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1.
J Infect Dis ; 220(10): 1609-1619, 2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31536132

RESUMO

BACKGROUND: Human papillomaviruses (HPV) cause over 500 000 cervical cancers each year, most of which occur in low-resource settings. Human papillomavirus genotyping is important to study natural history and vaccine efficacy. We evaluated TypeSeq, a novel, next-generation, sequencing-based assay that detects 51 HPV genotypes, in 2 large international epidemiologic studies. METHODS: TypeSeq was evaluated in 2804 cervical specimens from the Study to Understand Cervical Cancer Endpoints and Early Determinants (SUCCEED) and in 2357 specimens from the Costa Rica Vaccine Trial (CVT). Positive agreement and risks of precancer for individual genotypes were calculated for TypeSeq in comparison to Linear Array (SUCCEED). In CVT, positive agreement and vaccine efficacy were calculated for TypeSeq and SPF10-LiPA. RESULTS: We observed high overall and positive agreement for most genotypes between TypeSeq and Linear Array in SUCCEED and SPF10-LiPA in CVT. There was no significant difference in risk of precancer between TypeSeq and Linear Array in SUCCEED or in estimates of vaccine efficacy between TypeSeq and SPF10-LiPA in CVT. CONCLUSIONS: The agreement of TypeSeq with Linear Array and SPF10-LiPA, 2 well established standards for HPV genotyping, demonstrates its high accuracy. TypeSeq provides high-throughput, affordable HPV genotyping for world-wide studies of cervical precancer risk and of HPV vaccine efficacy.

2.
Sci Rep ; 9(1): 9916, 2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31289279

RESUMO

Genetic susceptibility is likely involved in nasopharyngeal carcinoma (NPC), a cancer caused by Epstein-Barr virus (EBV) infection. Understanding of genetic factors involved in NPC and how they contribute to EBV-induced carcinogenesis is limited. We conducted whole-exome capture/sequencing among 251 individuals from 97 multiplex families from Taiwan (205 affected, 21 obligate carriers, and 25 unaffected) using SeqCap EZ Human Exome Library v3.0 and Illumina HiSeq. Aligned sequences were filtered to identify likely-to-be-functional deleterious variants that co-segregated with disease. Ingenuity Pathway analysis was performed. Circulating magnesium levels were measured in 13 individuals in 2 families with NIPAL1 mutations and in 197 sporadic NPC cases and 237 controls. We identified variants in 12 genes likely involved in cancer pathogenesis, viral infection or immune responses to infection. These included genes postulated to be involved in magnesium transport (NIPAL1), EBV cell entry (ITGB6), modulation of EBV infection (BCL2L12, NEDD4L), telomere biology (CLPTM1L, BRD2, HNRNPU), modulation of cAMP signaling (RAPGEF3), DNA repair (PRKDC, MLH1), and Notch signaling (NOTCH1, DLL3). Pathway based analysis demonstrated enrichment for Notch signaling genes (p-value = 0.0006). Evaluation of individuals within NIPAL1 families suggested lower serum magnesium in NPC compared to unaffected members. A significant reduction in serum magnesium levels was observed among sporadic NPC cases compared to controls (7.1% NPC/1.7% controls below normal range; OR = 4.5; 95% CI = 1.4,14) and is consistent with findings demonstrating a role for magnesium channeling in T-cell responses to EBV. We identified novel genes associated with NPC that point to new areas of inquiry to better understand genetic factors that determine the fate of viral infections and/or otherwise predisposes to NPC.

