanos , Masculino , Transdução de Sinais
20.
PLoS One ; 5(1): e8884, 2010 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-20111712

RESUMO

BACKGROUND: We previously identified a panel of genes associated with outcome of ovarian cancer. The purpose of the current study was to assess whether variants in these genes correlated with ovarian cancer risk. METHODS AND FINDINGS: Women with and without invasive ovarian cancer (749 cases, 1,041 controls) were genotyped at 136 single nucleotide polymorphisms (SNPs) within 13 candidate genes. Risk was estimated for each SNP and for overall variation within each gene. At the gene-level, variation within MSL1 (male-specific lethal-1 homolog) was associated with risk of serous cancer (p = 0.03); haplotypes within PRPF31 (PRP31 pre-mRNA processing factor 31 homolog) were associated with risk of invasive disease (p = 0.03). MSL1 rs7211770 was associated with decreased risk of serous disease (OR 0.81, 95% CI 0.66-0.98; p = 0.03). SNPs in MFSD7, BTN3A3, ZNF200, PTPRS, and CCND1A were inversely associated with risk (p<0.05), and there was increased risk at HEXIM1 rs1053578 (p = 0.04, OR 1.40, 95% CI 1.02-1.91). CONCLUSIONS: Tumor studies can reveal novel genes worthy of follow-up for cancer susceptibility. Here, we found that inherited markers in the gene encoding MSL1, part of a complex that modifies the histone H4, may decrease risk of invasive serous ovarian cancer.


Assuntos
Predisposição Genética para Doença , Neoplasias Ovarianas/genética , Idoso , Estudos de Casos e Controles , Feminino , Haplótipos , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Recidiva
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