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1.
Hum Mol Genet ; 29(21): 3578-3587, 2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33410475

RESUMO

Germline genetic variants have been identified, which predispose individuals and families to develop melanoma. Tumor thickness is the strongest predictor of outcome for clinically localized primary melanoma patients. We sought to determine whether there is a heritable genetic contribution to variation in tumor thickness. If confirmed, this will justify the search for specific genetic variants influencing tumor thickness. To address this, we estimated the proportion of variation in tumor thickness attributable to genome-wide genetic variation (variant-based heritability) using unrelated patients with measured primary cutaneous melanoma thickness. As a secondary analysis, we conducted a genome-wide association study (GWAS) of tumor thickness. The analyses utilized 10 604 individuals with primary cutaneous melanoma drawn from nine GWAS datasets from eight cohorts recruited from the general population, primary care and melanoma treatment centers. Following quality control and filtering to unrelated individuals with study phenotypes, 8125 patients were used in the primary analysis to test whether tumor thickness is heritable. An expanded set of 8505 individuals (47.6% female) were analyzed for the secondary GWAS meta-analysis. Analyses were adjusted for participant age, sex, cohort and ancestry. We found that 26.6% (SE 11.9%, P = 0.0128) of variation in tumor thickness is attributable to genome-wide genetic variation. While requiring replication, a chromosome 11 locus was associated (P < 5 × 10-8) with tumor thickness. Our work indicates that sufficiently large datasets will enable the discovery of genetic variants associated with greater tumor thickness, and this will lead to the identification of host biological processes influencing melanoma growth and invasion.

2.
J Med Genet ; 2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-32994281

RESUMO

BACKGROUND: Familial clustering of melanoma suggests a shared genetic predisposition among family members, but only 10%-40% of familial cases carry a pathogenic variant in a known high-risk melanoma susceptibility gene. We investigated whether a melanoma-specific Polygenic Risk Score (PRS) is associated with melanoma risk in patients with genetically unexplained familial melanoma. METHODS: Dutch familial melanoma cases (n=418) were genotyped for 46 SNPs previously identified as independently associated with melanoma risk. The 46-SNP PRS was calculated and standardised to 3423 healthy controls (sPRS) and the association between PRS and melanoma risk was modelled using logistic regression. Within the case series, possible differences were further explored by investigating the PRS in relation to (1) the number of primary melanomas in a patient and (2) the extent of familial clustering of melanoma. RESULTS: The PRS was significantly associated with melanoma risk, with a per-SD OR of 2.12 (95% CI 1.90 to 2.35, p<0.001), corresponding to a 5.70-fold increased risk (95% CI 3.93 to 8.28) when comparing the top 90th to the middle 40-60th PRS percentiles. The mean PRS was significantly higher in cases with multiple primary melanomas than in cases with a single melanoma (sPRS 1.17 vs 0.71, p=0.001). Conversely, cases from high-density melanoma families had a lower (but non-significant) mean PRS than cases from low-density families (sPRS 0.60 vs 0.94, p=0.204). CONCLUSION: Our work underlines the significance of a PRS in determining melanoma susceptibility and encourages further exploration of the diagnostic value of a PRS in genetically unexplained melanoma families.

3.
Lifestyle Genom ; 13(5): 146-153, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32791511

RESUMO

BACKGROUND: Globally, 1 in 11 adults has diabetes mellitus, and most of these cases are type 2 diabetes (T2D). The risk of T2D is influenced by many factors, including diet. The synthesis of long-chain n-6 polyunsaturated fatty acids (LC n-6 PUFA) has been posited as a risk factor for T2D; however, its causal role is uncertain. AIM: To test the causal effect of LC n-6 PUFA synthesis on insulin resistance and transgenerational T2D risk in a large cohort of men and women. METHODS: Two-sample mendelian randomization (MR) was conducted to evaluate the effect of low or high levels of LC n-6 PUFA synthesis on glycemia and development of T2D in the UK Biobank (n = 463,010) and Meta-Analysis of Glucose- and Insulin-Related Traits Consortium (MAGIC; n = 5,130) cohorts. The increased likelihood of a predisposition to low or high LC n-6 PUFA synthesis and the risk of T2D was also investigated using the participants' siblings and parents. In MR-Base, 4 genetic variants associated with LC n-6 PUFA synthesis were found (p < 10-8). After pruning, 1 variant (rs174547) on the FADS1 gene was retained. RESULTS: Lower LC n-6 PUFA synthesis and abundance (per % unit decrease) are associated with small reductions in the insulin disposition index (-0.038 ± 0.012 mM-1; p = 0.002) within MAGIC. In the UK Biobank, we report negligible effects of low n-6 PUFA synthesis on the odds of T2D (OR <1%; p < 0.05). Additionally, reduced LC n-6 PUFA synthesis does not appear to be a contributor to familial T2D risk. No significant association was observed between LC n-6 PUFA synthesis and BMI. CONCLUSION: In a primarily white European population, LC n-6 PUFA synthesis is not a major contributor to T2D risk.

