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1.
Sci Rep ; 10(1): 22099, 2020 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-33328623

RESUMO

We monitored the burden of cancer in Italy and its trends over the last three decades, providing estimates of cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years (DALYs), for cancer overall and 30 cancer sites using data from the Global Burden of Disease study 2017. An overview of mortality trends between 1990 and 2017 was also provided. In 2017, there were 254,336 new cancer cases in men and 214,994 in women, corresponding to an age-standardized incidence rate (ASIR) of 438 and 330/100,000, respectively. Between 1990 and 2017, incident cancer cases, and, to a lesser extent, ASIRs significantly increased overall and for almost all cancer sites, but ASIRs significantly declined for lung and other tobacco-related neoplasms. In 2017, there were 101,659 cancer deaths in men (age-standardized death rate, ASDR, 158.5/100,000) and 78,918 in women (ASDR 93.9/100,000). Cancer deaths significantly increased between 1990 and 2017 (+ 18%), but ASDR significantly decreased (- 28%). Deaths significantly increased for many cancer sites, but decreased for stomach, esophageal, laryngeal, Hodgkin lymphoma, and testicular cancer. ASDRs significantly decreased for most neoplasms, with the main exceptions of cancer of the pancreas and uterus, and multiple myeloma. In 2017, cancer caused 3,204,000 DALYs. Between 1990 and 2017, DALYs and age-standardized DALY rates significantly declined (-3.4% and -33%, respectively). Age-standardized mortality rates in Italy showed favorable patterns over the last few decades. However, the absolute number of cancer cases and, to a lower extent, of cancer deaths increased likely due to the progressive ageing of the population, this calling for a continuous effort in cancer prevention, early diagnosis, and treatment.

2.
PLoS One ; 14(10): e0223574, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31622379

RESUMO

BACKGROUND: Increased serum levels of C-reactive protein (CRP), an important component of the innate immune response, are associated with increased risk of cardiovascular disease (CVD). Multiple single nucleotide polymorphisms (SNP) have been identified which are associated with CRP levels, and Mendelian randomization studies have shown a positive association between SNPs increasing CRP expression and risk of colon cancer (but thus far not CVD). The effects of individual genetic variants often interact with the genetic background of a population and hence we sought to resolve the genetic determinants of serum CRP in a number of American Indian populations. METHODS: The Strong Heart Family Study (SHFS) has serum CRP measurements from 2428 tribal members, recruited as large families from three regions of the United States. Microsatellite markers and MetaboChip defined SNP genotypes were incorporated into variance components, decomposition-based linkage and association analyses. RESULTS: CRP levels exhibited significant heritability (h2 = 0.33 ± 0.05, p<1.3 X 10-20). A locus on chromosome (chr) 6, near marker D6S281 (approximately at 169.6 Mb, GRCh38/hg38) showed suggestive linkage (LOD = 1.9) to CRP levels. No individual SNPs were found associated with CRP levels after Bonferroni adjustment for multiple testing (threshold <7.77 x 10-7), however, we found nominal associations, many of which replicate previous findings at the CRP, HNF1A and 7 other loci. In addition, we report association of 46 SNPs located at 7 novel loci on chromosomes 2, 5, 6(2 loci), 9, 10 and 17, with an average of 15.3 Kb between SNPs and all with p-values less than 7.2 X 10-4. CONCLUSION: In agreement with evidence from other populations, these data show CRP serum levels are under considerable genetic influence; and include loci, such as near CRP and other genes, that replicate results from other ethnic groups. These findings also suggest possible novel loci on chr 6 and other chromosomes that warrant further investigation.


Assuntos
Biomarcadores , Proteína C-Reativa/genética , Variação Genética , Genética Populacional , Índios Norte-Americanos/genética , Alelos , Biomarcadores/sangue , Feminino , Ligação Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único
3.
Nature ; 570(7762): 514-518, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31217584

