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1.
PLoS One ; 15(9): e0237792, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32881892

RESUMO

BACKGROUND: Ewing sarcoma (EwS) is a rare, aggressive solid tumor of childhood, adolescence and young adulthood associated with pathognomonic EWSR1-ETS fusion oncoproteins altering transcriptional regulation. Genome-wide association studies (GWAS) have identified 6 common germline susceptibility loci but have not investigated low-frequency inherited variants with minor allele frequencies below 5% due to limited genotyped cases of this rare tumor. METHODS: We investigated the contribution of rare and low-frequency variation to EwS susceptibility in the largest EwS genome-wide association study to date (733 EwS cases and 1,346 unaffected controls of European ancestry). RESULTS: We identified two low-frequency variants, rs112837127 and rs2296730, on chromosome 20 that were associated with EwS risk (OR = 0.186 and 2.038, respectively; P-value < 5×10-8) and located near previously reported common susceptibility loci. After adjusting for the most associated common variant at the locus, only rs112837127 remained a statistically significant independent signal (OR = 0.200, P-value = 5.84×10-8). CONCLUSIONS: These findings suggest rare variation residing on common haplotypes are important contributors to EwS risk. IMPACT: Motivate future targeted sequencing studies for a comprehensive evaluation of low-frequency and rare variation around common EwS susceptibility loci.


Assuntos
Loci Gênicos , Predisposição Genética para Doença , Variação Genética , Células Germinativas/metabolismo , Sarcoma de Ewing/genética , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação/genética , Razão de Chances , Polimorfismo de Nucleotídeo Único/genética
2.
Int J Cancer ; 147(10): 2677-2686, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32363580

RESUMO

HPV35 has been found in only ∼2% of invasive cervical cancers (ICC) worldwide but up to 10% in Sub-Saharan Africa, warranting further investigation and consideration of impact on preventive strategies. We studied HPV35 and ethnicity, in relation to the known steps in cervical carcinogenesis, using multiple large epidemiologic studies in the U.S. and internationally. Combining five U.S. studies, we measured HPV35 positivity and, in Northern California, observed HPV35 type-specific population prevalence and estimated 5-year risk of developing precancer when HPV35-positive. HPV35 genetic variation was examined for differences in carcinogenicity in 1053 HPV35+ cervical specimens from a U.S. cohort and an international collection. African-American women had more HPV35 (12.1% vs 5.1%, P < .001) and more HPV35-associated precancers (7.4% vs 2.1%, P < .001) compared to other ethnicities. Precancer risks after HPV35 infection did not vary by ethnicity (global P = .52). The HPV35 A2 sublineage showed an increased association with precancer/cancer in African-Americans (OR = 5.6 vs A1, 95% CI = 1.3-24.8) and A2 was more prevalent among ICC in Africa than other world regions (41.9% vs 10.4%, P < .01). Our analyses support a strong link between HPV35 and cervical carcinogenesis in women of African ancestry. Current HPV vaccines cover the majority of cervical precancer/cancer across all ethnic groups; additional analyses are required to determine whether the addition of HPV35 to the already highly effective nine-valent HPV vaccine would provide better protection for women in Africa or of African ancestry.

3.
Nat Commun ; 11(1): 886, 2020 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-32060290

RESUMO

HPV16 causes half of cervical cancers worldwide; for unknown reasons, most infections resolve within two years. Here, we analyze the viral genomes of 5,328 HPV16-positive case-control samples to investigate mutational signatures and the role of human APOBEC3-induced mutations in viral clearance and cervical carcinogenesis. We identify four de novo mutational signatures, one of which matches the COSMIC APOBEC-associated signature 2. The viral genomes of the precancer/cancer cases are less likely to contain within-host somatic HPV16 APOBEC3-induced mutations (Fisher's exact test, P = 6.2 x 10-14), and have a 30% lower nonsynonymous APOBEC3 mutation burden compared to controls. We replicate the low prevalence of HPV16 APOBEC3-induced mutations in 1,749 additional cases. APOBEC3 mutations also historically contribute to the evolution of HPV16 lineages. We demonstrate that cervical infections with a greater burden of somatic HPV16 APOBEC3-induced mutations are more likely to be benign or subsequently clear, suggesting they may reduce persistence, and thus progression, within the host.


