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1.
Nat Commun ; 12(1): 246, 2021 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-33431812

RESUMO

Previous Mendelian randomization (MR) studies on 25-hydroxyvitamin D (25(OH)D) and cancer have typically adopted a handful of variants and found no relationship between 25(OH)D and cancer; however, issues of horizontal pleiotropy cannot be reliably addressed. Using a larger set of variants associated with 25(OH)D (74 SNPs, up from 6 previously), we perform a unified MR analysis to re-evaluate the relationship between 25(OH)D and ten cancers. Our findings are broadly consistent with previous MR studies indicating no relationship, apart from ovarian cancers (OR 0.89; 95% C.I: 0.82 to 0.96 per 1 SD change in 25(OH)D concentration) and basal cell carcinoma (OR 1.16; 95% C.I.: 1.04 to 1.28). However, after adjustment for pigmentation related variables in a multivariable MR framework, the BCC findings were attenuated. Here we report that lower 25(OH)D is unlikely to be a causal risk factor for most cancers, with our study providing more precise confidence intervals than previously possible.


Assuntos
Predisposição Genética para Doença , Análise da Randomização Mendeliana , Neoplasias/genética , Vitamina D/metabolismo , Estudos de Casos e Controles , Criança , Humanos , Análise Multivariada , Pigmentação/genética , Fatores de Risco , Queimadura Solar/genética
2.
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.

3.
Int J Epidemiol ; 2020 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-33370439

RESUMO

BACKGROUND: Epidemiological studies have consistently documented an increased risk of developing primary non-cutaneous malignancies among people with a history of keratinocyte carcinoma (KC). However, the mechanisms underlying this association remain unclear. We conducted two separate analyses to test whether genetically predicted KC is related to the risk of developing cancers at other sites. METHODS: In the first approach (one-sample), we calculated the polygenic risk scores (PRS) for KC using individual-level data in the UK Biobank (n = 394 306) and QSkin cohort (n = 16 896). The association between the KC PRS and each cancer site was assessed using logistic regression. In the secondary (two-sample) approach, we used genome-wide association study (GWAS) summary statistics identified from the most recent GWAS meta-analysis of KC and obtained GWAS data for each cancer site from the UK-Biobank participants only. We used inverse-variance-weighted methods to estimate risks across all genetic variants. RESULTS: Using the one-sample approach, we found that the risks of cancer at other sites increased monotonically with KC PRS quartiles, with an odds ratio (OR) of 1.16, 95% confidence interval (CI): 1.13-1.19 for those in KC PRS quartile 4 compared with those in quartile 1. In the two-sample approach, the pooled risk of developing other cancers was statistically significantly elevated, with an OR of 1.05, 95% CI: 1.03-1.07 per doubling in the odds of KC. We observed similar trends of increasing cancer risk with increasing KC PRS in the QSkin cohort. CONCLUSION: Two different genetic approaches provide compelling evidence that an instrumental variable for KC constructed from genetic variants predicts the risk of cancers at other sites.

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.
J Invest Dermatol ; 2020 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-32615124

RESUMO

Organ-transplant recipients have an elevated risk of keratinocyte cancers: basal cell carcinoma (BCC) and squamous cell carcinoma. We assessed whether polygenic risk scores (PRSs) generated in nontransplantees from the UK Biobank and 23andMe (13,981 squamous cell carcinoma, 33,736 BCC, and >560,000 controls) can predict keratinocyte cancer risk in an independent organ-transplant recipient cohort. After adjusting for traditional risk factors, compared with the bottom 20%, organ-transplant recipients in the top 20% PRS had an increased risk of BCC (OR = 3.25, 95% confidence interval = 1.44-7.31, P = 4.4 × 10-3) and squamous cell carcinoma (OR = 2.11, 95% confidence interval = 0.98-4.53, P = 0.055). For BCC, the top 20% PRS individuals had an absolute risk of 23%, whereas the risk in the bottom 20% was similar to that in the general nontransplantee population. Adding PRS to a model containing traditional skin cancer risk factors yielded a 3% increase in the area under the curve for receiver operating characteristic curve for BCC (0.73 vs. 0.70); adding the PRS did not significantly increase the area under the curve for receiver operating characteristic curve for squamous cell carcinoma. Organ-transplant recipients in the highest genetic risk quintile could benefit from more intense keratinocyte cancer screening and preventive strategies compared with their counterparts. The BCC PRS improves prediction over and above the traditional skin cancer risk factors by 3%.