RESUMO

Genome-wide association studies (GWAS) have laid the foundation for investigations into the biology of complex traits, drug development and clinical guidelines. However, the majority of discovery efforts are based on data from populations of European ancestry1-3. In light of the differential genetic architecture that is known to exist between populations, bias in representation can exacerbate existing disease and healthcare disparities. Critical variants may be missed if they have a low frequency or are completely absent in European populations, especially as the field shifts its attention towards rare variants, which are more likely to be population-specific4-10. Additionally, effect sizes and their derived risk prediction scores derived in one population may not accurately extrapolate to other populations11,12. Here we demonstrate the value of diverse, multi-ethnic participants in large-scale genomic studies. The Population Architecture using Genomics and Epidemiology (PAGE) study conducted a GWAS of 26 clinical and behavioural phenotypes in 49,839 non-European individuals. Using strategies tailored for analysis of multi-ethnic and admixed populations, we describe a framework for analysing diverse populations, identify 27 novel loci and 38 secondary signals at known loci, as well as replicate 1,444 GWAS catalogue associations across these traits. Our data show evidence of effect-size heterogeneity across ancestries for published GWAS associations, substantial benefits for fine-mapping using diverse cohorts and insights into clinical implications. In the United States-where minority populations have a disproportionately higher burden of chronic conditions13-the lack of representation of diverse populations in genetic research will result in inequitable access to precision medicine for those with the highest burden of disease. We strongly advocate for continued, large genome-wide efforts in diverse populations to maximize genetic discovery and reduce health disparities.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Grupo com Ancestrais do Continente Asiático/genética , Estudo de Associação Genômica Ampla/métodos , Hispano-Americanos/genética , Grupos Minoritários , Herança Multifatorial/genética , Saúde da Mulher , Estatura/genética , Estudos de Coortes , Feminino , Genética Médica/métodos , Equidade em Saúde/tendências , Disparidades nos Níveis de Saúde , Humanos , Masculino , Estados Unidos
4.
PLoS One ; 13(10): e0206519, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30379922

RESUMO

BACKGROUND: High levels of serum leptin and low levels of serum adiponectin are strongly correlated with obesity, a well-established risk factor for colorectal cancer (CRC). Growing evidence suggests that dysregulation of leptin and adiponectin levels may play an etiological role in colorectal carcinogenesis. We evaluated 20 candidate variants in 4 genes previously shown to alter serum leptin and adiponectin levels for associations with obesity (BMI>30 kg/m2) and CRC risk. METHODS: We analyzed 6,246 CRC cases and 7,714 population-based controls from 11 studies within the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Associations of each variant with obesity or CRC were evaluated using multivariate logistic regression models stratified by sex and adjusted for age, a study variable, and the first three principal components of genetic ancestry. Gene-specific False Discovery Rate (FDR)-adjusted p-values <0.05 denoted statistical significance. RESULTS: Two variants in the leptin gene showed statistically significant associations with CRC among women: LEP rs2167270 (OR = 1.13, 95% CI: 1.06-1.21) and LEP rs4731426 (OR = 1.09, 95% CI: 1.02-1.17). These associations remained significant after adjustment for obesity, suggesting that leptin SNPs may influence CRC risk independent of obesity. We observed statistically significant interactions of the leptin variants with hormone replacement therapy (HRT) for CRC risk; these variant associations were strengthened when analyses were restricted to post-menopausal women with low estrogen exposure, as estimated by 'never use' of HRT and/or non-obese BMI. No variants were associated with CRC among men. CONCLUSIONS: Leptin gene variants may exhibit sex-specific associations with CRC risk. Endogenous and exogenous estrogen exposure may modify the association between these variants, leptin levels, and CRC risk.


Assuntos
Neoplasias Colorretais/genética , Predisposição Genética para Doença , Leptina/genética , Polimorfismo de Nucleotídeo Único , Adiponectina/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Neoplasias Colorretais/patologia , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Leptina/sangue , Masculino , Pessoa de Meia-Idade , Fatores Sexuais
5.
Hum Mol Genet ; 27(16): 2940-2953, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-29878111