3.
Cancer Epidemiol Biomarkers Prev ; 28(10): 1682-1686, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31270100

RESUMO

BACKGROUND: Genetic susceptibility is associated with nasopharyngeal carcinoma (NPC). We previously identified rare variants potentially involved in familial NPC and common variants significantly associated with sporadic NPC. METHODS: We conducted targeted gene sequencing of 20 genes [16 identified from the study of multiplex families, three identified from a pooled analysis of NPC genome-wide association study (GWAS), and one identified from both studies] among 819 NPC cases and 938 controls from two case-control studies in Taiwan (independent from previous studies). A targeted, multiplex PCR primer panel was designed using the custom Ion AmpliSeq Designer v4.2 targeting the regions of the selected genes. Gene-based and single-variant tests were conducted. RESULTS: We found that NPC was associated with combined common and rare variants in CDKN2A/2B (P = 1.3 × 10-4), BRD2 (P = 1.6 × 10-3), TNFRSF19 (P = 4.0 × 10-3), and CLPTM1L/TERT (P = 5.4 × 10-3). Such associations were likely driven by common variants within these genes, based on gene-based analyses evaluating common variants and rare variants separately (e.g., for common variants of CDKN2A/2B, P = 4.6 × 10-4; for rare variants, P = 0.04). We also observed a suggestive association with rare variants in HNRNPU (P = 3.8 × 10-3) for NPC risk. In addition, we validated four previously reported NPC risk-associated SNPs. CONCLUSIONS: Our findings confirm previously reported associated variants and suggest that some common variants in genes previously linked to familial NPC are associated with the development of sporadic NPC. IMPACT: NPC-associated genes, including CLPTM1L/TERT, BRD2, and HNRNPU, suggest a role for telomere length maintenance in NPC etiology.

4.
BMC Bioinformatics ; 20(1): 389, 2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31299914

RESUMO

BACKGROUND: Human papillomavirus (HPV) is a common sexually transmitted infection associated with cervical cancer that frequently occurs as a coinfection of types and subtypes. Highly similar sublineages that show over 100-fold differences in cancer risk are not distinguishable in coinfections with current typing methods. RESULTS: We describe an efficient set of computational tools, rkmh, for analyzing complex mixed infections of related viruses based on sequence data. rkmh makes extensive use of MinHash similarity measures, and includes utilities for removing host DNA and classifying reads by type, lineage, and sublineage. We show that rkmh is capable of assigning reads to their HPV type as well as HPV16 lineage and sublineages. CONCLUSIONS: Accurate read classification enables estimates of percent composition when there are multiple infecting lineages or sublineages. While we demonstrate rkmh for HPV with multiple sequencing technologies, it is also applicable to other mixtures of related sequences.


Assuntos
Coinfecção/diagnóstico , Coinfecção/virologia , Biologia Computacional/métodos , Papillomavirus Humano 16/fisiologia , Software , DNA Viral/genética , Papillomavirus Humano 16/classificação , Humanos , Infecções por Papillomavirus/virologia , Filogenia , Análise de Sequência de DNA , Fatores de Tempo
5.
Eur J Hum Genet ; 27(10): 1589-1598, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31231134

RESUMO

Renal cell carcinoma (RCC) has an undisputed genetic component and a stable 2:1 male to female sex ratio in its incidence across populations, suggesting possible sexual dimorphism in its genetic susceptibility. We conducted the first sex-specific genome-wide association analysis of RCC for men (3227 cases, 4916 controls) and women (1992 cases, 3095 controls) of European ancestry from two RCC genome-wide scans and replicated the top findings using an additional series of men (2261 cases, 5852 controls) and women (1399 cases, 1575 controls) from two independent cohorts of European origin. Our study confirmed sex-specific associations for two known RCC risk loci at 14q24.2 (DPF3) and 2p21(EPAS1). We also identified two additional suggestive male-specific loci at 6q24.3 (SAMD5, male odds ratio (ORmale) = 0.83 [95% CI = 0.78-0.89], Pmale = 1.71 × 10-8 compared with female odds ratio (ORfemale) = 0.98 [95% CI = 0.90-1.07], Pfemale = 0.68) and 12q23.3 (intergenic, ORmale = 0.75 [95% CI = 0.68-0.83], Pmale = 1.59 × 10-8 compared with ORfemale = 0.93 [95% CI = 0.82-1.06], Pfemale = 0.21) that attained genome-wide significance in the joint meta-analysis. Herein, we provide evidence of sex-specific associations in RCC genetic susceptibility and advocate the necessity of larger genetic and genomic studies to unravel the endogenous causes of sex bias in sexually dimorphic traits and diseases like RCC.

