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1.
Gigascience ; 8(7)2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31289836

RESUMO

BACKGROUND: Mammalian X and Y chromosomes share a common evolutionary origin and retain regions of high sequence similarity. Similar sequence content can confound the mapping of short next-generation sequencing reads to a reference genome. It is therefore possible that the presence of both sex chromosomes in a reference genome can cause technical artifacts in genomic data and affect downstream analyses and applications. Understanding this problem is critical for medical genomics and population genomic inference. RESULTS: Here, we characterize how sequence homology can affect analyses on the sex chromosomes and present XYalign, a new tool that (1) facilitates the inference of sex chromosome complement from next-generation sequencing data; (2) corrects erroneous read mapping on the sex chromosomes; and (3) tabulates and visualizes important metrics for quality control such as mapping quality, sequencing depth, and allele balance. We find that sequence homology affects read mapping on the sex chromosomes and this has downstream effects on variant calling. However, we show that XYalign can correct mismapping, resulting in more accurate variant calling. We also show how metrics output by XYalign can be used to identify XX and XY individuals across diverse sequencing experiments, including low- and high-coverage whole-genome sequencing, and exome sequencing. Finally, we discuss how the flexibility of the XYalign framework can be leveraged for other uses including the identification of aneuploidy on the autosomes. XYalign is available open source under the GNU General Public License (version 3). CONCLUSIONS: Sex chromsome sequence homology causes the mismapping of short reads, which in turn affects downstream analyses. XYalign provides a reproducible framework to correct mismapping and improve variant calling on the sex chromsomes.

2.
Breast Cancer Res ; 21(1): 62, 2019 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-31101124

RESUMO

BACKGROUND: Environmental and genetic factors play an important role in the etiology of breast cancer. Several small blood-based DNA methylation studies have reported risk associations with methylation at individual CpGs and average methylation levels; however, these findings require validation in larger prospective cohort studies. To investigate the role of blood DNA methylation on breast cancer risk, we conducted a meta-analysis of four prospective cohort studies, including a total of 1663 incident cases and 1885 controls, the largest study of blood DNA methylation and breast cancer risk to date. METHODS: We assessed associations with methylation at 365,145 CpGs present in the HumanMethylation450 (HM450K) Beadchip, after excluding CpGs that did not pass quality controls in all studies. Each of the four cohorts estimated odds ratios (ORs) and 95% confidence intervals (CI) for the association between each individual CpG and breast cancer risk. In addition, each study assessed the association between average methylation measures and breast cancer risk, adjusted and unadjusted for cell-type composition. Study-specific ORs were combined using fixed-effect meta-analysis with inverse variance weights. Stratified analyses were conducted by age at diagnosis (< 50, ≥ 50), estrogen receptor (ER) status (+/-), and time since blood collection (< 5, 5-10, > 10 years). The false discovery rate (q value) was used to account for multiple testing. RESULTS: The average age at blood draw ranged from 52.2 to 62.2 years across the four cohorts. Median follow-up time ranged from 6.6 to 8.4 years. The methylation measured at individual CpGs was not associated with breast cancer risk (q value > 0.59). In addition, higher average methylation level was not associated with risk of breast cancer (OR = 0.94, 95% CI = 0.85, 1.05; P = 0.26; P for study heterogeneity = 0.86). We found no evidence of modification of this association by age at diagnosis (P = 0.17), ER status (P = 0.88), time since blood collection (P = 0.98), or CpG location (P = 0.98). CONCLUSIONS: Our data indicate that DNA methylation measured in the blood prior to breast cancer diagnosis in predominantly postmenopausal women is unlikely to be associated with substantial breast cancer risk on the HM450K array. Larger studies or with greater methylation coverage are needed to determine if associations exist between blood DNA methylation and breast cancer risk.

4.
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.

