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1.
AIDS ; 33(13): 2091-2096, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31335808

RESUMO

OBJECTIVES: Zidovudine (ZDV) is a nucleoside reverse transcriptase inhibitor that could cause telomere shortening through inhibition of telomerase. We examined the association between in utero exposure to ZDV and telomere length at birth in HIV-exposed-uninfected (HEU) newborns. METHODS: We selected 94 ZDV-exposed HEU children and 85 antiretroviral therapy (ART)-unexposed HEU children from the Surveillance Monitoring for ART Toxicities Study and the Women and Infants Transmission Study. We assessed relative telomere length in stored peripheral blood mononuclear cells taken in the first 7 days of life using quantitative polymerase chain reaction. We used linear regression to compare relative telomere length between ZDV-exposed and ART-unexposed children. We additionally evaluated relative telomere length according to maternal and infant characteristics. RESULTS: Relative telomere length was longer in ZDV-exposed children compared with ART-unexposed individuals (adjusted mean ratio difference 0.21, 95% confidence interval 0.15-0.28, P < 0.001). We found an inverse correlation between maternal HIV RNA levels and infant relative telomere length (-0.06 per log10 copies, 95% confidence interval -0.08 to -0.03, P < 0.001). Relative telomere length was not associated with maternal CD4 cell count, maternal age, gestational age, sex, sample storage time, or maternal substance use (P > 0.05). CONCLUSION: Relative telomere length was longer in ZDV-exposed infants. This difference may reflect beneficial health effects of ART during pregnancy, as we observed an inverse association with maternal HIV RNA levels.

2.
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.

3.
J Hum Genet ; 64(6): 545-550, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30850729

RESUMO

Mosaic protein truncating variants (PTVs) in the phosphatase, Mg2+/Mn2+dependent 1D (PPM1D) gene in blood-derived DNA have been associated with increased risk of breast cancer. We analyzed PPM1D PTVs in blood from 3817 breast cancer cases and 3058 controls by deep sequencing of a previously defined region in exon 6 of PPM1D. We identified 50 of 6875 (0.73%) participants having a mosaic PPM1D PTV. We observed a higher frequency of mosaic PPM1D PTVs with increasing age (Ptrend = 2.9 × 10-6). We did not observe an overall association between PPM1D PTVs and increased breast cancer risk (OR = 1.51, 95% CI = 0.84-2.71). Evidence for an association was observed in a subset of cases with DNA collected 1-year or more before breast cancer diagnosis (OR = 3.44, 95% CI = 1.62-7.30, P-value = 0.001); however, no significant association was observed for the larger series of cases with DNA collected post diagnosis (OR = 1.01, 95% CI = 0.51-2.01, P-value = 0.98). Our study indicates that the PPM1D PTVs are present at higher rates than previously reported and the frequency of PPM1D PTVs increases with age. We observed limited evidence for an association between mosaic PPM1D PTVs and breast cancer risk, suggesting mosaic PPM1D PTVs in the blood likely do not influence risk of breast cancer.


Assuntos
Envelhecimento/genética , Neoplasias da Mama/genética , Predisposição Genética para Doença , Proteína Fosfatase 2C/genética , Idoso , Envelhecimento/patologia , Neoplasias da Mama/patologia , Éxons , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Pessoa de Meia-Idade , Mutação , Fatores de Risco
4.
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
5.
Curr Opin Oncol ; 31(2): 108-113, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30585859

RESUMO

PURPOSE OF REVIEW: Genetic mosaicism is the presence of a somatic mutation in a subset of cells that differs from the inherited germline genome. Detectable genetic mosaicism is attractive as a potential early biomarker for cancer risk because of its established relationship with aging, introduction of potentially deleterious mutations, and clonal selection and expansion of mutated cells. The aim of this review is to survey shared risk factors associated with genetic mosaicism, aging and cancer risk. RECENT FINDINGS: Studies have associated aging, cigarette smoking and several genetic susceptibility loci with increased risk of acquiring genetic mosaicism. Genetic mosaicism has also been associated with numerous outcomes including cancer risk and cancer mortality; however, the level of evidence supporting these associations varies considerably. SUMMARY: Ample evidence exists for shared risk factors for genetic mosaicism and cancer risk as well as abundant support linking genetic mosaicism in leukocytes to hematologic malignancies. The relationship between genetic mosaicism in circulating leukocytes and solid malignancies remains an active area of research.