4.
Hum Mol Genet ; 29(17): 2976-2985, 2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-32716505

RESUMO

Cancers, including cutaneous melanoma, can cluster in families. In addition to environmental etiological factors such as ultraviolet radiation, cutaneous melanoma has a strong genetic component. Genetic risks for cutaneous melanoma range from rare, high-penetrance mutations to common, low-penetrance variants. Known high-penetrance mutations account for only about half of all densely affected cutaneous melanoma families, and the causes of familial clustering in the remainder are unknown. We hypothesize that some clustering is due to the cumulative effect of a large number of variants of individually small effect. Common, low-penetrance genetic risk variants can be combined into polygenic risk scores. We used a polygenic risk score for cutaneous melanoma to compare families without known high-penetrance mutations with unrelated melanoma cases and melanoma-free controls. Family members had significantly higher mean polygenic load for cutaneous melanoma than unrelated cases or melanoma-free healthy controls (Bonferroni-corrected t-test P = 1.5 × 10-5 and 6.3 × 10-45, respectively). Whole genome sequencing of germline DNA from 51 members of 21 families with low polygenic risk for melanoma identified a CDKN2A p.G101W mutation in a single family but no other candidate high-penetrance melanoma susceptibility genes. This work provides further evidence that melanoma, like many other common complex disorders, can arise from the joint action of multiple predisposing factors, including rare high-penetrance mutations, as well as via a combination of large numbers of alleles of small effect.

5.
Nat Commun ; 11(1): 3353, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32620889

RESUMO

Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that sample sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence.


Assuntos
Predisposição Genética para Doença , Modelos Genéticos , Herança Multifatorial , Neoplasias/epidemiologia , Animais , Feminino , Estudo de Associação Genômica Ampla , Humanos , Incidência , Masculino , Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Medição de Risco/métodos , Fatores de Risco
6.
Nat Commun ; 11(1): 2718, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32483191

RESUMO

Genome-wide association studies (GWAS) have identified ~20 melanoma susceptibility loci, most of which are not functionally characterized. Here we report an approach integrating massively-parallel reporter assays (MPRA) with cell-type-specific epigenome and expression quantitative trait loci (eQTL) to identify susceptibility genes/variants from multiple GWAS loci. From 832 high-LD variants, we identify 39 candidate functional variants from 14 loci displaying allelic transcriptional activity, a subset of which corroborates four colocalizing melanocyte cis-eQTL genes. Among these, we further characterize the locus encompassing the HIV-1 restriction gene, MX2 (Chr21q22.3), and validate a functional intronic variant, rs398206. rs398206 mediates the binding of the transcription factor, YY1, to increase MX2 levels, consistent with the cis-eQTL of MX2 in primary human melanocytes. Melanocyte-specific expression of human MX2 in a zebrafish model demonstrates accelerated melanoma formation in a BRAFV600E background. Our integrative approach streamlines GWAS follow-up studies and highlights a pleiotropic function of MX2 in melanoma susceptibility.


Assuntos
Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Melanoma/genética , Mutação , Proteínas de Resistência a Myxovirus/genética , Polimorfismo de Nucleotídeo Único , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Regulação da Expressão Gênica , Genes Reporter/genética , Células HEK293 , Humanos , Melanócitos/metabolismo , Melanoma/patologia , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Locos de Características Quantitativas/genética , Peixe-Zebra/genética , Peixe-Zebra/metabolismo
7.
Acta Neuropathol ; 139(5): 963, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32172342

RESUMO

The original version of this article unfortunately contained a mistake. Supplementary Tables 3 and 4 are not available with the rest of the supplementary material available online.