RESUMO

C-reactive protein (CRP) is a circulating biomarker indicative of systemic inflammation. We aimed to evaluate genetic associations with CRP levels among non-European-ancestry populations through discovery, fine-mapping and conditional analyses. A total of 30 503 non-European-ancestry participants from 6 studies participating in the Population Architecture using Genomics and Epidemiology study had serum high-sensitivity CRP measurements and ∼200 000 single nucleotide polymorphisms (SNPs) genotyped on the Metabochip. We evaluated the association between each SNP and log-transformed CRP levels using multivariate linear regression, with additive genetic models adjusted for age, sex, the first four principal components of genetic ancestry, and study-specific factors. Differential linkage disequilibrium patterns between race/ethnicity groups were used to fine-map regions associated with CRP levels. Conditional analyses evaluated for multiple independent signals within genetic regions. One hundred and sixty-three unique variants in 12 loci in overall or race/ethnicity-stratified Metabochip-wide scans reached a Bonferroni-corrected P-value <2.5E-7. Three loci have no (HACL1, OLFML2B) or only limited (PLA2G6) previous associations with CRP levels. Six loci had different top hits in race/ethnicity-specific versus overall analyses. Fine-mapping refined the signal in six loci, particularly in HNF1A. Conditional analyses provided evidence for secondary signals in LEPR, IL1RN and HNF1A, and for multiple independent signals in CRP and APOE. We identified novel variants and loci associated with CRP levels, generalized known CRP associations to a multiethnic study population, refined association signals at several loci and found evidence for multiple independent signals at several well-known loci. This study demonstrates the benefit of conducting inclusive genetic association studies in large multiethnic populations.


Assuntos
Proteína C-Reativa/genética , Estudo de Associação Genômica Ampla , Metagenômica , Epidemiologia Molecular/métodos , Carbono-Carbono Liases , Enoil-CoA Hidratase/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Glicoproteínas/genética , Fosfolipases A2 do Grupo VI/genética , Humanos , Desequilíbrio de Ligação , Masculino , Polimorfismo de Nucleotídeo Único
6.
Cancer ; 123(23): 4701-4708, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-28841225

RESUMO

BACKGROUND: Body weight is associated with colorectal cancer (CRC) risk and survival, but to the authors' knowledge, the impact of long-term postdiagnostic weight change is unclear. Herein, the authors investigated whether weight change over the 5 years after a diagnosis of CRC is associated with survival. METHODS: CRC cases diagnosed from 1997 to 2008 were identified through 4 population-based cancer registry sites. Participants enrolled within 2 years of diagnosis and reported their height and weight 2 years prior. Follow-up questionnaires were administered approximately 5 years after diagnosis. Associations between change in weight (in kg) or body mass index (BMI) with overall and CRC-specific survival were estimated using Cox regression analysis adjusted for age, sex, American Joint Committee on Cancer stage of disease, baseline BMI, nonsteroidal anti-inflammatory drug use, smoking, time between diagnosis and enrollment, and study site. RESULTS: At the 5-year postdiagnostic survey, 2049 participants reported higher (53%; median plus 5 kg), unchanged (12%), or lower (35%; median -4 kg) weight. Over a median of 5.1 years of subsequent follow-up (range, 0.3-9.9 years), 344 participants died (91 of CRC). Long-term weight loss (per 5 kg) was found to be associated with poorer overall survival (hazard ratio, 1.13; 95% confidence interval, 1.07-1.21) and CRC-specific survival (hazard ratio, 1.25; 95% confidence interval, 1.13-1.39). Significantly lower survival was similarly observed for relative weight loss (>5% vs ≤5% change), BMI reduction (per 1 unit), or BMI category change (overweight to normal vs remaining overweight). CONCLUSIONS: Weight loss 5 years after a diagnosis of CRC was found to be significantly associated with decreased long-term survival, suggesting the importance of avoiding weight loss in survivors of CRC. Future research should attempt to further evaluate this association, accounting for whether this weight change was intentional or represents a marker of declining health. Cancer 2017;123:4701-4708. © 2017 American Cancer Society.


Assuntos
Sobreviventes de Câncer , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/mortalidade , Perda de Peso , Índice de Massa Corporal , Neoplasias Colorretais/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Sistema de Registros , Fatores de Risco , Taxa de Sobrevida
7.
J Clin Oncol ; 35(24): 2806-2813, 2017 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-28617623