Assuntos
Citidina Desaminase/metabolismo , Genoma Viral , Papillomavirus Humano 16/genética , Infecções por Papillomavirus/enzimologia , Adulto , Estudos de Casos e Controles , Colo do Útero/virologia , Citidina Desaminase/genética , Feminino , Interações Hospedeiro-Patógeno , Papillomavirus Humano 16/fisiologia , Humanos , Pessoa de Meia-Idade , Mutação , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/virologia , Neoplasias do Colo do Útero/enzimologia , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/virologia
4.
Am J Hum Genet ; 106(2): 264-271, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-32004448

RESUMO

Severe aplastic anemia (SAA) is a rare disorder characterized by hypoplastic bone marrow and progressive pancytopenia. The etiology of acquired SAA is not understood but is likely related to abnormal immune responses and environmental exposures. We conducted a genome-wide association study of individuals with SAA genetically matched to healthy controls in discovery (359 cases, 1,396 controls) and validation sets (175 cases, 1,059 controls). Combined analyses identified linked SNPs in distinct blocks within the major histocompatibility complex on 6p21. The top SNP encodes p.Met76Val in the P4 binding pocket of the HLA class II gene HLA-DPB1 (rs1042151A>G, odds ratio [OR] 1.75, 95% confidence interval [CI] 1.50-2.03, p = 1.94 × 10-13) and was associated with HLA-DP cell surface expression in healthy individuals (p = 2.04 × 10-6). Phylogenetic analyses indicate that Val76 is not monophyletic and likely occurs in conjunction with different HLA-DP binding groove conformations. Imputation of HLA-DPB1 alleles revealed increased risk of SAA associated with Val76-encoding alleles DPB1∗03:01, (OR 1.66, p = 1.52 × 10-7), DPB1∗10:01 (OR 2.12, p = 0.0003), and DPB1∗01:01 (OR 1.60, p = 0.0008). A second SNP near HLA-B, rs28367832G>A, reached genome-wide significance (OR 1.49, 95% CI 1.22-1.78, p = 7.27 × 10-9) in combined analyses; the association remained significant after excluding cases with clonal copy-neutral loss-of-heterozygosity affecting class I HLA genes (8.6% of cases and 0% of controls). SNPs in the HLA class II gene HLA-DPB1 and possibly class I (HLA-B) are associated with SAA. The replacement of Met76 to Val76 in certain HLA-DPB1 alleles might influence risk of SAA through mechanisms involving DP peptide binding specificity, expression, and/or other factors affecting DP function.


Assuntos
Anemia Aplástica/etiologia , Marcadores Genéticos , Predisposição Genética para Doença , Cadeias beta de HLA-DP/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idoso , Anemia Aplástica/patologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Filogenia , Fatores de Risco , Índice de Gravidade de Doença , Adulto Jovem
5.
Eur J Hum Genet ; 27(10): 1589-1598, 2019 10.
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.


Assuntos
Carcinoma de Células Renais/epidemiologia , Carcinoma de Células Renais/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Neoplasias Renais/epidemiologia , Neoplasias Renais/genética , Biologia Computacional , Feminino , Humanos , Masculino , Razão de Chances , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Fatores Sexuais
6.
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.


Assuntos
Perfilação da Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Sarcoma de Ewing/genética , Alelos , Proteínas de Ciclo Celular/genética , Proliferação de Células/genética , Proteínas de Ligação a DNA/genética , Grupo com Ancestrais do Continente Europeu , Regulação Neoplásica da Expressão Gênica , Genótipo , Proteínas de Homeodomínio/genética , Humanos , Proteínas de Fusão Oncogênica/genética , Polimorfismo de Nucleotídeo Único , Proteína Proto-Oncogênica c-fli-1/genética , Controle de Qualidade , Locos de Características Quantitativas , Proteína EWS de Ligação a RNA/genética , Risco , Sarcoma de Ewing/etnologia , Fatores de Transcrição/genética , Proteínas de Peixe-Zebra
7.
Br J Haematol ; 181(5): 604-613, 2018 06.
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.