8.
Int J Epidemiol ; 49(4): 1236-1245, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32068838

RESUMO

BACKGROUND: Height and body mass index (BMI) have both been positively associated with melanoma risk, although findings for BMI have been less consistent than height. It remains unclear, however, whether these associations reflect causality or are due to residual confounding by environmental and lifestyle risk factors. We re-evaluated these associations using a two-sample Mendelian randomization (MR) approach. METHODS: We identified single nucleotide polymorphisms (SNPs) for BMI and height from separate genome-wide association study (GWAS) meta-analyses. We obtained melanoma SNPs from the most recent melanoma GWAS meta-analysis comprising 12 874 cases and 23 203 controls. We used the inverse variance-weighted estimator to derive separate causal risk estimates across all SNP instruments for BMI and height. RESULTS: Based on the combined estimate derived from 730 SNPs for BMI, we found no evidence of an association between genetically predicted BMI and melanoma [odds ratio (OR) per one standard deviation (1 SD) (4.6 kg/m2) increase in BMI 1.00, 95% confidence interval (CI): 0.91-1.11]. In contrast, we observed a positive association between genetically-predicted height (derived from a pooled estimate of 3290 SNPs) and melanoma risk [OR 1.08, 95% CI: 1.02-1.13, per 1 SD (9.27 cm) increase in height]. Sensitivity analyses using two alternative MR methods yielded similar results. CONCLUSIONS: These findings provide no evidence for a causal association between higher BMI and melanoma, but support the notion that height is causally associated with melanoma risk. Mechanisms through which height influences melanoma risk remain unclear, and it remains possible that the effect could be mediated through diverse pathways including growth factors and even socioeconomic status.

9.
Carcinogenesis ; 41(3): 284-295, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31605138

RESUMO

Neuroblastoma (NB) and malignant cutaneous melanoma (CMM) are neural crest cells (NCC)-derived tumors and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association studies (GWAS). We took a three-staged approach to conduct cross-disease meta-analysis of GWAS for NB and CMM (2101 NB cases and 4202 controls; 12 874 CMM cases and 23 203 controls) to identify shared loci. Findings were replicated in 1403 NB cases and 1403 controls of European ancestry and in 636 NB, 508 CMM cases and 2066 controls of Italian origin. We found a cross-association at locus 1p13.2 (rs2153977, odds ratio = 0.91, P = 5.36 × 10-8). We also detected a suggestive (P < 10-7) NB-CMM cross-association at 2q37.1 with opposite effect on cancer risk. Pathway analysis of 110 NB-CMM risk loci with P < 10-4 demonstrated enrichment of biological processes such as cell migration, cell cycle, metabolism and immune response, which are essential of human NCC development, underlying both tumors. In vitro and in silico analyses indicated that the rs2153977-T protective allele, located in an NB and CMM enhancer, decreased expression of SLC16A1 via long-range loop formation and altered a T-box protein binding site. Upon depletion of SLC16A1, we observed a decrease of cellular proliferation and invasion in both NB and CMM cell lines, suggesting its role as oncogene. This is the largest study to date examining pleiotropy across two NC cell-derived tumors identifying 1p13.2 as common susceptibility locus for NB and CMM risk. We demonstrate that combining genome-wide association studies results across cancers with same origins can identify new loci common to neuroblastoma and melanoma arising from tissues which originate from neural crest cells. Our results also show 1p13.2 confer risk to neuroblastoma and melanoma by regulating SLC16A1.


Assuntos
Neoplasias das Glândulas Suprarrenais/genética , Melanoma/genética , Transportadores de Ácidos Monocarboxílicos/genética , Neuroblastoma/genética , Neoplasias Cutâneas/genética , Simportadores/genética , Neoplasias das Glândulas Suprarrenais/patologia , Diferenciação Celular/genética , Movimento Celular/genética , Cromossomos Humanos Par 1/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Melanoma/patologia , Crista Neural/patologia , Neuroblastoma/patologia , Polimorfismo de Nucleotídeo Único/genética , Neoplasias Cutâneas/patologia
10.
Acta Neuropathol ; 139(2): 347-364, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31845298

RESUMO

Epidemiologic studies have reported inconsistent results regarding an association between Parkinson disease (PD) and cutaneous melanoma (melanoma). Identifying shared genetic architecture between these diseases can support epidemiologic findings and identify common risk genes and biological pathways. Here, we apply polygenic, linkage disequilibrium-informed methods to the largest available case-control, genome-wide association study summary statistic data for melanoma and PD. We identify positive and significant genetic correlation (correlation: 0.17, 95% CI 0.10-0.24; P = 4.09 × 10-06) between melanoma and PD. We further demonstrate melanoma and PD-inferred gene expression to overlap across tissues (correlation: 0.14, 95% CI 0.06 to 0.22; P = 7.87 × 10-04) and highlight seven genes including PIEZO1, TRAPPC2L, and SOX6 as potential mediators of the genetic correlation between melanoma and PD. These findings demonstrate specific, shared genetic architecture between PD and melanoma that manifests at the level of gene expression.