6.
PLoS Genet ; 15(3): e1008027, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30849090

RESUMO

Populations in sub-Saharan Africa have historically been exposed to intense selection from chronic infection with falciparum malaria. Interestingly, populations with the highest malaria intensity can be identified by the increased occurrence of endemic Burkitt Lymphoma (eBL), a pediatric cancer that affects populations with intense malaria exposure, in the so called "eBL belt" in sub-Saharan Africa. However, the effects of intense malaria exposure and sub-Saharan populations' genetic histories remain poorly explored. To determine if historical migrations and intense malaria exposure have shaped the genetic composition of the eBL belt populations, we genotyped ~4.3 million SNPs in 1,708 individuals from Ghana and Northern Uganda, located on opposite sides of eBL belt and with ≥ 7 months/year of intense malaria exposure and published evidence of high incidence of BL. Among 35 Ghanaian tribes, we showed a predominantly West-Central African ancestry and genomic footprints of gene flow from Gambian and East African populations. In Uganda, the North West population showed a predominantly Nilotic ancestry, and the North Central population was a mixture of Nilotic and Southern Bantu ancestry, while the Southwest Ugandan population showed a predominant Southern Bantu ancestry. Our results support the hypothesis of diverse ancestral origins of the Ugandan, Kenyan and Tanzanian Great Lakes African populations, reflecting a confluence of Nilotic, Cushitic and Bantu migrations in the last 3000 years. Natural selection analyses suggest, for the first time, a strong positive selection signal in the ATP2B4 gene (rs10900588) in Northern Ugandan populations. These findings provide important baseline genomic data to facilitate disease association studies, including of eBL, in eBL belt populations.


Assuntos
Linfoma de Burkitt/genética , Fluxo Gênico , Malária Falciparum/genética , Seleção Genética , Adolescente , África ao Sul do Saara , Idoso , Linfoma de Burkitt/epidemiologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Doenças Endêmicas , Feminino , Genética Populacional , Estudo de Associação Genômica Ampla , Gana/epidemiologia , Migração Humana , Humanos , Incidência , Lactente , Recém-Nascido , Malária Falciparum/epidemiologia , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , ATPases Transportadoras de Cálcio da Membrana Plasmática/genética , Polimorfismo de Nucleotídeo Único , Uganda/epidemiologia
7.
J Clin Microbiol ; 57(5)2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30814267

RESUMO

We have developed a new human papillomavirus (HPV) genotyping assay for detection of 51 HPV genotypes by next-generation sequencing (NGS). The TypeSeq assay consists of 3 PCR steps that equalize viral load and each type's amplicon copies prior to genotyping by NGS, thereby maximizing multiple-type sensitivity with minimal sequencing reads. The analytical sensitivity of the TypeSeq assay is 10 copies per reaction for 49 of the 51 types, including 13 high-risk (HR) types. We tested 863 clinical cervical specimens previously evaluated with the Roche Linear Array HPV genotyping test (LA). TypeSeq achieved 94.4% positive agreement with LA for detection of any HR type. Positive agreement was 91.4% and 85.5% for HPV16 and HPV18, respectively. Low-risk (LR) types ranged from 40.0% positive agreement (HPV83) to 90.9% (HPV69). Our unique approach to HPV amplification achieved a multiple-type sensitivity comparable to that of LA, with 83.9% and 84.2% of specimens positive for multiple HPV types by TypeSeq or LA, respectively. A total of 48.2% of specimens showed perfect agreement for all 37 types common to both assays. The simplicity of our open-source TypeSeq assay allows for high-throughput yet scalable processing, with a single technician able to process up to 768 specimens within 3 days. By leveraging NGS sample multiplexing capabilities, the per-sample labor requirements are greatly reduced compared to those of traditional genotyping methods. These features and the broad spectrum of detectable types make TypeSeq highly suitable for a wide range of applications.