RESUMO

Purpose Regular use of aspirin is associated with improved survival for patients with colorectal cancer (CRC). However, the timing of and the subtype of CRC that would benefit the most from using aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) in relation to survival is unclear. Patients and Methods In all, 2,419 patients age 18 to 74 years with incident invasive CRC who were diagnosed from 1997 to 2008 were identified from population-based cancer registries in the United States, Canada, and Australia. Detailed epidemiologic questionnaires were administered at study enrollment and at 5-year follow-up. Survival outcomes were completed through linkage to national death registries. BRAF- and KRAS-mutation status, microsatellite instability, and CpG island methylator phenotype were also evaluated. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs for overall survival (OS) and CRC-specific survival. Results After a median of 10.8 years of follow-up since diagnosis, 381 deaths (100 as a result of CRC) were observed. Compared with nonusers, postdiagnostic aspirin-only users had more favorable OS (HR, 0.75; 95% CI, 0.59 to 0.95) and CRC-specific survival (HR, 0.44; 95% CI, 0.25 to 0.71), especially among those who initiated aspirin use (OS: HR, 0.64; 95% CI, 0.47 to 0.86; CRC-specific survival: HR, 0.40; 95% CI, 0.20 to 0.80). The association between any NSAID use after diagnosis and OS differed significantly by KRAS-mutation status ( Pinteraction = .01). Use of any NSAID after diagnosis was associated with improved OS only among participants with KRAS wild-type tumors (HR, 0.60; 95% CI, 0.46 to 0.80) but not among those with KRAS-mutant tumors (HR, 1.24; 95% CI, 0.78 to 1.96). Conclusion Among long-term CRC survivors, regular use of NSAIDs after CRC diagnosis was significantly associated with improved survival in individuals with KRAS wild-type tumors.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Aspirina/administração & dosagem , Biomarcadores Tumorais/análise , Neoplasias Colorretais/mortalidade , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Feminino , Humanos , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Sistema de Registros , Taxa de Sobrevida
8.
PLoS One ; 11(12): e0167758, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27973554

RESUMO

Investigating genetic architecture of complex traits in ancestrally diverse populations is imperative to understand the etiology of disease. However, the current paucity of genetic research in people of African and Latin American ancestry, Hispanic and indigenous peoples in the United States is likely to exacerbate existing health disparities for many common diseases. The Population Architecture using Genomics and Epidemiology, Phase II (PAGE II), Study was initiated in 2013 by the National Human Genome Research Institute to expand our understanding of complex trait loci in ethnically diverse and well characterized study populations. To meet this goal, the Multi-Ethnic Genotyping Array (MEGA) was designed to substantially improve fine-mapping and functional discovery by increasing variant coverage across multiple ethnicities at known loci for metabolic, cardiovascular, renal, inflammatory, anthropometric, and a variety of lifestyle traits. Studying the frequency distribution of clinically relevant mutations, putative risk alleles, and known functional variants across multiple populations will provide important insight into the genetic architecture of complex diseases and facilitate the discovery of novel, sometimes population-specific, disease associations. DNA samples from 51,650 self-identified African ancestry (17,328), Hispanic/Latino (22,379), Asian/Pacific Islander (8,640), and American Indian (653) and an additional 2,650 participants of either South Asian or European ancestry, and other reference panels have been genotyped on MEGA by PAGE II. MEGA was designed as a new resource for studying ancestrally diverse populations. Here, we describe the methodology for selecting trait-specific content for use in multi-ethnic populations and how enriching MEGA for this content may contribute to deeper biological understanding of the genetic etiology of complex disease.


Assuntos
Grupos Étnicos/genética , Variação Genética , Genoma Humano , Genômica/métodos , Alelos , Antropometria , Mapeamento Cromossômico , Exoma , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Mutação , Estados Unidos
9.
Int J Cancer ; 139(5): 1065-72, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27121247

RESUMO

Higher body mass index (BMI) is a well-established risk factor for colorectal cancer (CRC), but is inconsistently associated with CRC survival. In 6 prospective studies participating in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), 2,249 non-Hispanic white CRC cases were followed for a median 4.5 years after diagnosis, during which 777 died, 554 from CRC-related causes. Associations between prediagnosis BMI and survival (overall and CRC-specific) were evaluated using Cox regression models adjusted for age at diagnosis, sex, study and smoking status (current/former/never). The association between BMI category and CRC survival varied by cancer stage at diagnosis (I-IV) for both all-cause (p-interaction = 0.03) and CRC-specific mortality (p-interaction = 0.04). Compared to normal BMI (18.5-24.9 kg/m(2) ), overweight (BMI 25.0-29.9) was associated with increased mortality among those with Stage I disease, and decreased mortality among those with Stages II-IV disease. Similarly, obesity (BMI ≥30) was associated with increased mortality among those with Stages I-II disease, and decreased mortality among those with Stages III-IV disease. These results suggest the relationship between BMI and survival after CRC diagnosis differs by stage at diagnosis, and may emphasize the importance of adequate metabolic reserves for colorectal cancer survival in patients with late-stage disease.