12.
Nat Commun ; 9(1): 4774, 2018 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-30429480

RESUMO

The total number of acquired melanocytic nevi on the skin is strongly correlated with melanoma risk. Here we report a meta-analysis of 11 nevus GWAS from Australia, Netherlands, UK, and USA comprising 52,506 individuals. We confirm known loci including MTAP, PLA2G6, and IRF4, and detect novel SNPs in KITLG and a region of 9q32. In a bivariate analysis combining the nevus results with a recent melanoma GWAS meta-analysis (12,874 cases, 23,203 controls), SNPs near GPRC5A, CYP1B1, PPARGC1B, HDAC4, FAM208B, DOCK8, and SYNE2 reached global significance, and other loci, including MIR146A and OBFC1, reached a suggestive level. Overall, we conclude that most nevus genes affect melanoma risk (KITLG an exception), while many melanoma risk loci do not alter nevus count. For example, variants in TERC and OBFC1 affect both traits, but other telomere length maintenance genes seem to affect melanoma risk only. Our findings implicate multiple pathways in nevogenesis.


Assuntos
Grupo com Ancestrais do Continente Europeu/genética , Pleiotropia Genética/genética , Melanoma/genética , Nevo Pigmentado/genética , Neoplasias Cutâneas/genética , Proteínas de Transporte/genética , Citocromo P-450 CYP1B1/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Fosfolipases A2 do Grupo VI/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Histona Desacetilases/genética , Humanos , Fatores Reguladores de Interferon/genética , MicroRNAs/genética , Proteínas dos Microfilamentos/genética , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Polimorfismo de Nucleotídeo Único , RNA/genética , Proteínas de Ligação a RNA , Receptores Acoplados a Proteínas-G/genética , Proteínas Repressoras/genética , Fator de Células-Tronco/genética , Telomerase/genética , Proteínas de Ligação a Telômeros/genética
13.
Genome Res ; 28(11): 1621-1635, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30333196

RESUMO

Most expression quantitative trait locus (eQTL) studies to date have been performed in heterogeneous tissues as opposed to specific cell types. To better understand the cell-type-specific regulatory landscape of human melanocytes, which give rise to melanoma but account for <5% of typical human skin biopsies, we performed an eQTL analysis in primary melanocyte cultures from 106 newborn males. We identified 597,335 cis-eQTL SNPs prior to linkage disequilibrium (LD) pruning and 4997 eGenes (FDR < 0.05). Melanocyte eQTLs differed considerably from those identified in the 44 GTEx tissue types, including skin. Over a third of melanocyte eGenes, including key genes in melanin synthesis pathways, were unique to melanocytes compared to those of GTEx skin tissues or TCGA melanomas. The melanocyte data set also identified trans-eQTLs, including those connecting a pigmentation-associated functional SNP with four genes, likely through cis-regulation of IRF4 Melanocyte eQTLs are enriched in cis-regulatory signatures found in melanocytes as well as in melanoma-associated variants identified through genome-wide association studies. Melanocyte eQTLs also colocalized with melanoma GWAS variants in five known loci. Finally, a transcriptome-wide association study using melanocyte eQTLs uncovered four novel susceptibility loci, where imputed expression levels of five genes (ZFP90, HEBP1, MSC, CBWD1, and RP11-383H13.1) were associated with melanoma at genome-wide significant P-values. Our data highlight the utility of lineage-specific eQTL resources for annotating GWAS findings, and present a robust database for genomic research of melanoma risk and melanocyte biology.


Assuntos
Predisposição Genética para Doença , Melanócitos/metabolismo , Melanoma/genética , Locos de Características Quantitativas , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Proteínas de Transporte/genética , Células Cultivadas , Proteínas Ligantes de Grupo Heme , Hemeproteínas/genética , Humanos , Fatores Reguladores de Interferon/genética , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único , Proteínas Repressoras
14.
J Invest Dermatol ; 138(12): 2617-2624, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29890168