Assuntos
Cromossomos Humanos/genética , Variações do Número de Cópias de DNA , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/mortalidade , Proteínas de Neoplasias/genética , Mutação Puntual , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Taxa de Sobrevida
8.
Cell ; 170(6): 1164-1174.e6, 2017 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-28886384

RESUMO

Although most cervical human papillomavirus type 16 (HPV16) infections become undetectable within 1-2 years, persistent HPV16 causes half of all cervical cancers. We used a novel HPV whole-genome sequencing technique to evaluate an exceptionally large collection of 5,570 HPV16-infected case-control samples to determine whether viral genetic variation influences risk of cervical precancer and cancer. We observed thousands of unique HPV16 genomes; very few women shared the identical HPV16 sequence, which should stimulate a careful re-evaluation of the clinical implications of HPV mutation rates, transmission, clearance, and persistence. In case-control analyses, HPV16 in the controls had significantly more amino acid changing variants throughout the genome. Strikingly, E7 was devoid of variants in precancers/cancers compared to higher levels in the controls; we confirmed this in cancers from around the world. Strict conservation of the 98 amino acids of E7, which disrupts Rb function, is critical for HPV16 carcinogenesis, presenting a highly specific target for etiologic and therapeutic research.


Assuntos
Alphapapillomavirus/genética , Alphapapillomavirus/isolamento & purificação , Carcinoma/virologia , Infecções por Papillomavirus/virologia , Neoplasias do Colo do Útero/virologia , Adulto , Alphapapillomavirus/classificação , Estudos de Casos e Controles , Feminino , Genoma Viral , Humanos , Pessoa de Meia-Idade , Proteínas E7 de Papillomavirus/genética , Polimorfismo de Nucleotídeo Único , Adulto Jovem
9.
Sci Rep ; 7(1): 4642, 2017 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-28680059

RESUMO

Based on our initial genome-wide association study (GWAS) on esophageal squamous cell carcinoma (ESCC) in Han Chinese, we conducted a follow-up study to examine the single nucleotide polymorphisms (SNPs) associated with family history (FH) of upper gastrointestinal cancer (UGI) cancer in cases with ESCC. We evaluated the association between SNPs and FH of UGI cancer among ESCC cases in a stage-1 case-only analysis of the National Cancer Institute (NCI, 541 cases with FH and 1399 without FH) and Henan GWAS (493 cases with FH and 869 without FH) data (discovery phase). The top SNPs (or their surrogates) from discovery were advanced to a stage-2 evaluation in additional Henan subjects (2801 cases with FH and 3136 without FH, replication phase). A total of 19 SNPs were associated with FH of UGI cancer in ESCC cases with P < 10-5 in the stage-1 meta-analysis of NCI and Henan GWAS data. In stage-2, the association for rs79747906 (located at 18p11.31, P = 5.79 × 10-6 in discovery) was replicated (P = 0.006), with a pooled-OR of 1.59 (95%CI: 1.11-2.28). We identified potential genetic variants associated with FH of UGI cancer. Our findings may provide important insights into new low-penetrance susceptibility regions involved in the susceptibility of families with multiple UGI cancer cases.


Assuntos
Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Neoplasias Gastrointestinais/genética , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único , Grupo com Ancestrais do Continente Asiático/genética , China , Feminino , Seguimentos , Loci Gênicos , Predisposição Genética para Doença , Humanos , Masculino , Estadiamento de Neoplasias
10.
Front Oncol ; 6: 237, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27917368