8.
Papillomavirus Res ; 7: 67-74, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30738204

RESUMO

BACKGROUND: Human papillomavirus (HPV)16 can be separated into genetic sub-lineages (A1-4, B1-4, C1-4, D1-4) which may have differential cervical cancer risk. METHODS: A next-generation sequencing assay was used to whole-genome sequence 7116 HPV16-positive cervical samples from well-characterised international epidemiological studies, including 2076 controls, 1878 squamous cell carcinoma (SCC) and 186 adenocarcinoma/adenosquamous cell carcinoma (ADC), and to assign HPV16 sub-lineage. Logistic regression was used to estimate region-stratified country-adjusted odds ratios (OR) and 95%CI. RESULTS: A1 was the most globally widespread sub-lineage, with others showing stronger regional specificity (A3 and A4 for East Asia, B1-4 and C1-4 for Africa, D2 for the Americas, B4, C4 and D4 for North Africa). Increased cancer risks versus A1 were seen for A3, A4 and D (sub)lineages in regions where they were common: A3 in East Asia (OR=2.2, 95%CI:1.0-4.7); A4 in East Asia (6.6, 3.1-14.1) and North America (3.8, 1.7-8.3); and D in North (6.2, 4.1-9.3) and South/Central America (2.2, 0.8-5.7), where D lineages were also more frequent in ADC than SCC (3.2, 1.5-6.5; 12.1, 5.7-25.6, respectively). CONCLUSIONS: HPV16 genetic variation can strongly influence cervical cancer risk. However, burden of cervical cancer attributable to different sub-lineages worldwide is largely driven by historical HPV16 sub-lineage dispersal.

9.
PLoS Med ; 16(1): e1002724, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30605491

RESUMO

BACKGROUND: Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation. METHODS AND FINDINGS: Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval [CI] 1.44-1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40-1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44-1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30-2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11-1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84-1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose. CONCLUSIONS: This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk.


Assuntos
Carcinoma de Células Renais/etiologia , Neoplasias Renais/etiologia , Obesidade/complicações , Glicemia/análise , Pressão Sanguínea , Índice de Massa Corporal , Carcinoma de Células Renais/genética , Diabetes Mellitus Tipo 2/complicações , Feminino , Marcadores Genéticos , Estudo de Associação Genômica Ampla , Humanos , Insulina/sangue , Neoplasias Renais/genética , Lipídeos/sangue , Masculino , Análise da Randomização Mendeliana , Obesidade/genética , Fatores de Risco
10.
Cancer Res ; 2018 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-30510122

RESUMO

Mosaic loss of the Y chromosome (mLOY) in peripheral leukocytes is a somatic event in which a fraction of leukocytes have lost the entire Y chromosome. The frequency of mLOY increases with age and may reflect poor genomic maintenance as well as clonal imbalances in normal immune function, making mLOY an attractive candidate marker for cancer risk. Here we investigated the relationship between mLOY and incident cancer in a large sample of 207,603 cancer-free men from the UK Biobank in which 13,895 men developed an incident solid tumor during follow-up. We identified mLOY by scanning for deviations in genotyping array log R intensity ratios (LRR) across the male-specific chromosome Y region. Overall, we detected low proportions of cells with mLOY in 3,358 (1.6%) men and high proportions of mLOY in 524 (0.3%) men. We found an association of mLOY with overall solid tumor incidence using both low and high mLOY thresholds (HRlow=1.18, 95% CIlow=1.07-1.30, P-valuelow=0.001; HRhigh=1.36, 95% CIhigh=1.09-1.71, P-valuehigh=0.007) and more specifically we observed an association with lung cancer (HRhigh=2.25, 95% CIhigh=1.36-3.71, P-valuehigh=0.002). Stronger associations were observed without adjustment for smoking, suggesting that smoking is an important confounder of tumor incidence. It is unlikely that mLOY is a major mediator of the effect of cigarette smoking on cancer risk, as mLOY was observed in only a small fraction of smokers who developed cancer. In summary, mLOY was modestly associated with incidence of solid tumors in the UK Biobank, although for some cancer subtypes these findings may reflect residual confounding by smoking.