Assuntos
Índice de Massa Corporal , Neoplasias Colorretais/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Obesidade/complicações , Sobrepeso/complicações , Vigilância da População , Modelos de Riscos Proporcionais , Fatores de Risco , Taxa de Sobrevida
10.
Gastroenterol Rep (Oxf) ; 3(4): 269-76, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26337942

RESUMO

Colorectal cancer (CRC) is a heterogeneous disease, arising from many possible etiological pathways. This heterogeneity can have important implications for CRC prognosis and clinical management. Epidemiological studies of CRC risk and prognosis-as well as clinical trials for the treatment of CRC-must therefore be sensitive to the molecular phenotype of colorectal tumors in patients under study. In this review, we describe four tumor markers that have been widely studied as reflections of CRC heterogeneity: (i) microsatellite instability (MSI) or DNA mismatch repair (MMR) deficiency, (ii) the CpG island methylator phenotype (CIMP), and somatic mutations in (iii) BRAF and (iv) KRAS. These tumor markers have been used to better characterize CRC epidemiology and, increasingly, may be used to guide clinical decision-making. Going beyond these traditional tumor markers, we also briefly review some more novel markers likely to be of clinical significance. Lastly, recognizing that none of these individual tumor markers are isolated attributes but, rather, a reflection of broader tumor phenotypes, we review some of the hypothesized etiological pathways of CRC development and their associated clinical differences.

11.
PLoS One ; 10(3): e0120491, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25789475

RESUMO

BACKGROUND: Several regions of the genome show pleiotropic associations with multiple cancers. We sought to evaluate whether 181 single-nucleotide polymorphisms previously associated with various cancers in genome-wide association studies were also associated with melanoma risk. METHODS: We evaluated 2,131 melanoma cases and 20,353 controls from three studies in the Population Architecture using Genomics and Epidemiology (PAGE) study (EAGLE-BioVU, MEC, WHI) and two collaborating studies (HPFS, NHS). Overall and sex-stratified analyses were performed across studies. RESULTS: We observed statistically significant associations with melanoma for two lung cancer SNPs in the TERT-CLPTM1L locus (Bonferroni-corrected p<2.8x10-4), replicating known pleiotropic effects at this locus. In sex-stratified analyses, we also observed a potential male-specific association between prostate cancer risk variant rs12418451 and melanoma risk (OR=1.22, p=8.0x10-4). No other variants in our study were associated with melanoma after multiple comparisons adjustment (p>2.8e-4). CONCLUSIONS: We provide confirmatory evidence of pleiotropic associations with melanoma for two SNPs previously associated with lung cancer, and provide suggestive evidence for a male-specific association with melanoma for prostate cancer variant rs12418451. This SNP is located near TPCN2, an ion transport gene containing SNPs which have been previously associated with hair pigmentation but not melanoma risk. Previous evidence provides biological plausibility for this association, and suggests a complex interplay between ion transport, pigmentation, and melanoma risk that may vary by sex. If confirmed, these pleiotropic relationships may help elucidate shared molecular pathways between cancers and related phenotypes.


Assuntos
Estudo de Associação Genômica Ampla , Neoplasias Pulmonares/genética , Melanoma/genética , Neoplasias Cutâneas/genética , Idoso , Idoso de 80 Anos ou mais , Alelos , Estudos de Casos e Controles , Feminino , Pleiotropia Genética , Genótipo , Humanos , Neoplasias Pulmonares/patologia , Masculino , Melanoma/patologia , Proteínas de Membrana/genética , Metagenômica , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Risco , Fatores Sexuais , Neoplasias Cutâneas/metabolismo , Telomerase/genética
12.
Cancer Epidemiol Biomarkers Prev ; 23(12): 2971-6, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25192705

RESUMO

BACKGROUND: Calcium intake may reduce risk of colorectal cancer, but the mechanisms remain unclear. Studies of interaction between calcium intake and SNPs in calcium-related pathways have yielded inconsistent results. METHODS: To identify gene-calcium interactions, we tested interactions between approximately 2.7 million SNPs across the genome with self-reported calcium intake (from dietary or supplemental sources) in 9,006 colorectal cancer cases and 9,503 controls of European ancestry. To test for multiplicative interactions, we used multivariable logistic regression and defined statistical significance using the conventional genome-wide α = 5E-08. RESULTS: After accounting for multiple comparisons, there were no statistically significant SNP interactions with total, dietary, or supplemental calcium intake. CONCLUSIONS: We found no evidence of SNP interactions with calcium intake for colorectal cancer risk in a large population of 18,509 individuals. IMPACT: These results suggest that in genome-wide analysis common genetic variants do not strongly modify the association between calcium intake and colorectal cancer in European populations.