RESUMO

Experimental and epidemiologic investigations suggest that certain pesticides may alter sex steroid hormone synthesis, metabolism or regulation, and the risk of hormone-related cancers. Here, we evaluated whether single-nucleotide polymorphisms (SNPs) involved in hormone homeostasis alter the effect of pesticide exposure on prostate cancer risk. We evaluated pesticide-SNP interactions between 39 pesticides and SNPs with respect to prostate cancer among 776 cases and 1,444 controls nested in the Agricultural Health Study cohort. In these interactions, we included candidate SNPs involved in hormone synthesis, metabolism or regulation (N = 1,100), as well as SNPs associated with circulating sex steroid concentrations, as identified by genome-wide association studies (N = 17). Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Multiplicative SNP-pesticide interactions were calculated using a likelihood ratio test. We translated p-values for interaction into q-values, which reflected the false discovery rate, to account for multiple comparisons. We observed a significant interaction, which was robust to multiple comparison testing, between the herbicide dicamba and rs8192166 in the testosterone metabolizing gene SRD5A1 (p-interaction = 4.0 × 10-5; q-value = 0.03), such that men with two copies of the wild-type genotype CC had a reduced risk of prostate cancer associated with low use of dicamba (OR = 0.62 95% CI: 0.41, 0.93) and high use of dicamba (OR = 0.44, 95% CI: 0.29, 0.68), compared to those who reported no use of dicamba; in contrast, there was no significant association between dicamba and prostate cancer among those carrying one or two copies of the variant T allele at rs8192166. In addition, interactions between two organophosphate insecticides and SNPs related to estradiol metabolism were observed to result in an increased risk of prostate cancer. While replication is needed, these data suggest both agonistic and antagonistic effects on circulating hormones, due to the combination of exposure to pesticides and genetic susceptibility, may impact prostate cancer risk.

12.
Haematologica ; 101(7): 853-60, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27365461

RESUMO

Hodgkin lymphoma shows strong familial aggregation but no major susceptibility genes have been identified to date. The goal of this study was to identify high-penetrance variants using whole exome sequencing in 17 Hodgkin lymphoma prone families with three or more affected cases or obligate carriers (69 individuals), followed by targeted sequencing in an additional 48 smaller HL families (80 individuals). Alignment and variant calling were performed using standard methods. Dominantly segregating, rare, coding or potentially functional variants were further prioritized based on predicted deleteriousness, conservation, and potential importance in lymphoid malignancy pathways. We selected 23 genes for targeted sequencing. Only the p.A1065T variant in KDR (kinase insert domain receptor) also known as VEGFR2 (vascular endothelial growth factor receptor 2) was replicated in two independent Hodgkin lymphoma families. KDR is a type III receptor tyrosine kinase, the main mediator of vascular endothelial growth factor induced proliferation, survival, and migration. Its activity is associated with several diseases including lymphoma. Functional experiments have shown that p.A1065T, located in the activation loop, can promote constitutive autophosphorylation on tyrosine in the absence of vascular endothelial growth factor and that the kinase activity was abrogated after exposure to kinase inhibitors. A few other promising mutations were identified but appear to be "private". In conclusion, in the largest sequenced cohort of Hodgkin lymphoma families to date, we identified a causal mutation in the KDR gene. While independent validation is needed, this mutation may increase downstream tumor cell proliferation activity and might be a candidate for targeted therapy.


Assuntos
Exoma , Estudos de Associação Genética , Predisposição Genética para Doença , Doença de Hodgkin/genética , Mutação , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Adulto , Biologia Computacional/métodos , Família , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Doença de Hodgkin/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Anotação de Sequência Molecular , Linhagem , Conformação Proteica , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/química , Adulto Jovem
13.
Hum Genet ; 135(11): 1241-1249, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27449771

RESUMO

The risk of pancreatic cancer (PC) is increased in melanoma-prone families but the causal relationship between germline CDKN2A mutations and PC risk is uncertain, suggesting the existence of non-CDKN2A factors. One genetic possibility involves patients having mutations in multiple high-risk PC-related genes; however, no systematic examination has yet been conducted. We used next-generation sequencing data to examine 24 putative PC-related genes in 43 PC patients with and 23 PC patients without germline CDKN2A mutations and 1001 controls. For each gene and the four pathways in which they occurred, we tested whether PC patients (overall or CDKN2A+ and CDKN2A- cases separately) had an increased number of rare nonsynonymous variants. Overall, we identified 35 missense variants in PC patients, 14 in CDKN2A+ and 21 in CDKN2A- PC cases. We found nominally significant associations for mismatch repair genes (MLH1, MSH2, MSH6, PMS2) in all PC patients and for ATM, CPA1, and PMS2 in CDKN2A- PC patients. Further, nine CDKN2A+ and four CDKN2A- PC patients had rare potentially deleterious variants in multiple PC-related genes. Loss-of-function variants were only observed in CDKN2A- PC patients, with ATM having the most pathogenic variants. Also, ATM variants (n = 5) were only observed in CDKN2A- PC patients with a family history that included digestive system tumors. Our results suggest that a subset of PC patients may have increased risk because of germline mutations in multiple PC-related genes.