12.
Nat Commun ; 9(1): 4182, 2018 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-30305637

RESUMO

Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is a rare, chronic B-cell lymphoma with high heritability. We conduct a two-stage genome-wide association study of WM/LPL in 530 unrelated cases and 4362 controls of European ancestry and identify two high-risk loci associated with WM/LPL at 6p25.3 (rs116446171, near EXOC2 and IRF4; OR = 21.14, 95% CI: 14.40-31.03, P = 1.36 × 10-54) and 14q32.13 (rs117410836, near TCL1; OR = 4.90, 95% CI: 3.45-6.96, P = 8.75 × 10-19). Both risk alleles are observed at a low frequency among controls (~2-3%) and occur in excess in affected cases within families. In silico data suggest that rs116446171 may have functional importance, and in functional studies, we demonstrate increased reporter transcription and proliferation in cells transduced with the 6p25.3 risk allele. Although further studies are needed to fully elucidate underlying biological mechanisms, together these loci explain 4% of the familial risk and provide insights into genetic susceptibility to this malignancy.

13.
Int J Cancer ; 143(10): 2359-2366, 2018 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-30152087

RESUMO

Glioblastoma (GBM) is the most common malignant brain tumor in the United States. Incidence of GBM increases with age, and younger age-at-diagnosis is significantly associated with improved prognosis. While the relationship between candidate GBM risk SNPs and age-at-diagnosis has been explored, genome-wide association studies (GWAS) have not previously been stratified by age. Potential age-specific genetic effects were assessed in autosomal SNPs for GBM patients using data from four previous GWAS. Using age distribution tertiles (18-53, 54-64, 65+) datasets were analyzed using age-stratified logistic regression to generate p values, odds ratios (OR), and 95% confidence intervals (95%CI), and then combined using meta-analysis. There were 4,512 total GBM cases, and 10,582 controls used for analysis. Significant associations were detected at two previously identified SNPs in 7p11.2 (rs723527 [p54-63 = 1.50x10-9 , OR54-63 = 1.28, 95%CI54-63 = 1.18-1.39; p64+ = 2.14x10-11 , OR64+ = 1.32, 95%CI64+ = 1.21-1.43] and rs11979158 [p54-63 = 6.13x10-8 , OR54-63 = 1.35, 95%CI54-63 = 1.21-1.50; p64+ = 2.18x10-10 , OR64+ = 1.42, 95%CI64+ = 1.27-1.58]) but only in persons >54. There was also a significant association at the previously identified lower grade glioma (LGG) risk locus at 8q24.21 (rs55705857) in persons ages 18-53 (p18-53 = 9.30 × 10-11 , OR18-53 = 1.76, 95%CI18-53 = 1.49-2.10). Within The Cancer Genome Atlas (TCGA) there was higher prevalence of 'LGG'-like tumor characteristics in GBM samples in those 18-53, with IDH1/2 mutation frequency of 15%, as compared to 2.1% [54-63] and 0.8% [64+] (p = 0.0005). Age-specific differences in cancer susceptibility can provide important clues to etiology. The association of a SNP known to confer risk for IDH1/2 mutant glioma and higher prevalence of IDH1/2 mutation within younger individuals 18-53 suggests that more younger individuals may present initially with 'secondary glioblastoma.'

14.
Neuro Oncol ; 2018 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-30124908

RESUMO

Background: To date, genome-wide association studies (GWAS) have identified 25 risk variants for glioma, explaining 30% of heritable risk. Most histologies occur with significantly higher incidence in males, and this difference is not explained by currently-known risk factors. A previous GWAS identified sex-specific glioma risk variants, and this analysis aims to further elucidate risk variation by sex using gene- and pathway-based approaches. Methods: Results from the Glioma International Case-Control Study were used as a testing set, and results from three GWAS were combined via meta-analysis and used as a validation set. Using summary statistics for nominally significant autosomal SNPs (p<0.01 in a previous meta-analysis) and nominally significant X-chromosome SNPs (p<0.01), three algorithms (Pascal, BimBam, and GATES) were used to generate gene-scores, and Pascal was used to generate pathway-scores. Results were considered statistically significant in the discovery set when p<3.3x10-6 and in the validation set when p<0.001 in 2/3 algorithms. Results: 25 genes within 5 regions and 19 genes within 6 regions reached statistical significance in at least 2/3 algorithms in males and females, respectively. EGFR was significantly associated with all glioma and glioblastoma in males only, and a female-specific association in TERT, all of which remained nominally significant after conditioning on known risk loci. There were nominal associations with the Biocarta telomeres pathway in both males and females. Conclusions: These results provide additional evidence that there may be differences by sex in genetic risk for glioma. Additional analyses may further elucidate the biological processes through which this risk is conferred.