RESUMO

It is unclear to what degree genomic and traditional (phenotypic and environmental) risk factors overlap in their prediction of melanoma risk. We evaluated the incremental contribution of common genomic variants (in pigmentation, nevus, and other pathways) and their overlap with traditional risk factors, using data from two population-based case-control studies from Australia (n = 1,035) and the United Kingdom (n = 1,460) that used the same questionnaires. Polygenic risk scores were derived from 21 gene regions associated with melanoma and odds ratios from published meta-analyses. Logistic regression models were adjusted for age, sex, center, and ancestry. Adding the polygenic risk score to a model with traditional risk factors increased the area under the receiver operating characteristic curve (AUC) by 2.3% (P = 0.003) for Australia and by 2.8% (P = 0.002) for Leeds. Gene variants in the pigmentation pathway, particularly MC1R, were responsible for most of the incremental improvement. In a cross-tabulation of polygenic by traditional tertile risk scores, 59% (Australia) and 49% (Leeds) of participants were categorized in the same (concordant) tertile. Of participants with low traditional risk, 9% (Australia) and 21% (Leeds) had high polygenic risk. Testing of genomic variants can identify people who are susceptible to melanoma despite not having a traditional phenotypic risk profile.


Assuntos
Melanoma/diagnóstico , Patologia Molecular/estatística & dados numéricos , Grupos Populacionais , Neoplasias Cutâneas/diagnóstico , Adolescente , Adulto , Idoso , Alelos , Austrália/epidemiologia , Grupos Étnicos , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Melanoma/epidemiologia , Melanoma/genética , Pessoa de Meia-Idade , Polimorfismo Genético , Prognóstico , Medição de Risco , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/genética , Reino Unido/epidemiologia , Adulto Jovem
15.
Nat Commun ; 9(1): 1684, 2018 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-29739929

RESUMO

The skin's tendency to sunburn rather than tan is a major risk factor for skin cancer. Here we report a large genome-wide association study of ease of skin tanning in 176,678 subjects of European ancestry. We identify significant association with tanning ability at 20 loci. We confirm previously identified associations at six of these loci, and report 14 novel loci, of which ten have never been associated with pigmentation-related phenotypes. Our results also suggest that variants at the AHR/AGR3 locus, previously associated with cutaneous malignant melanoma the underlying mechanism of which is poorly understood, might act on disease risk through modulation of tanning ability.


Assuntos
Proteínas de Transporte/genética , Grupo com Ancestrais do Continente Europeu/genética , Loci Gênicos , Proteínas de Neoplasias/genética , Receptores de Hidrocarboneto Arílico/genética , Queimadura Solar/genética , Bronzeado/genética , Adulto , Idoso , Mapeamento Cromossômico , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Cor de Cabelo/genética , Humanos , Masculino , Melanoma/etiologia , Melanoma/genética , Pessoa de Meia-Idade , Neoplasias Induzidas por Radiação/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Exposição à Radiação , Fatores de Risco , Fatores Sexuais , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/genética , Reino Unido
17.
Int J Cancer ; 143(3): 508-514, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29473154

RESUMO

Melanoma is the deadliest form of skin cancer, mainly affecting populations of European ancestry. Some observational studies suggest that particular diets reduce melanoma risk, putatively through an increase in polyunsaturated fatty acid (PUFA) consumption. However, interpretation of these observational findings is difficult due to residual confounding or reverse causality. To date, a randomized controlled trial has not been carried out to examine the relationship between PUFAs and melanoma. Hence, we performed a Mendelian randomisation (MR) study to evaluate the link between PUFAs and melanoma. To perform MR, we used summary results from the largest risk genome-wide association study (GWAS) meta-analysis of melanoma, consisting of 12,874 cases and 23,203 controls. As instrumental variables we selected SNPs associated with PUFA levels from a GWAS meta-analysis of PUFA levels, from the CHARGE consortium. We used the inverse variance weighted method to estimate a causal odds ratio. To aid interpretation, we established a benchmark "large" predicted change in PUFAs in which, for example, an increase in docosahexaenoic acid (DPA) of 0.17 units (equal to 1 standard deviation) moves a person from the 17th percentile to the median. Raising PUFA levels by a large amount (increasing DPA by 0.17 units) only negligibly changed melanoma risk: odds ratio [OR] = 1.03 (95% confidence interval [CI] = 0.96-1.10). Other PUFAs yielded similar results as DPA. Our MR analysis suggests that the effect of PUFA levels on melanoma risk is either zero or very small.