Assuntos
Inibidor de Quinase Dependente de Ciclina p18/genética , Melanoma/genética , Proteínas de Neoplasias/genética , Neoplasias Pancreáticas/genética , Inibidor p16 de Quinase Dependente de Ciclina , Feminino , Predisposição Genética para Doença , Mutação em Linhagem Germinativa/genética , Humanos , Masculino , Melanoma/patologia , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/patologia , Linhagem , Fatores de Risco , Transdução de Sinais/genética , Neoplasias Cutâneas
14.
Nat Commun ; 7: 11843, 2016 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-27291797

RESUMO

To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP microarray intensity data of 38,303 women from cancer genome-wide association studies (20,878 cases and 17,425 controls) and detected 124 mosaic X events >2 Mb in 97 (0.25%) women. Here we show rates for X-chromosome mosaicism are four times higher than mean autosomal rates; X mosaic events more often include the entire chromosome and participants with X events more likely harbour autosomal mosaic events. X mosaicism frequency increases with age (0.11% in 50-year olds; 0.45% in 75-year olds), as reported for Y and autosomes. Methylation array analyses of 33 women with X mosaicism indicate events preferentially involve the inactive X chromosome. Our results provide further evidence that the sex chromosomes undergo mosaic events more frequently than autosomes, which could have implications for understanding the underlying mechanisms of mosaic events and their possible contribution to risk for chronic diseases.


Assuntos
Envelhecimento/genética , Cromossomos Humanos X/genética , Mosaicismo , Inativação do Cromossomo X/genética , Metilação de DNA/genética , Feminino , Humanos , Masculino , Reação em Cadeia da Polimerase , Reprodutibilidade dos Testes
15.
J Natl Cancer Inst ; 108(9)2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27130930

RESUMO

BACKGROUND: HPV16 is a common sexually transmitted infection although few infections lead to cervical precancer/cancer; we cannot distinguish nor mechanistically explain why only certain infections progress. HPV16 can be classified into four main evolutionary-derived variant lineages (A, B, C, D) that have been previously suggested to have varying disease risks. METHODS: We used a high-throughput HPV16 whole-genome sequencing assay to investigate variant lineage risk among 3215 HPV16-infected women. Using sublineages A1/A2 as the reference, we assessed all variant lineage associations with infection outcome over three or more years of follow-up: 1107 control subjects (

Assuntos
Carcinoma/virologia , Papillomavirus Humano 16/classificação , Papillomavirus Humano 16/genética , Infecções por Papillomavirus/virologia , Lesões Pré-Cancerosas/virologia , Neoplasias do Colo do Útero/virologia , Adenocarcinoma/etnologia , Adenocarcinoma/virologia , Adenocarcinoma in Situ/etnologia , Adenocarcinoma in Situ/virologia , Adulto , Assistência ao Convalescente , California/epidemiologia , Carcinoma/etnologia , Carcinoma de Células Escamosas/etnologia , Carcinoma de Células Escamosas/virologia , Neoplasia Intraepitelial Cervical/etnologia , Neoplasia Intraepitelial Cervical/virologia , Feminino , Genoma , Sequenciamento de Nucleotídeos em Larga Escala , Papillomavirus Humano 16/patogenicidade , Humanos , Pessoa de Meia-Idade , Infecções por Papillomavirus/etnologia , Filogenia , Lesões Pré-Cancerosas/etnologia , Fatores de Risco , Neoplasias do Colo do Útero/etnologia , Adulto Jovem
16.
Nat Commun ; 7: 10933, 2016 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-26956414

RESUMO

Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy with strong heritability. To further understand the genetic susceptibility for CLL and identify common loci associated with risk, we conducted a meta-analysis of four genome-wide association studies (GWAS) composed of 3,100 cases and 7,667 controls with follow-up replication in 1,958 cases and 5,530 controls. Here we report three new loci at 3p24.1 (rs9880772, EOMES, P=2.55 × 10(-11)), 6p25.2 (rs73718779, SERPINB6, P=1.97 × 10(-8)) and 3q28 (rs9815073, LPP, P=3.62 × 10(-8)), as well as a new independent SNP at the known 2q13 locus (rs9308731, BCL2L11, P=1.00 × 10(-11)) in the combined analysis. We find suggestive evidence (P<5 × 10(-7)) for two additional new loci at 4q24 (rs10028805, BANK1, P=7.19 × 10(-8)) and 3p22.2 (rs1274963, CSRNP1, P=2.12 × 10(-7)). Pathway analyses of new and known CLL loci consistently show a strong role for apoptosis, providing further evidence for the importance of this biological pathway in CLL susceptibility.