6.
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
7.
Hum Mol Genet ; 29(R2): R165-R176, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-32620971

RESUMO

Genetic testing is used widely for diagnostic, carrier and predictive testing in monogenic diseases. Until recently, there were no genetic testing options available for multifactorial complex diseases like heart disease, diabetes and cancer. Genome-wide association studies (GWAS) have been invaluable in identifying single-nucleotide polymorphisms (SNPs) associated with increased or decreased risk for hundreds of complex disorders. For a given disease, SNPs can be combined to generate a cumulative estimation of risk known as a polygenic risk score (PRS). After years of research, PRSs are increasingly used in clinical settings. In this article, we will review the literature on how both genome-wide and restricted PRSs are developed and the relative merit of each. The validation and evaluation of PRSs will also be discussed, including the recognition that PRS validity is intrinsically linked to the methodological and analytical approach of the foundation GWAS together with the ethnic characteristics of that cohort. Specifically, population differences may affect imputation accuracy, risk magnitude and direction. Even as PRSs are being introduced into clinical practice, there is a push to combine them with clinical and demographic risk factors to develop a holistic disease risk. The existing evidence regarding the clinical utility of PRSs is considered across four different domains: informing population screening programs, guiding therapeutic interventions, refining risk for families at high risk, and facilitating diagnosis and predicting prognostic outcomes. The evidence for clinical utility in relation to five well-studied disorders is summarized. The potential ethical, legal and social implications are also highlighted.

8.
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
9.
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.

10.
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.

11.
Nat Genet ; 52(2): 160-166, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31959993

RESUMO

Glaucoma, a disease characterized by progressive optic nerve degeneration, can be prevented through timely diagnosis and treatment. We characterize optic nerve photographs of 67,040 UK Biobank participants and use a multitrait genetic model to identify risk loci for glaucoma. A glaucoma polygenic risk score (PRS) enables effective risk stratification in unselected glaucoma cases and modifies penetrance of the MYOC variant encoding p.Gln368Ter, the most common glaucoma-associated myocilin variant. In the unselected glaucoma population, individuals in the top PRS decile reach an absolute risk for glaucoma 10 years earlier than the bottom decile and are at 15-fold increased risk of developing advanced glaucoma (top 10% versus remaining 90%, odds ratio = 4.20). The PRS predicts glaucoma progression in prospectively monitored, early manifest glaucoma cases (P = 0.004) and surgical intervention in advanced disease (P = 3.6 × 10-6). This glaucoma PRS will facilitate the development of a personalized approach for earlier treatment of high-risk individuals, with less intensive monitoring and treatment being possible for lower-risk groups.


Assuntos
Glaucoma/genética , Polimorfismo de Nucleotídeo Único , Austrália , Estudos de Casos e Controles , Proteínas do Citoesqueleto/genética , Progressão da Doença , Proteínas do Olho/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Glaucoma/etiologia , Glaucoma/cirurgia , Glicoproteínas/genética , Humanos , Pressão Intraocular/genética , Herança Multifatorial , Razão de Chances , Nervo Óptico/fisiologia , Penetrância , Trabeculectomia/efeitos adversos , Reino Unido , Estados Unidos
12.
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
13.
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.

15.
Nat Commun ; 10(1): 4219, 2019 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-31527586

RESUMO

Gastroesophageal reflux disease (GERD) is caused by gastric acid entering the esophagus. GERD has high prevalence and is the major risk factor for Barrett's esophagus (BE) and esophageal adenocarcinoma (EA). We conduct a large GERD GWAS meta-analysis (80,265 cases, 305,011 controls), identifying 25 independent genome-wide significant loci for GERD. Several of the implicated genes are existing or putative drug targets. Loci discovery is greatest with a broad GERD definition (including cases defined by self-report or medication data). Further, 91% of the GERD risk-increasing alleles also increase BE and/or EA risk, greatly expanding gene discovery for these traits. Our results map genes for GERD and related traits and uncover potential new drug targets for these conditions.