5.
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
6.
Int J Cancer ; 142(8): 1594-1601, 2018 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-29210060

RESUMO

Survival rates for osteosarcoma, the most common primary bone cancer, have changed little over the past three decades and are particularly low for patients with metastatic disease. We conducted a multi-institutional genome-wide association study (GWAS) to identify germline genetic variants associated with overall survival in 632 patients with osteosarcoma, including 523 patients of European ancestry and 109 from Brazil. We conducted a time-to-event analysis and estimated hazard ratios (HR) and 95% confidence intervals (CI) using Cox proportional hazards models, with and without adjustment for metastatic disease. The results were combined across the European and Brazilian case sets using a random-effects meta-analysis. The strongest association after meta-analysis was for rs3765555 at 9p24.1, which was inversely associated with overall survival (HR = 1.76; 95% CI 1.41-2.18, p = 4.84 × 10-7 ). After imputation across this region, the combined analysis identified two SNPs that reached genome-wide significance. The strongest single association was with rs55933544 (HR = 1.9; 95% CI 1.5-2.4; p = 1.3 × 10-8 ), which localizes to the GLDC gene, adjacent to the IL33 gene and was consistent across both the European and Brazilian case sets. Using publicly available data, the risk allele was associated with lower expression of IL33 and low expression of IL33 was associated with poor survival in an independent set of patients with osteosarcoma. In conclusion, we have identified the GLDC/IL33 locus on chromosome 9p24.1 as associated with overall survival in patients with osteosarcoma. Further studies are needed to confirm this association and shed light on the biological underpinnings of this susceptibility locus.


Assuntos
Neoplasias Ósseas/genética , Neoplasias Ósseas/mortalidade , Interleucina-33/genética , Osteossarcoma/genética , Osteossarcoma/mortalidade , Adulto , Alelos , Brasil , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Modelos de Riscos Proporcionais , Taxa de Sobrevida
7.
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
8.
EBioMedicine ; 25: 58-65, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29033373

RESUMO

BACKGROUND: Plasmodium falciparum (Pf) malaria infection is suspected to cause endemic Burkitt Lymphoma (eBL), but the evidence remains unsettled. An inverse relationship between sickle cell trait (SCT) and eBL, which supports that between malaria and eBL, has been reported before, but in small studies with low power. We investigated this hypothesis in children in a population-based study in northern Uganda using Mendelian Randomization. METHODS: Malaria-related polymorphisms (SCT, IL10, IL1A, CD36, SEMA3C, and IFNAR1) were genotyped in 202 eBL cases and 624 controls enrolled during 2010-2015. We modeled associations between genotypes and eBL or malaria using logistic regression. FINDINGS: SCT was associated with decreased risk of eBL (adjusted odds ratio [OR] 0·37, 95% CI 0·21-0·66; p=0·0003). Decreased risk of eBL was associated with IL10 rs1800896-CT (OR 0·73, 95% CI 0·50-1·07) and -CC genotypes (OR 0·53, 95% CI 0·29-0·95, ptrend=0·019); IL1A rs2856838-AG (OR 0·56, 95% CI 0·39-0·81) and -AA genotype (OR 0·50, 95% CI 0·28-1·01, ptrend=0·0016); and SEMA3C rs4461841-CT or -CC genotypes (OR 0·57, 95% CI 0·35-0·93, p=0·0193). SCT and IL10 rs1800896, IL1A rs2856838, but not SEMA3C rs4461841, polymorphisms were associated with decreased risk of malaria in the controls. INTERPRETATION: Our results support a causal effect of malaria infection on eBL.


Assuntos
Linfoma de Burkitt/genética , Predisposição Genética para Doença , Malária Falciparum/genética , Análise da Randomização Mendeliana , Adolescente , Linfoma de Burkitt/complicações , Linfoma de Burkitt/epidemiologia , Linfoma de Burkitt/parasitologia , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Lactente , Recém-Nascido , Malária Falciparum/complicações , Malária Falciparum/epidemiologia , Malária Falciparum/parasitologia , Masculino , Plasmodium falciparum/patogenicidade , Uganda/epidemiologia
9.
Hum Mutat ; 38(12): 1723-1730, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28861920

RESUMO

Li-Fraumeni syndrome (LFS) is an autosomal-dominant cancer predisposition disorder associated with pathogenic germline variants in TP53, with a high penetrance over an individual's lifetime. The actual population prevalence of pathogenic germline TP53 mutations is still unclear, most likely due to biased selection of cancer affected families. The aim of this study was to estimate the population prevalence of potentially pathogenic TP53 exonic variants in three sequencing databases, totaling 63,983 unrelated individuals. Potential pathogenicity was defined using an original algorithm combining bioinformatic prediction tools, suggested clinical significance, and functional data. We identified 34 different potentially pathogenic TP53 variants in 131 out of 63,983 individuals (0.2%). Twenty-eight (82%) of these variants fell within the DNA-binding domain of TP53, with an enrichment for specific variants that were not previously identified as LFS mutation hotspots, such as the p.R290H and p.N235S variants. Our findings reveal that the population prevalence of potentially pathogenic TP53 variants may be up to 10 times higher than previously estimated from family-based studies. These results point to the need for further studies aimed at evaluating cancer penetrance modifiers as well as the risk associated between cancer and rare TP53 variants.