Assuntos
Cálcio na Dieta/uso terapêutico , Neoplasias Colorretais/genética , Polimorfismo de Nucleotídeo Único/genética , Neoplasias Colorretais/epidemiologia , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Fatores de Risco
13.
Carcinogenesis ; 35(9): 2068-73, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24832084

RESUMO

Genome-wide association studies (GWAS) have identified a large number of cancer-associated single nucleotide polymorphisms (SNPs), several of which have been associated with multiple cancer sites suggesting pleiotropic effects and shared biological mechanisms across some cancers. We hypothesized that SNPs associated with other cancers may be additionally associated with endometrial cancer. We examined 213 SNPs previously associated with 14 other cancers for their associations with endometrial cancer in 3758 endometrial cancer cases and 5966 controls of European ancestry from two consortia: Population Architecture Using Genomics and Epidemiology and the Epidemiology of Endometrial Cancer Consortium. Study-specific logistic regression estimates adjusted for age, body mass index and the most significant principal components of genetic ancestry were combined using fixed-effect meta-analysis to evaluate the association between each SNP and endometrial cancer risk. A Bonferroni-corrected P value of 2.35×10(-4) was used to determine statistical significance of the associations. SNP rs7679673, ~6.3kb upstream of TET2 and previously reported to be associated with prostate cancer risk, was associated with endometrial cancer risk in the direction opposite to that for prostate cancer [meta-analysis odds ratio = 0.87 (per copy of the C allele), 95% confidence interval = 0.81, 0.93; P = 7.37×10(-5)] with no evidence of heterogeneity across studies (P heterogeneity = 0.66). This pleiotropic analysis is the first to suggest TET2 as a susceptibility locus for endometrial cancer.


Assuntos
Proteínas de Ligação a DNA/genética , Neoplasias do Endométrio/genética , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas/genética , Estudos de Casos e Controles , Feminino , Pleiotropia Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Fatores de Risco
15.
J Natl Cancer Inst ; 106(4): dju061, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24681604

RESUMO

BACKGROUND: Genome-wide association studies have identified hundreds of genetic variants associated with specific cancers. A few of these risk regions have been associated with more than one cancer site; however, a systematic evaluation of the associations between risk variants for other cancers and lung cancer risk has yet to be performed. METHODS: We included 18023 patients with lung cancer and 60543 control subjects from two consortia, Population Architecture using Genomics and Epidemiology (PAGE) and Transdisciplinary Research in Cancer of the Lung (TRICL). We examined 165 single-nucleotide polymorphisms (SNPs) that were previously associated with at least one of 16 non-lung cancer sites. Study-specific logistic regression results underwent meta-analysis, and associations were also examined by race/ethnicity, histological cell type, sex, and smoking status. A Bonferroni-corrected P value of 2.5×10(-5) was used to assign statistical significance. RESULTS: The breast cancer SNP LSP1 rs3817198 was associated with an increased risk of lung cancer (odds ratio [OR] = 1.10; 95% confidence interval [CI] = 1.05 to 1.14; P = 2.8×10(-6)). This association was strongest for women with adenocarcinoma (P = 1.2×10(-4)) and not statistically significant in men (P = .14) with this cell type (P het by sex = .10). Two glioma risk variants, TERT rs2853676 and CDKN2BAS1 rs4977756, which are located in regions previously associated with lung cancer, were associated with increased risk of adenocarcinoma (OR = 1.16; 95% CI = 1.10 to 1.22; P = 1.1×10(-8)) and squamous cell carcinoma (OR = 1.13; CI = 1.07 to 1.19; P = 2.5×10(-5)), respectively. CONCLUSIONS: Our findings demonstrate a novel pleiotropic association between the breast cancer LSP1 risk region marked by variant rs3817198 and lung cancer risk.