Assuntos
Doenças do Esôfago/genética , Refluxo Gastroesofágico/genética , Estudo de Associação Genômica Ampla , Feminino , Loci Gênicos , Predisposição Genética para Doença , Humanos , Masculino , Polimorfismo de Nucleotídeo Único
16.
Int J Epidemiol ; 48(5): 1447-1456, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31412118

RESUMO

BACKGROUND: Previous observational studies have suggested that coffee intake may be associated with a reduction in cancer risk. Mendelian randomization (MR) studies can help clarify whether the observed associations are likely to be causal. Here we evaluated whether coffee intake is associated with: (i) overall risk of being diagnosed with/dying from any cancer; and (ii) risk of individual cancers. METHODS: We identified 46 155 cases (of which 6998 were fatal) and 270 342 controls of White British ancestry from the UK Biobank cohort (UKB), based on ICD10 diagnoses. Individuals with benign tumours were excluded. Coffee intake was self-reported and recorded based on cup/day consumption. We conducted both observational and summary data MR analyses. RESULTS: There was no observational association between coffee intake and overall cancer risk [odds ratio (OR) per one cup/day increase = 0.99, 95% confidence interval (CI) 0.98, 1.00] or cancer death (OR = 1.01, 0.99, 1.03); the estimated OR from MR is 1.01 (0.94, 1.08) for overall cancer risk and 1.11 (0.95, 1.31) for cancer death. The relationship between coffee intake and individual cancer risks were consistent with a null effect, with most cancers showing little or no associations with coffee. Meta-analysis of our MR findings with publicly available summary data on various cancers do not support a strong causal relationship between coffee and risk of breast, ovarian, lung or prostate cancer, upon correction for multiple testing. CONCLUSIONS: Taken together, coffee intake is not associated with overall risk of being diagnosed with or dying from cancer in UKB. For individual cancers, our findings were not statistically inconsistent with earlier observational studies, although for these we were unable to rule out a small effect on specific types of cancer.


Assuntos
Café , Neoplasias/epidemiologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Causalidade , Bases de Dados Factuais , Relação Dose-Resposta a Droga , Grupo com Ancestrais do Continente Europeu , Humanos , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Neoplasias/genética , Neoplasias/mortalidade , Estudos Observacionais como Assunto , Razão de Chances , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Fatores Sexuais , Reino Unido/epidemiologia
17.
Hum Mol Genet ; 28(18): 3148-3160, 2019 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-31174203

RESUMO

The keratinocyte cancers (KC), basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the most common cancers in fair-skinned people. KC treatment represents the second highest cancer healthcare expenditure in Australia. Increasing our understanding of the genetic architecture of KC may provide new avenues for prevention and treatment. We first conducted a series of genome-wide association studies (GWAS) of KC across three European ancestry datasets from Australia, Europe and USA, and used linkage disequilibrium (LD) Score regression (LDSC) to estimate their pairwise genetic correlations. We employed a multiple-trait approach to map genes across the combined set of KC GWAS (total N = 47 742 cases, 634 413 controls). We also performed meta-analyses of BCC and SCC separately to identify trait specific loci. We found substantial genetic correlations (generally 0.5-1) between BCC and SCC suggesting overlapping genetic risk variants. The multiple trait combined KC GWAS identified 63 independent genome-wide significant loci, 29 of which were novel. Individual separate meta-analyses of BCC and SCC identified an additional 13 novel loci not found in the combined KC analysis. Three new loci were implicated using gene-based tests. New loci included common variants in BRCA2 (distinct to known rare high penetrance cancer risk variants), and in CTLA4, a target of immunotherapy in melanoma. We found shared and trait specific genetic contributions to BCC and SCC. Considering both, we identified a total of 79 independent risk loci, 45 of which are novel.