15.
Nat Commun ; 9(1): 3184, 2018 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-30093639

RESUMO

Ewing sarcoma (EWS) is a pediatric cancer characterized by the EWSR1-FLI1 fusion. We performed a genome-wide association study of 733 EWS cases and 1346 unaffected individuals of European ancestry. Our study replicates previously reported susceptibility loci at 1p36.22, 10q21.3 and 15q15.1, and identifies new loci at 6p25.1, 20p11.22 and 20p11.23. Effect estimates exhibit odds ratios in excess of 1.7, which is high for cancer GWAS, and striking in light of the rarity of EWS cases in familial cancer syndromes. Expression quantitative trait locus (eQTL) analyses identify candidate genes at 6p25.1 (RREB1) and 20p11.23 (KIZ). The 20p11.22 locus is near NKX2-2, a highly overexpressed gene in EWS. Interestingly, most loci reside near GGAA repeat sequences and may disrupt binding of the EWSR1-FLI1 fusion protein. The high locus to case discovery ratio from 733 EWS cases suggests a genetic architecture in which moderate risk SNPs constitute a significant fraction of risk.

16.
Sci Rep ; 8(1): 12316, 2018 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-30120341

RESUMO

Mosaic loss of the Y chromosome (mLOY) is the most commonly reported large structural somatic event. Previous studies have indicated age and cigarette smoking increase the risk of mLOY, but the relationship of other exposures with mLOY and mLOY with disease has not been adequately investigated. We characterized mLOY in a large cohort of 223,338 men from the UK Biobank by scanning for deviations in genotyping array median log2 intensity ratios (mLRR) of the Y chromosome using a standard algorithm. A total of 3,789 (1.7%) men showed evidence for mLOY (mLRR < -0.15). In multivariable-adjusted logistic regression models, we found that mLOY increases exponentially with age (overall P-value < 4.9 × 10-324; p-value for the quadratic term = 2.1 × 10-7), and observed a strong association with current smoking (P-value = 7.8 × 10-184). We observed less mLOY in men of African ancestry (0.4%) compared to men of European ancestry (1.8%, P-value = 0.003). Although mLOY was not associated with prevalent cancer (P-value = 0.61), associations were observed for diabetes (P-value = 0.003) and cardiovascular disease (P-value = 0.01). Using Cox proportional hazards regression models, mLOY was associated with all-cause mortality among men with a high proportion of cells affected (mLRR < -0.40; HR = 1.35, 95% CI = 1.08-1.70, P-value = 0.009). In conclusion, mLOY was associated with several health-related factors as well as with all-cause mortality. Further functional studies are warranted to understand how and in what way mLOY could influence adult male health.

17.
Biol Blood Marrow Transplant ; 24(10): 2003-2008, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29879518

RESUMO

Studies of chromosomal aberrations in blood or bone marrow of patients with Fanconi anemia (FA) have focused on their associations with leukemic transformation. The role of such abnormalities on outcomes after hematopoietic cell transplantation (HCT) is unclear. We used genome-wide single nucleotide polymorphism arrays to identify chromosomal aberrations in pre-HCT blood samples from 73 patients with FA who received unrelated donor HCT for severe aplastic anemia between 1991 and 2007. Outcome data and blood samples were available through the Center for International Blood and Marrow Transplant Research. For survival analyses, we used the Kaplan-Meier estimator to calculate the survival probabilities and the exact log-rank test to compare the survival differences across groups. Chromosomal aberrations were detected in 16 (22%) patients; most frequent were clonal copy loss in chromosome 7 (9.6%), clonal copy gains in the long arm (q) of chromosome 1 (chr1q+) (8.2%), and clonal or complete copy gains in the q arm of chromosome 3 (chr3q+) (8.2%). Seven (9.6%) patients had alterations in 3 or more chromosomes. Poor post-HCT overall survival (OS) was noted in patients with chr3q+ (P = .04), or those with abnormalities in ≥3 chromosomes (P = .03). The 1-year OS was 0% versus 45% in patients with either alteration versus its absence. No statistically significant differences in OS were noted in patients carrying deletions in chr7 (1-year OS = 29% versus 42%; log-rank P = .74). The study is limited by the small sample size. A larger, prospective study is warranted to validate our findings in light of recent improvement in transplant modalities and outcomes.