Assuntos
Grupo com Ancestrais do Continente Europeu/genética , Estudo de Associação Genômica Ampla , Leucemia Linfocítica Crônica de Células B/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Reguladoras de Apoptose/genética , Proteína 11 Semelhante a Bcl-2 , Predisposição Genética para Doença , Humanos , Proteínas de Membrana/genética , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas/genética , Serpinas/genética , Proteínas com Domínio T/genética
17.
Hum Mol Genet ; 25(8): 1663-76, 2016 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-27008888

RESUMO

Evidence from a small number of studies suggests that longer telomere length measured in peripheral leukocytes is associated with an increased risk of non-Hodgkin lymphoma (NHL). However, these studies may be biased by reverse causation, confounded by unmeasured environmental exposures and might miss time points for which prospective telomere measurement would best reveal a relationship between telomere length and NHL risk. We performed an analysis of genetically inferred telomere length and NHL risk in a study of 10 102 NHL cases of the four most common B-cell histologic types and 9562 controls using a genetic risk score (GRS) comprising nine telomere length-associated single-nucleotide polymorphisms. This approach uses existing genotype data and estimates telomere length by weighing the number of telomere length-associated variant alleles an individual carries with the published change in kb of telomere length. The analysis of the telomere length GRS resulted in an association between longer telomere length and increased NHL risk [four B-cell histologic types combined; odds ratio (OR) = 1.49, 95% CI 1.22-1.82,P-value = 8.5 × 10(-5)]. Subtype-specific analyses indicated that chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) was the principal NHL subtype contributing to this association (OR = 2.60, 95% CI 1.93-3.51,P-value = 4.0 × 10(-10)). Significant interactions were observed across strata of sex for CLL/SLL and marginal zone lymphoma subtypes as well as age for the follicular lymphoma subtype. Our results indicate that a genetic background that favors longer telomere length may increase NHL risk, particularly risk of CLL/SLL, and are consistent with earlier studies relating longer telomere length with increased NHL risk.


Assuntos
Estudos de Associação Genética/métodos , Predisposição Genética para Doença , Linfoma de Células B/genética , Linfoma de Células B/patologia , Telômero/patologia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
18.
Hum Mol Genet ; 25(3): 620-9, 2016 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-26732429

RESUMO

Genome-wide association studies (GWAS) of lung cancer in Asian never-smoking women have previously identified six susceptibility loci associated with lung cancer risk. To further discover new susceptibility loci, we imputed data from four GWAS of Asian non-smoking female lung cancer (6877 cases and 6277 controls) using the 1000 Genomes Project (Phase 1 Release 3) data as the reference and genotyped additional samples (5878 cases and 7046 controls) for possible replication. In our meta-analysis, three new loci achieved genome-wide significance, marked by single nucleotide polymorphism (SNP) rs7741164 at 6p21.1 (per-allele odds ratio (OR) = 1.17; P = 5.8 × 10(-13)), rs72658409 at 9p21.3 (per-allele OR = 0.77; P = 1.41 × 10(-10)) and rs11610143 at 12q13.13 (per-allele OR = 0.89; P = 4.96 × 10(-9)). These findings identified new genetic susceptibility alleles for lung cancer in never-smoking women in Asia and merit follow-up to understand their biological underpinnings.