6.
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.

8.
Artigo em Inglês | MEDLINE | ID: mdl-30377209

RESUMO

BACKGROUND: Given the inverse relationship previously described between telomere content and thyroid subsequent malignant neoplasm (thyroid SMN) in survivors of childhood cancer, we investigated the relationship between known genetic determinants of leukocyte telomere length and thyroid SMN among survivors. METHODS: Leveraging data from a large, genotyped survivor cohort, the Childhood Cancer Survivor Study, we used a well-described genetic risk score method to estimate the hazard ratio for thyroid SMN among 5,324 genotyped survivors. RESULTS: We identified 118 survivors with thyroid SMN and 5,206 without thyroid SMN. No association between genetically-estimated leukocyte telomere length and risk for thyroid SMN was identified. CONCLUSIONS: Our results suggest that variation in common SNPs influencing leukocyte telomere length is not strongly associated with risk for thyroid SMN in survivors of childhood cancer. IMPACT: The previously-observed inverse relationship between leukocyte telomere length and thyroid SMN risk in survivors of childhood cancer may be related to alternative molecular mechanisms, and warrants further study.

9.
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.

10.
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.

12.
Bioinformatics ; 34(5): 887-889, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28968746

RESUMO

Motivation: Existing approaches to plot association results from genome-wide association studies (GWAS) are in the form of static Manhattan plots and often lack data integration with rich databases on variant regulatory potential as well as population-specific linkage disequilibrium patterns. Summary: We created an intuitive web module for uploading and efficiently exploring GWAS association results. Interactive plots and sortable tables allow researchers to query genomic regions of interest, facilitating the integration of data on linkage disequilibrium, variant regulatory potential and potential target genes. External links allow for visualization of association results in the UCSC genome browser as well as easy access to publically available databases (e.g. dbSNP and RegulomeDB). Through improved visualization and data integration, LDassoc offers genomic researchers a specialized environment to examine association signals and suggests variants for functional investigation. Availability and implementation: LDassoc is a free and publically available web tool which can be accessed online at https://analysistools.nci.nih.gov/LDlink/? tab=ldassoc. Contact: mitchell.machiela@nih.gov.


Assuntos
Bases de Dados Genéticas , Estudo de Associação Genômica Ampla/métodos , Desequilíbrio de Ligação , Polimorfismo Genético , Software , Genômica/métodos , Humanos , Grupos Populacionais
13.
Sci Rep ; 7(1): 16954, 2017 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-29209073

RESUMO

Multiple omic profiles have been generated for many cancer types; however, comprehensive assessment of their prognostic values across cancers is limited. We conducted a pan-cancer prognostic assessment and presented a multi-omic kernel machine learning method to systematically quantify the prognostic values of high-throughput genomic, epigenomic, and transcriptomic profiles individually, integratively, and in combination with clinical factors for 3,382 samples across 14 cancer types. We found that the prognostic performance varied substantially across cancer types. mRNA and miRNA expression profile frequently performed the best, followed by DNA methylation profile. Germline susceptibility variants displayed low prognostic performance consistently across cancer types. The integration of omic profiles with clinical variables can lead to substantially improved prognostic performance over the use of clinical variables alone in half of cancer types examined. Moreover, we showed that the kernel machine learning method consistently outperformed existing prognostic signatures, suggesting that including a large number of omic biomarkers may provide substantial improvement in prognostic assessment. Our study provides a comprehensive portrait of omic architecture for tumor prognosis across cancers, and highlights the prognostic value of genome-wide omic biomarker aggregation, which may facilitate refined prognostic assessment in the era of precision oncology.