18.
Sci Rep ; 8(1): 7352, 2018 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-29743610

RESUMO

Incidence of glioma is approximately 50% higher in males. Previous analyses have examined exposures related to sex hormones in women as potential protective factors for these tumors, with inconsistent results. Previous glioma genome-wide association studies (GWAS) have not stratified by sex. Potential sex-specific genetic effects were assessed in autosomal SNPs and sex chromosome variants for all glioma, GBM and non-GBM patients using data from four previous glioma GWAS. Datasets were analyzed using sex-stratified logistic regression models and combined using meta-analysis. There were 4,831 male cases, 5,216 male controls, 3,206 female cases and 5,470 female controls. A significant association was detected at rs11979158 (7p11.2) in males only. Association at rs55705857 (8q24.21) was stronger in females than in males. A large region on 3p21.31 was identified with significant association in females only. The identified differences in effect of risk variants do not fully explain the observed incidence difference in glioma by sex.

19.
Br J Haematol ; 181(5): 604-613, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29687880

RESUMO

Recurrent large-scale somatic copy number alterations (SCNAs), and somatic point mutations can be analysed to stratify patients with chronic lymphocytic leukaemia (CLL) into distinct prognostic groups. To investigate the relationship between SCNAs and somatic mutations, we performed whole-exome sequencing and single nucleotide polymorphism microarray analyses on 98 CLL patients from 40 families with a high burden of CLL. Overall, 69 somatic mutations in 29 CLL driver genes were detected among 45 subjects (46%), with the most frequently mutated genes being TP53 (8·2%), NOTCH1 (8·2%) and ATM (5·1%). Additionally, 142 SCNAs from 54 subjects (57%) were detected, including losses of chromosome 13q14 (28·9%), 11q (5·6%), 17p (2·1%), and gain of chromosome 12 (4·2%). We found that patients having both an adverse point mutation in a CLL driver gene and an unfavourable SCNA tended to have poorer survival (Hazard ratio [HR] = 3·17, 95% confidence interval [CI] = 0·97-10·35; P = 0·056) than patients having either a point mutation (HR = 1·34, 95%CI = 0·66-2·71; P = 0·42) or SCNAs (HR = 2·65, 95%CI = 0·77-9·13; P = 0·12). TP53 mutation carriers were associated with the poorest overall survival (HR = 4·39, 95%CI = 1·28-15·04; P = 0·018). Our study suggests that combining SCNA and mutational data could contribute to predicting outcome in familial CLL.

20.
BMC Genomics ; 19(1): 182, 2018 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-29510662

RESUMO

BACKGROUND: The recommended genomic DNA input requirements for whole genome single nucleotide polymorphism microarrays can limit the scope of molecular epidemiological studies. We performed a large-scale evaluation of whole genome amplified DNA as input into high-density, whole-genome Illumina® Infinium® SNP microarray. RESULTS: Overall, 6622 DNA samples from 5970 individuals were obtained from three distinct biospecimen sources and genotyped using gDNA and/or wgaDNA inputs. When genotypes from the same individual were compared with standard, native gDNA input amount, we observed 99.94% mean concordance with wgaDNA input. CONCLUSIONS: Our results demonstrate that carefully conducted studies with wgaDNA inputs can yield high-quality genotyping results. These findings should enable investigators to consider expansion of ongoing studies using high-density SNP microarrays, currently challenged by small amounts of available DNA.


Assuntos
DNA/genética , Genoma Humano , Mucosa Bucal/metabolismo , Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Saliva/metabolismo , DNA/análise , DNA/sangue , Genômica , Genótipo , Humanos , Neoplasias/sangue , Técnicas de Amplificação de Ácido Nucleico , Análise de Sequência com Séries de Oligonucleotídeos/métodos
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