Assuntos
Ácidos Graxos Insaturados/efeitos adversos , Melanoma/epidemiologia , Melanoma/etiologia , Alelos , Fatores de Confusão Epidemiológicos , Estudo de Associação Genômica Ampla , Humanos , Análise da Randomização Mendeliana , Razão de Chances , Polimorfismo de Nucleotídeo Único , Reprodutibilidade dos Testes , Medição de Risco , Fatores de Risco
18.
Nat Genet ; 49(9): 1326-1335, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28759004

RESUMO

Previous genome-wide association studies have identified a melanoma-associated locus at 1q42.1 that encompasses a ∼100-kb region spanning the PARP1 gene. Expression quantitative trait locus (eQTL) analysis in multiple cell types of the melanocytic lineage consistently demonstrated that the 1q42.1 melanoma risk allele (rs3219090[G]) is correlated with higher PARP1 levels. In silico fine-mapping and functional validation identified a common intronic indel, rs144361550 (-/GGGCCC; r2 = 0.947 with rs3219090), as displaying allele-specific transcriptional activity. A proteomic screen identified RECQL as binding to rs144361550 in an allele-preferential manner. In human primary melanocytes, PARP1 promoted cell proliferation and rescued BRAFV600E-induced senescence phenotypes in a PARylation-independent manner. PARP1 also transformed TERT-immortalized melanocytes expressing BRAFV600E. PARP1-mediated senescence rescue was accompanied by transcriptional activation of the melanocyte-lineage survival oncogene MITF, highlighting a new role for PARP1 in melanomagenesis.


Assuntos
Proliferação de Células/genética , Íntrons/genética , Melanócitos/metabolismo , Fator de Transcrição Associado à Microftalmia/genética , Poli(ADP-Ribose) Polimerase-1/genética , Polimorfismo de Nucleotídeo Único , Sequência de Bases , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Células Cultivadas , Senescência Celular/genética , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Humanos , Mutação INDEL , Immunoblotting , Melanoma/genética , Melanoma/metabolismo , Melanoma/patologia , Fator de Transcrição Associado à Microftalmia/metabolismo , Microscopia Confocal , Poli(ADP-Ribose) Polimerase-1/metabolismo , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Fatores de Risco , Telomerase/genética , Telomerase/metabolismo
19.
Nat Commun ; 8: 15034, 2017 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-28447668

RESUMO

Genome wide association studies (GWAS) have mapped multiple independent cancer susceptibility loci to chr5p15.33. Here, we show that fine-mapping of pancreatic and testicular cancer GWAS within one of these loci (Region 2 in CLPTM1L) focuses the signal to nine highly correlated SNPs. Of these, rs36115365-C associated with increased pancreatic and testicular but decreased lung cancer and melanoma risk, and exhibited preferred protein-binding and enhanced regulatory activity. Transcriptional gene silencing of this regulatory element repressed TERT expression in an allele-specific manner. Proteomic analysis identifies allele-preferred binding of Zinc finger protein 148 (ZNF148) to rs36115365-C, further supported by binding of purified recombinant ZNF148. Knockdown of ZNF148 results in reduced TERT expression, telomerase activity and telomere length. Our results indicate that the association with chr5p15.33-Region 2 may be explained by rs36115365, a variant influencing TERT expression via ZNF148 in a manner consistent with elevated TERT in carriers of the C allele.


Assuntos
Proteínas de Ligação a DNA/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , Melanoma/genética , Neoplasias Pancreáticas/genética , Neoplasias Cutâneas/genética , Telomerase/genética , Neoplasias Testiculares/genética , Fatores de Transcrição/genética , Alelos , Linhagem Celular Tumoral , Mapeamento Cromossômico , Cromossomos Humanos Par 5 , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/metabolismo , Feminino , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Histonas/genética , Histonas/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Melanoma/metabolismo , Melanoma/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Polimorfismo de Nucleotídeo Único , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Telomerase/antagonistas & inibidores , Telomerase/metabolismo , Homeostase do Telômero , Neoplasias Testiculares/metabolismo , Neoplasias Testiculares/patologia , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismo
20.
JAMA Oncol ; 3(5): 636-651, 2017 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-28241208

RESUMO

Importance: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. Objective: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases. Data Sources: Genomewide association studies (GWAS) published up to January 15, 2015. Study Selection: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available. Data Extraction and Synthesis: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population. Main Outcomes and Measures: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation. Results: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]). Conclusions and Relevance: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.


Assuntos
Predisposição Genética para Doença/genética , Análise da Randomização Mendeliana/métodos , Neoplasias/genética , Homeostase do Telômero/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Cardiovasculares/genética , Feminino , Estudo de Associação Genômica Ampla , Mutação em Linhagem Germinativa , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Medição de Risco/métodos , Telômero/genética
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