14.
Hum Mol Genet ; 26(22): 4388-4394, 2017 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-28973384

RESUMO

Recent studies have reported a higher than anticipated frequency of large clonal autosomal mosaic events >2 Mb in size in the aging population. Mosaic events are detected from analyses of intensity parameters of linear stretches with deviations in heterozygous probes of single nucleotide polymorphism microarrays. The non-random distribution of detected mosaic events throughout the genome suggests common mechanisms could influence the formation of mosaic events. Here we use publicly available data tracks from the University of California Santa Cruz Genome Browser to investigate the genomic characteristics of the regions at the terminal ends of two frequent types of large structural mosaic events: telomeric neutral events and interstitial losses. We observed breakpoints are more likely to occur in regions enriched for open chromatin, increased gene density, elevated meiotic recombination rates and in the proximity of repetitive elements. These observations suggest that detected mosaic event breakpoints are preferentially recovered in genomic regions that are observed to be active and thus more accessible to environmental exposures and events related to gene transcription. We propose that errors in DNA repair pathways, such as non-homologous end joining and homologous recombination, may be important cellular mechanisms that lead to the formation of large structural mosaic events such as interstitial losses and copy neutral events that include telomeres. Further studies using next generation sequencing technologies should be instrumental in mapping the specific junctions of mosaic events to the nucleotide and provide insights into the molecular mechanisms responsible for clonal somatic structural events.


Assuntos
Quebra Cromossômica , Cromossomos Humanos , Cromatina , Quebras de DNA , Variações do Número de Cópias de DNA , Bases de Dados de Ácidos Nucleicos , Genoma Humano , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Mosaicismo , Polimorfismo de Nucleotídeo Único , Recombinação Genética
15.
J Natl Cancer Inst ; 109(11)2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-29059430

RESUMO

Background: Childhood cancer survivors treated with chest-directed radiotherapy have substantially elevated risk for developing breast cancer. Although genetic susceptibility to breast cancer in the general population is well studied, large-scale evaluation of breast cancer susceptibility after chest-directed radiotherapy for childhood cancer is lacking. Methods: We conducted a genome-wide association study of breast cancer in female survivors of childhood cancer, pooling two cohorts with detailed treatment data and systematic, long-term follow-up: the Childhood Cancer Survivor Study and St. Jude Lifetime Cohort. The study population comprised 207 survivors who developed breast cancer and 2774 who had not developed any subsequent neoplasm as of last follow-up. Genotyping and subsequent imputation yielded 16 958 466 high-quality variants for analysis. We tested associations in the overall population and in subgroups stratified by receipt of lower than 10 and 10 or higher gray breast radiation exposure. We report P values and pooled per-allele risk estimates from Cox proportional hazards regression models. All statistical tests were two-sided. Results: Among survivors who received 10 or higher gray breast radiation exposure, a locus on 1q41 was associated with subsequent breast cancer risk (rs4342822, nearest gene PROX1 , risk allele frequency in control subjects [RAF controls ] = 0.46, hazard ratio = 1.92, 95% confidence interval = 1.49 to 2.44, P = 7.09 × 10 -9 ). Two rare variants also showed potentially promising associations (breast radiation ≥10 gray: rs74949440, 11q23, TAGLN , RAF controls = 0.02, P = 5.84 × 10 -8 ; <10 gray: rs17020562, 1q32.3, RPS6KC1 , RAF controls = 0.0005, P = 6.68 × 10 -8 ). Associations were restricted to these dose subgroups, with consistent findings in the two survivor cohorts. Conclusions: Our study provides strong evidence that germline genetics outside high-risk syndromes could modify the effect of radiation exposure on breast cancer risk after childhood cancer.


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Proteínas de Homeodomínio/genética , Proteínas dos Microfilamentos/genética , Proteínas Musculares/genética , Neoplasias Induzidas por Radiação/genética , Segunda Neoplasia Primária/genética , Proteínas Quinases S6 Ribossômicas/genética , Proteínas Supressoras de Tumor/genética , Adolescente , Adulto , Mama/efeitos da radiação , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Doença de Hodgkin/radioterapia , Humanos , Lactente , Leucemia/radioterapia , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Dosagem Radioterapêutica , Estudos Retrospectivos , Sobreviventes , Adulto Jovem , Quinases raf/genética
16.
Eur Urol ; 72(5): 747-754, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28797570