Assuntos
Bases de Dados Genéticas , Exoma/genética , Variação Genética , Síndrome de Li-Fraumeni/genética , Proteína Supressora de Tumor p53/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Família , Feminino , Genótipo , Mutação em Linhagem Germinativa , Humanos , Pessoa de Meia-Idade , Penetrância , Prevalência , Sequenciamento Completo do Exoma
10.
Oncotarget ; 8(1): 1495-1507, 2017 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-27902461

RESUMO

Prostate cancer (PCa) susceptibility is defined by a continuum from rare, high-penetrance to common, low-penetrance alleles. Research to date has concentrated on identification of variants at the ends of that continuum. Taking an alternate approach, we focused on the important but elusive class of low-frequency, moderately penetrant variants by performing disease model-based variant filtering of whole exome sequence data from 75 hereditary PCa families. Analysis of 341 candidate risk variants identified nine variants significantly associated with increased PCa risk in a population-based, case-control study of 2,495 men. In an independent nested case-control study of 7,121 men, there was risk association evidence for TANGO2 p.Ser17Ter and the established HOXB13 p.Gly84Glu variant. Meta-analysis combining the case-control studies identified two additional variants suggestively associated with risk, OR5H14 p.Met59Val and CHAD p.Ala342Asp. The TANGO2 and HOXB13 variants co-occurred in cases more often than expected by chance and never in controls. Finally, TANGO2 p.Ser17Ter was associated with aggressive disease in both case-control studies separately. Our analyses identified three new PCa susceptibility alleles in the TANGO2, OR5H14 and CHAD genes that not only segregate in multiple high-risk families but are also of importance in altering disease risk for men from the general population. This is the first successful study to utilize sequencing in high-risk families for the express purpose of identifying low-frequency, moderately penetrant PCa risk mutations.


Assuntos
Neoplasias da Próstata/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Sequenciamento Completo do Exoma
11.
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
12.
Am J Hum Genet ; 98(5): 818-829, 2016 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-27087322

RESUMO

To identify clinically important molecular subtypes of prostate cancer (PCa), we characterized the somatic landscape of aggressive tumors via deep, whole-genome sequencing. In our discovery set of ten tumor/normal subject pairs with Gleason scores of 8-10 at diagnosis, coordinated analysis of germline and somatic variants, including single-nucleotide variants, indels, and structural variants, revealed biallelic BRCA2 disruptions in a subset of samples. Compared to the other samples, the PCa BRCA2-deficient tumors exhibited a complex and highly specific mutation signature, featuring a 2.88-fold increased somatic mutation rate, depletion of context-specific C>T substitutions, and an enrichment for deletions, especially those longer than 10 bp. We next performed a BRCA2 deficiency-targeted reanalysis of 150 metastatic PCa tumors, and each of the 18 BRCA2-mutated samples recapitulated the BRCA2 deficiency-associated mutation signature, underscoring the potent influence of these lesions on somatic mutagenesis and tumor evolution. Among all 21 individuals with BRCA2-deficient tumors, only about half carried deleterious germline alleles. Importantly, the somatic mutation signature in tumors with one germline and one somatic risk allele was indistinguishable from those with purely somatic mutations. Our observations clearly demonstrate that BRCA2-disrupted tumors represent a unique and clinically relevant molecular subtype of aggressive PCa, highlighting both the promise and utility of this mutation signature as a prognostic and treatment-selection biomarker. Further, any test designed to leverage BRCA2 status as a biomarker for PCa must consider both germline and somatic mutations and all types of deleterious mutations.