Assuntos
Loci Gênicos , Predisposição Genética para Doença , Neoplasias Pulmonares/genética , Polimorfismo de Nucleotídeo Único , Adulto , Alelos , Grupo com Ancestrais do Continente Asiático , Estudos de Casos e Controles , Cromossomos Humanos Par 12 , Cromossomos Humanos Par 6 , Cromossomos Humanos Par 9 , Feminino , Estudo de Associação Genômica Ampla , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Razão de Chances , Fumar
19.
Int J Epidemiol ; 45(1): 206-20, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26635288

RESUMO

BACKGROUND: Oesophageal cancer is the fourth leading cause of cancer death in China where essentially all cases are histologically oesophageal squamous cell carcinoma (ESCC). Agnostic pathway-based analyses of genome-wide association study (GWAS) data combined with tissue-specific expression quantitative trait loci (eQTL) analysis and publicly available functional data can identify biological pathways and/or genes enriched with functionally-relevant disease-associated variants. METHOD: We used the adaptive multilocus joint test to analyse 1827 pathways containing 6060 genes using GWAS data from 1942 ESCC cases and 2111 controls with Chinese ancestry. We examined the function of risk alleles using in silico and eQTL analyses in oesophageal tissues. RESULTS: Associations with ESCC risk were observed for 36 pathways predominantly involved in apoptosis, cell cycle regulation and DNA repair and containing known GWAS-associated genes. After excluding genes with previous GWAS signals, candidate pathways (and genes) for ESCC risk included taste transduction (KEGG_hsa04742; TAS2R13, TAS2R42, TAS2R14, TAS2R46,TAS2R50), long-patch base excision repair (Reactome_pid; POLD2) and the metabolics pathway (KEGG_hsa01100; MTAP, GAPDH, DCTD, POLD2, AMDHD1). We identified and validated CASP8 rs13016963 and IDH2 rs11630814 as eQTLs, and CASP8 rs3769823 and IDH2 rs4561444 as the potential functional variants in high-linkage disequilibrium with these single nucleotide polymorphisms (SNPs), respectively. Further, IDH2 mRNA levels were down-regulated in ESCC (tumour:normal-fold change = 0.69, P = .75E-14). CONCLUSION: Agnostic pathway-based analyses and integration of multiple types of functional data provide new evidence for the contribution of genes in taste transduction and metabolism to ESCC susceptibility, and for the functionality of both established and new ESCC risk-related SNPs.


Assuntos
Carcinoma de Células Escamosas/genética , Caspase 8/genética , Neoplasias Esofágicas/genética , Isocitrato Desidrogenase/genética , Polimorfismo de Nucleotídeo Único , Transdução de Sinais/genética , Grupo com Ancestrais do Continente Asiático/genética , China , Carcinoma de Células Escamosas do Esôfago , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Modelos Logísticos , Locos de Características Quantitativas
20.
Cancer Discov ; 5(9): 920-31, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26084801

RESUMO

UNLABELLED: Metastasis is the leading cause of death in patients with osteosarcoma, the most common pediatric bone malignancy. We conducted a multistage genome-wide association study of osteosarcoma metastasis at diagnosis in 935 osteosarcoma patients to determine whether germline genetic variation contributes to risk of metastasis. We identified an SNP, rs7034162, in NFIB significantly associated with metastasis in European osteosarcoma cases, as well as in cases of African and Brazilian ancestry (meta-analysis of all cases: P = 1.2 × 10(-9); OR, 2.43; 95% confidence interval, 1.83-3.24). The risk allele was significantly associated with lowered NFIB expression, which led to increased osteosarcoma cell migration, proliferation, and colony formation. In addition, a transposon screen in mice identified a significant proportion of osteosarcomas harboring inactivating insertions in Nfib and with lowered NFIB expression. These data suggest that germline genetic variation at rs7034162 is important in osteosarcoma metastasis and that NFIB is an osteosarcoma metastasis susceptibility gene. SIGNIFICANCE: Metastasis at diagnosis in osteosarcoma is the leading cause of death in these patients. Here we show data that are supportive for the NFIB locus as associated with metastatic potential in osteosarcoma.


Assuntos
Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Variação Genética , Estudo de Associação Genômica Ampla , Fatores de Transcrição NFI/genética , Osteossarcoma/genética , Osteossarcoma/patologia , Alelos , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células , Cromossomos Humanos Par 9 , Elementos de DNA Transponíveis , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Estudos de Associação Genética , Ligação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Desequilíbrio de Ligação , Camundongos , Mutagênese Insercional , Metástase Neoplásica , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
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