RESUMO

BACKGROUND: Relative telomere length in peripheral blood leukocytes has been evaluated as a potential biomarker for renal cell carcinoma (RCC) risk in several studies, with conflicting findings. OBJECTIVE: We performed an analysis of genetic variants associated with leukocyte telomere length to assess the relationship between telomere length and RCC risk using Mendelian randomization, an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations. DESIGN, SETTING, AND PARTICIPANTS: Genotypes from nine telomere length-associated variants for 10 784 cases and 20 406 cancer-free controls from six genome-wide association studies (GWAS) of RCC were aggregated into a weighted genetic risk score (GRS) predictive of leukocyte telomere length. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Odds ratios (ORs) relating the GRS and RCC risk were computed in individual GWAS datasets and combined by meta-analysis. RESULTS AND LIMITATIONS: Longer genetically inferred telomere length was associated with an increased risk of RCC (OR=2.07 per predicted kilobase increase, 95% confidence interval [CI]:=1.70-2.53, p<0.0001). As a sensitivity analysis, we excluded two telomere length variants in linkage disequilibrium (R2>0.5) with GWAS-identified RCC risk variants (rs10936599 and rs9420907) from the telomere length GRS; despite this exclusion, a statistically significant association between the GRS and RCC risk persisted (OR=1.73, 95% CI=1.36-2.21, p<0.0001). Exploratory analyses for individual histologic subtypes suggested comparable associations with the telomere length GRS for clear cell (N=5573, OR=1.93, 95% CI=1.50-2.49, p<0.0001), papillary (N=573, OR=1.96, 95% CI=1.01-3.81, p=0.046), and chromophobe RCC (N=203, OR=2.37, 95% CI=0.78-7.17, p=0.13). CONCLUSIONS: Our investigation adds to the growing body of evidence indicating some aspect of longer telomere length is important for RCC risk. PATIENT SUMMARY: Telomeres are segments of DNA at chromosome ends that maintain chromosomal stability. Our study investigated the relationship between genetic variants associated with telomere length and renal cell carcinoma risk. We found evidence suggesting individuals with inherited predisposition to longer telomere length are at increased risk of developing renal cell carcinoma.


Assuntos
Carcinoma de Células Renais/genética , Neoplasias Renais/genética , Polimorfismo de Nucleotídeo Único , Homeostase do Telômero , Telômero/genética , Carcinoma de Células Renais/sangue , Carcinoma de Células Renais/patologia , Estudos de Casos e Controles , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Neoplasias Renais/sangue , Neoplasias Renais/patologia , Leucócitos/química , Análise da Randomização Mendeliana , Razão de Chances , Fenótipo , Medição de Risco , Fatores de Risco , Telômero/patologia
17.
Nat Commun ; 8: 15724, 2017 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-28598434

RESUMO

Previous genome-wide association studies (GWAS) have identified six risk loci for renal cell carcinoma (RCC). We conducted a meta-analysis of two new scans of 5,198 cases and 7,331 controls together with four existing scans, totalling 10,784 cases and 20,406 controls of European ancestry. Twenty-four loci were tested in an additional 3,182 cases and 6,301 controls. We confirm the six known RCC risk loci and identify seven new loci at 1p32.3 (rs4381241, P=3.1 × 10-10), 3p22.1 (rs67311347, P=2.5 × 10-8), 3q26.2 (rs10936602, P=8.8 × 10-9), 8p21.3 (rs2241261, P=5.8 × 10-9), 10q24.33-q25.1 (rs11813268, P=3.9 × 10-8), 11q22.3 (rs74911261, P=2.1 × 10-10) and 14q24.2 (rs4903064, P=2.2 × 10-24). Expression quantitative trait analyses suggest plausible candidate genes at these regions that may contribute to RCC susceptibility.