Assuntos
Proteína BRCA2/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Mutação/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/secundário , Idoso , Alelos , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Prognóstico
13.
Genome Res ; 25(11): 1646-55, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26232412

RESUMO

Canine transmissible venereal tumor (CTVT) is a parasitic cancer clone that has propagated for thousands of years via sexual transfer of malignant cells. Little is understood about the mechanisms that converted an ancient tumor into the world's oldest known continuously propagating somatic cell lineage. We created the largest existing catalog of canine genome-wide variation and compared it against two CTVT genome sequences, thereby separating alleles derived from the founder's genome from somatic mutations that must drive clonal transmissibility. We show that CTVT has undergone continuous adaptation to its transmissible allograft niche, with overlapping mutations at every step of immunosurveillance, particularly self-antigen presentation and apoptosis. We also identified chronologically early somatic mutations in oncogenesis- and immune-related genes that may represent key initiators of clonal transmissibility. Thus, we provide the first insights into the specific genomic aberrations that underlie CTVT's dogged perseverance in canids around the world.


Assuntos
Doenças do Cão/genética , Cães/genética , Estudos de Associação Genética , Tumores Venéreos Veterinários/genética , Animais , Apoptose , Autoantígenos/genética , Proteínas Adaptadoras de Sinalização CARD/genética , Moléculas de Adesão Celular/genética , Linhagem Celular Tumoral , Linhagem da Célula/genética , Colágeno Tipo XI/genética , Proteínas de Ligação a DNA/genética , Doenças do Cão/diagnóstico , Variação Genética , Genoma , Fatores de Troca do Nucleotídeo Guanina/genética , Proteoglicanas de Heparan Sulfato/genética , Proteínas dos Microfilamentos/genética , Mutação , Miotonina Proteína Quinase/genética , Filogenia , Análise de Componente Principal , Análise de Sequência de DNA , Tumores Venéreos Veterinários/diagnóstico
14.
Mol Cancer Res ; 13(6): 993-1002, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25767210

RESUMO

UNLABELLED: Targeted cancer therapies offer great clinical promise, but treatment resistance is common, and basic research aimed at overcoming this challenge is limited by reduced genomic and biologic complexity in artificially induced rodent tumors compared with their human counterparts. Animal models that more faithfully recapitulate genotype-specific human pathology could improve the predictive value of these investigations. Here, a newly identified animal model for oncogenic BRAF-driven cancers is described. With 20,000 new cases in the United States each year, canine invasive transitional cell carcinoma of the bladder (InvTCC) is a common, naturally occurring malignancy that shares significant histologic, biologic, and clinical phenotypes with human muscle invasive bladder cancer. In order to identify somatic drivers of canine InvTCC, the complete transcriptome for multiple tumors was determined by RNAseq. All tumors harbored a somatic mutation that is homologous to the human BRAF(V600E) mutation, and an identical mutation was present in 87% of 62 additional canine InvTCC tumors. The mutation was also detectable in the urine sediments of all dogs tested with mutation-positive tumors. Functional experiments suggest that, like human tumors, canine activating BRAF mutations potently stimulate the MAPK pathway. Cell lines with the mutation have elevated levels of phosphorylated MEK, compared with a line with wild-type BRAF. This effect can be diminished through application of the BRAF(V600E) inhibitor vemurafenib. These findings set the stage for canine InvTCC as a powerful system to evaluate BRAF-targeted therapies, as well as therapies designed to overcome resistance, which could enhance treatment of both human and canine cancers IMPLICATIONS: This study demonstrates the activating BRAF mutation (V600E), which is found in multiple human cancers, is a driver of canine InvTCC, and highlights a urine-based test for quick diagnosis.


Assuntos
Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Homologia de Sequência do Ácido Nucleico , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/genética , Animais , Testes Diagnósticos de Rotina/métodos , Cães , Humanos , Proteínas Proto-Oncogênicas B-raf/urina , Neoplasias da Bexiga Urinária/urina
15.
PLoS Genet ; 9(3): e1003409, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23555311