Assuntos
Carcinoma Basocelular/genética , Carcinoma de Células Escamosas/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Queratinócitos/metabolismo , Locos de Características Quantitativas , Neoplasias Cutâneas/genética , Alelos , Carcinoma Basocelular/metabolismo , Carcinoma Basocelular/patologia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Estudos de Casos e Controles , Biologia Computacional/métodos , Perfilação da Expressão Gênica , Humanos , Queratinócitos/patologia , Anotação de Sequência Molecular , Razão de Chances , Polimorfismo de Nucleotídeo Único , Característica Quantitativa Herdável , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia
18.
Cancer Epidemiol Biomarkers Prev ; 28(6): 1015-1023, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30948449

RESUMO

BACKGROUND: Observational studies evaluating the link between polyunsaturated fatty acids (PUFA) and cancers have yielded mixed findings. We used Mendelian randomization (MR) to evaluate whether genetic evidence supports a causal role for PUFAs on overall cancer outcomes. METHODS: We identified genetic instruments for six PUFAs from previous literature and evaluated their association with overall cancer risk (46,155 cases, 270,342 controls) and cancer mortality (6,998 deaths, 270,342 controls) among the UK Biobank cohort. We used the inverse variance weighted model to combine SNP estimates, and derived log (OR) estimates per SD change in each PUFA. RESULTS: None of the six PUFAs showed association with overall cancer risk or mortality, with narrow confidence interval (CI) ruling out all but very small effects, for example, arachidonic acid (AA) overall cancer risk (OR, 1.02; 95% CI, 1.00-1.03). Sex-specific analysis revealed no associations except α-linolenic acid for potentially reducing cancer risk in men (OR, 0.92; 95% CI, 0.86-0.98; P = 0.02); however, this was nonsignificant after multiple testing correction. From individual cancers, only colorectal cancer showed evidence for a causal association for higher AA levels (OR, 1.05; 95% CI, 1.03-1.07), with similar results for the other correlated PUFAs. CONCLUSIONS: Our study provides no support for the hypothesis that PUFAs reduce overall cancer risk or mortality. Higher AA levels increased the risk for colorectal cancer. IMPACT: Our well-powered MR study provides robust causal inferences for the PUFAs on overall cancer risk and mortality. Future larger studies are warranted to replicate the individual cancer findings.


Assuntos
Ácidos Graxos Insaturados/metabolismo , Neoplasias/genética , Neoplasias/mortalidade , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Análise da Randomização Mendeliana/métodos , Pessoa de Meia-Idade , Neoplasias/metabolismo , Polimorfismo de Nucleotídeo Único , Prognóstico , Medição de Risco/métodos , Fatores de Risco , Taxa de Sobrevida , Reino Unido/epidemiologia
19.
Br J Cancer ; 120(5): 565-570, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30733581

RESUMO

BACKGROUND: Whether body mass index (BMI) is causally associated with the risk of being diagnosed with or dying from any cancer remains unclear. Weight reduction has clinical importance for cancer control only if weight gain causes cancer development or death. We aimed to answer the question 'does genetically predicted BMI influence my risk of being diagnosed with or dying from any cancer'. METHODS: We used a Mendelian randomisation (MR) approach to estimate causal effect of BMI in 46,155 white-British participants aged between 40 and 69 years at recruitment (median age at follow-up 61 years) from the UK Biobank, who developed any type of cancer, among whom 6998 died from cancer. To derive MR instruments for BMI, we selected up to 390,628 cancer-free participants. RESULTS: For each standard deviation (4.78 units) increase in genetically predicted BMI, we estimated a causal odds ratio (COR) of 1.07 (1.02-1.12) and 1.28 (1.16-1.41) for overall cancer risk and mortality, respectively. The corresponding estimates were similar for males and females, and smokers and non-smokers. CONCLUSIONS: Higher genetically predicted BMI increases the risk of being diagnosed with or dying from any cancer. These data suggest that increased overall weight may causally increase overall cancer incidence and mortality among Europeans.


Assuntos
Neoplasias/epidemiologia , Neoplasias/mortalidade , Obesidade/epidemiologia , Adulto , Idoso , Índice de Massa Corporal , Grupo com Ancestrais do Continente Europeu , Feminino , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Neoplasias/genética , Obesidade/genética , Sobrepeso/epidemiologia , Sobrepeso/genética , Reino Unido
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