Assuntos
Carcinoma de Células Renais/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Neoplasias Renais/genética , Adolescente , Adulto , Idoso , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Loci Gênicos , Mutação em Linhagem Germinativa , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Adulto Jovem
18.
Cancer Res ; 77(13): 3666-3671, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28446466

RESUMO

Cancer treatments composed of immune checkpoint inhibitors and oncogene-targeted drugs might improve cancer management, but there has been little investigation of their combined potential as yet. To estimate the fraction of cancer cases that might benefit from such combination therapy, we conducted an exploratory study of cancer genomic datasets to determine the proportion with somatic mutation profiles amenable to either immunotherapy or targeted therapy. We surveyed 13,349 genomic profiles from public databases for cases with specific mutations targeted by current agents or a burden of exome-wide nonsynonymous mutations (NsM) that exceed a proposed threshold for response to checkpoint inhibitors. Overall, 8.9% of cases displayed profiles that could benefit from combination therapy, which corresponded to approximately 11.2% of U.S. annual incident cancer cases. Frequently targetable mutations were in PIK3CA, BRAF, NF1, NRAS, and PTEN We also noted a high burden of NsM in cases with targetable mutations in SMO, DDR2, FGFR1, PTCH1, FGFR2, and MET Our results indicate that a significant proportion of solid tumor patients are eligible for immuno-targeted combination therapy, and they suggest prioritizing specific cancers for trials of certain targeted and checkpoint inhibitor drugs. Cancer Res; 77(13); 3666-71. ©2017 AACR.


Assuntos
Imunoterapia/métodos , Neoplasias/terapia , Terapia Combinada , Humanos , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/imunologia
19.
J Hum Genet ; 62(6): 637-640, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28275244

RESUMO

Studies have suggested mosaic loss of chromosome Y (mLOY) in blood-derived DNA is common in older men. Cohort studies investigating mLOY and mortality have reported contradictory results. Previous work found that a 1.6 Mb deletion of the AZFc region on the Y chromosome (the 'gr/gr' deletion) is associated with both male infertility and increased risk of testicular germ cell tumors (TGCT). We investigated whether mosaic loss across the entire Y chromosome was associated with TGCT. We obtained blood- and buccal-derived DNA from two case-control studies: the NCI Familial Testicular Cancer Study (cases=172; controls=163) and the NCI US Servicemen's Testicular Tumor Environmental and Endocrine Determinants Study (cases=506; controls=611). We used 15 quantitative polymerase chain reactions spanning the Y chromosome to assess mLOY. Multivariate logistic regression models adjusted for study batch effects detected no significant overall relationship between mean chromosome Y target-to-reference (T/R) ratio and TGCT (odds ratio=0.34, 95% confidence interval=0.10-1.17, P=0.09). When restricted to familial TGCT cases, a significantly lower T/R ratio was observed in cases compared with controls (0.993 vs 1.014, P-value=0.01). Our study suggests that mLOY, as measured by 15 probes spanning the Y chromosome, could be associated with familial TGCT, but larger studies are required to confirm this observation.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Y/genética , Infertilidade Masculina/genética , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Testiculares/genética , Adulto , Estudos de Coortes , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Infertilidade Masculina/patologia , Masculino , Mosaicismo , Neoplasias Embrionárias de Células Germinativas/patologia , Fatores de Risco , Neoplasias Testiculares/patologia
20.
Curr Opin Genet Dev ; 42: 8-13, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28068559

RESUMO

Clonal mosaicism arises when a postzygotic mutational event is detectable in subpopulations of cells as an alternative genotype while not present in the germline genome. Although described in a subset of pediatric disorders, new genomic technologies have detected higher than anticipated frequencies of clonal mosaicism in adult population studies, stimulating investigation as to how clonal mosaicism could contribute to chronic human diseases, such as cancer, diabetes and neurodegenerative disorders. It has also been postulated to be an important mechanism for functional cellular diversity, including the brain. Early studies have characterized the spectrum of detectable mosaic alterations and have begun to investigate whether detectable mosaicism could be important as an overall biomarker for risk or in the case of hematologic cancers, identification of preleukemic clones.


Assuntos
Envelhecimento/genética , Doença Crônica , Genoma Humano , Mosaicismo , Envelhecimento/patologia , Genótipo , Humanos , Mutação , Neoplasias/genética , Neoplasias/patologia , Polimorfismo de Nucleotídeo Único/genética
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