RESUMO

The domestic dog is a robust model for studying the genetics of complex disease susceptibility. The strategies used to develop and propagate modern breeds have resulted in an elevated risk for specific diseases in particular breeds. One example is that of Standard Poodles (STPOs), who have increased risk for squamous cell carcinoma of the digit (SCCD), a locally aggressive cancer that causes lytic bone lesions, sometimes with multiple toe recurrence. However, only STPOs of dark coat color are at high risk; light colored STPOs are almost entirely unaffected, suggesting that interactions between multiple pathways are necessary for oncogenesis. We performed a genome-wide association study (GWAS) on STPOs, comparing 31 SCCD cases to 34 unrelated black STPO controls. The peak SNP on canine chromosome 15 was statistically significant at the genome-wide level (P(raw) = 1.60 × 10(-7); P(genome) = 0.0066). Additional mapping resolved the region to the KIT Ligand (KITLG) locus. Comparison of STPO cases to other at-risk breeds narrowed the locus to a 144.9-Kb region. Haplotype mapping among 84 STPO cases identified a minimal region of 28.3 Kb. A copy number variant (CNV) containing predicted enhancer elements was found to be strongly associated with SCCD in STPOs (P = 1.72 × 10(-8)). Light colored STPOs carry the CNV risk alleles at the same frequency as black STPOs, but are not susceptible to SCCD. A GWAS comparing 24 black and 24 light colored STPOs highlighted only the MC1R locus as significantly different between the two datasets, suggesting that a compensatory mutation within the MC1R locus likely protects light colored STPOs from disease. Our findings highlight a role for KITLG in SCCD susceptibility, as well as demonstrate that interactions between the KITLG and MC1R loci are potentially required for SCCD oncogenesis. These findings highlight how studies of breed-limited diseases are useful for disentangling multigene disorders.


Assuntos
Carcinoma de Células Escamosas , Dosagem de Genes , Estudo de Associação Genômica Ampla , Fator de Células-Tronco/genética , Alelos , Animais , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Mapeamento Cromossômico , Cães , Elementos Facilitadores Genéticos/genética , Predisposição Genética para Doença , Haplótipos , Humanos , Desequilíbrio de Ligação , Mutação , Polimorfismo de Nucleotídeo Único , Dedo em Gatilho/genética , Dedo em Gatilho/fisiopatologia
16.
Hum Mol Genet ; 19(12): 2507-15, 2010 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-20332101

RESUMO

Recent genome-wide association studies have identified a breast cancer susceptibility locus on 16q12 with an unknown biological basis. We used a set of single nucleotide polymorphism (SNP) markers to generate a fine-scale map and narrowed the region of association to a 133 kb DNA segment containing the largely uncharacterized hypothetical gene LOC643714, a short intergenic region and the 5' end of TOX3. Re-sequencing this segment in European subjects identified 293 common polymorphisms, including a set of 26 highly correlated candidate causal variants. By evaluation of these SNPs in five breast cancer case-control studies involving more than 23 000 subjects from populations of European and Southeast Asian ancestry, all but 14 variants could be excluded at odds of <1:100. Most of the remaining variants lie in the intergenic region, which exhibits evolutionary conservation and open chromatin conformation, consistent with a regulatory function. African-American case-control studies exhibit a different pattern of association suggestive of an additional causative variant.


Assuntos
Neoplasias da Mama/genética , Cromossomos Humanos Par 16/genética , Predisposição Genética para Doença , Mapeamento Cromossômico , Feminino , Marcadores Genéticos , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único
17.
BMC Res Notes ; 2: 94, 2009 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-19476645

RESUMO

BACKGROUND: Germline mutations in the BRCA2 gene have been suggested to account for about 5% of familial prostate cancer; mutations have been reported in 2% of early onset (i.e.,

18.
Hum Mol Genet ; 18(9): 1692-703, 2009 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-19223389

RESUMO

Genome-wide association studies have identified FGFR2 as a breast cancer (BC) susceptibility gene in populations of European and Asian descent, but a causative variant has not yet been conclusively identified. We hypothesized that the weaker linkage disequilibrium across this associated region in populations of African ancestry might help refine the set of candidate-causal single nucleotide polymorphisms (SNPs) previously identified by our group. Eight candidate-causal SNPs were evaluated in 1253 African American invasive BC cases and 1245 controls. A significant association with BC risk was found with SNP rs2981578 (unadjusted per-allele odds ratio = 1.20, 95% confidence interval 1.03-1.41, P(trend) = 0.02), with the odds ratio estimate similar to that reported in European and Asian subjects. To extend the fine-mapping, genotype data from the African American studies were analyzed jointly with data from European (n = 7196 cases, 7275 controls) and Asian (n = 3901 cases, 3205 controls) studies. In the combined analysis, SNP rs2981578 was the most strongly associated. Five other SNPs were too strongly correlated to be excluded at a likelihood ratio of < 1/100 relative to rs2981578. Analysis of DNase I hypersensitive sites indicated that only two of these map to highly accessible chromatin, one of which, SNP rs2981578, has previously been implicated in up-regulating FGFR2 expression. Our results demonstrate that the association of SNPs in FGFR2 with BC risk extends to women of African American ethnicity, and illustrate the utility of combining association analysis in datasets of diverse ethnic groups with functional experiments to identify disease susceptibility variants.


Assuntos
Afro-Americanos/genética , Neoplasias da Mama/genética , Cromatina/genética , Polimorfismo de Nucleotídeo Único , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/etnologia , Estudos de Casos e Controles , Linhagem Celular Tumoral , Feminino , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Adulto Jovem
19.
Science ; 316(5821): 112-5, 2007 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-17412960

RESUMO

The domestic dog exhibits greater diversity in body size than any other terrestrial vertebrate. We used a strategy that exploits the breed structure of dogs to investigate the genetic basis of size. First, through a genome-wide scan, we identified a major quantitative trait locus (QTL) on chromosome 15 influencing size variation within a single breed. Second, we examined genetic variation in the 15-megabase interval surrounding the QTL in small and giant breeds and found marked evidence for a selective sweep spanning a single gene (IGF1), encoding insulin-like growth factor 1. A single IGF1 single-nucleotide polymorphism haplotype is common to all small breeds and nearly absent from giant breeds, suggesting that the same causal sequence variant is a major contributor to body size in all small dogs.


Assuntos
Cães/anatomia & histologia , Cães/genética , Fator de Crescimento Insulin-Like I/genética , Polimorfismo de Nucleotídeo Único , Alelos , Animais , Tamanho Corporal/genética , Cruzamento , Éxons , Variação Genética , Genótipo , Haplótipos , Heterozigoto , Fator de Crescimento Insulin-Like I/metabolismo , Íntrons , Mutação , Locos de Características Quantitativas , Seleção Genética , Análise de Sequência de DNA
20.
Arch Neurol ; 63(4): 548-52, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16606767

RESUMO

BACKGROUND: Mutations in parkin are estimated to account for as much as 50% of familial Parkinson disease (PD) and 18% of sporadic PD. Single heterozygous mutations in parkin in both familial and sporadic cases may also increase susceptibility to PD. To our knowledge, all previous studies have been restricted to PD cases; this is the first study to systematically screen the parkin coding regions and exon deletions and duplications in controls. OBJECTIVE: To determine the frequency and spectrum of parkin variants in early-onset PD cases (aged < or =50 years) and controls participating in a familial aggregation study. PATIENTS AND METHODS: We sequenced the parkin gene in 101 cases and 105 controls. All cases and controls were also screened for exon deletions and duplications by semiquantitative multiplex polymerase chain reaction. RESULTS: Thirteen (12.9% [95% confidence interval, 7%-21%]) of the 101 cases had a previously described parkin mutation: 1 was homozygous, 11 were heterozygous, and 1 was a compound heterozygote. The mutations Arg42Pro (exon 2) and Arg275Trp (exon 7) were recurrent. The previously reported synonymous substitution Leu261Leu (c.884A>G) was identified in 4 (3.9%) of 101 cases and 2 (2%) of 105 controls (P = .44). Excluding the synonymous substitution Leu261Leu (heterozygotes), 10 (9.9% [95% confidence interval, 4.6%-17.5%]) carried mutations. CONCLUSIONS: The frequency of mutations among cases that were not selected based on family history of PD is similar to what has previously been reported in sporadic PD. The similar frequency of Leu261Leu in cases and controls suggests it is a normal variant rather than a disease-associated mutation. We confirmed that heterozygous parkin mutations may increase susceptibility for early-onset PD.


Assuntos
Predisposição Genética para Doença/genética , Mutação/genética , Doença de Parkinson/diagnóstico , Doença de Parkinson/genética , Ubiquitina-Proteína Ligases/genética , Idade de Início , Idoso , Substituição de Aminoácidos/genética , Estudos de Casos e Controles , Estudos de Coortes , Análise Mutacional de DNA , Éxons/genética , Feminino , Deleção de Genes , Testes Genéticos , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/fisiopatologia , Mutação Puntual/genética
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