Assuntos
Adenocarcinoma/epidemiologia , Neoplasias da Mama/epidemiologia , Neoplasias Pulmonares/epidemiologia , Proteínas dos Microfilamentos/genética , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas/genética , Adenocarcinoma/etnologia , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adulto , Idoso , Neoplasias da Mama/etnologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Inibidor de Quinase Dependente de Ciclina p15/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Comunicação Interdisciplinar , Modelos Logísticos , Neoplasias Pulmonares/etnologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Proteínas dos Microfilamentos/metabolismo , Pessoa de Meia-Idade , Razão de Chances , Proteínas Proto-Oncogênicas/metabolismo , Fatores de Risco , Fatores Sexuais , Fumar/epidemiologia , Telomerase/genética
16.
PLoS One ; 9(3): e89791, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24598796

RESUMO

BACKGROUND: Risk of non-Hodgkin lymphoma (NHL) is higher among individuals with a family history or a prior diagnosis of other cancers. Genome-wide association studies (GWAS) have suggested that some genetic susceptibility variants are associated with multiple complex traits (pleiotropy). OBJECTIVE: We investigated whether common risk variants identified in cancer GWAS may also increase the risk of developing NHL as the first primary cancer. METHODS: As part of the Population Architecture using Genomics and Epidemiology (PAGE) consortium, 113 cancer risk variants were analyzed in 1,441 NHL cases and 24,183 controls from three studies (BioVU, Multiethnic Cohort Study, Women's Health Initiative) for their association with the risk of overall NHL and common subtypes [diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL)] using an additive genetic model adjusted for age, sex and ethnicity. Study-specific results for each variant were meta-analyzed across studies. RESULTS: The analysis of NHL subtype-specific GWAS SNPs and overall NHL suggested a shared genetic susceptibility between FL and DLBCL, particularly involving variants in the major histocompatibility complex region (rs6457327 in 6p21.33: FL OR=1.29, p=0.013; DLBCL OR=1.23, p=0.013; NHL OR=1.22, p=5.9 × E-05). In the pleiotropy analysis, six risk variants for other cancers were associated with NHL risk, including variants for lung (rs401681 in TERT: OR per C allele=0.89, p=3.7 × E-03; rs4975616 in TERT: OR per A allele=0.90, p=0.01; rs3131379 in MSH5: OR per T allele=1.16, p=0.03), prostate (rs7679673 in TET2: OR per C allele=0.89, p=5.7 × E-03; rs10993994 in MSMB: OR per T allele=1.09, p=0.04), and breast (rs3817198 in LSP1: OR per C allele=1.12, p=0.01) cancers, but none of these associations remained significant after multiple test correction. CONCLUSION: This study does not support strong pleiotropic effects of non-NHL cancer risk variants in NHL etiology; however, larger studies are warranted.


Assuntos
Pleiotropia Genética , Linfoma não Hodgkin/genética , Estudos de Casos e Controles , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único , Risco
17.
Circ Cardiovasc Genet ; 7(2): 178-88, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24622110

RESUMO

BACKGROUND: C-reactive protein (CRP) is a biomarker of inflammation. Genome-wide association studies (GWAS) have identified single-nucleotide polymorphisms (SNPs) associated with CRP concentrations and inflammation-related traits such as cardiovascular disease, type 2 diabetes mellitus, and obesity. We aimed to replicate previous CRP-SNP associations, assess whether these associations generalize to additional race/ethnicity groups, and evaluate inflammation-related SNPs for a potentially pleiotropic association with CRP. METHODS AND RESULTS: We selected and analyzed 16 CRP-associated and 250 inflammation-related GWAS SNPs among 40 473 African American, American Indian, Asian/Pacific Islander, European American, and Hispanic participants from 7 studies collaborating in the Population Architecture using Genomics and Epidemiology (PAGE) study. Fixed-effect meta-analyses combined study-specific race/ethnicity-stratified linear regression estimates to evaluate the association between each SNP and high-sensitivity CRP. Overall, 18 SNPs in 8 loci were significantly associated with CRP (Bonferroni-corrected P<3.1×10(-3) for replication, P<2.0×10(-4) for pleiotropy): Seven of these were specific to European Americans, while 9 additionally generalized to African Americans (1), Hispanics (5), or both (3); 1 SNP was seen only in African Americans and Hispanics. Two SNPs in the CELSR2/PSRC1/SORT1 locus showed a potentially novel association with CRP: rs599839 (P=2.0×10(-6)) and rs646776 (P=3.1×10(-5)). CONCLUSIONS: We replicated 16 SNP-CRP associations, 10 of which generalized to African Americans and/or Hispanics. We also identified potentially novel pleiotropic associations with CRP for two SNPs previously associated with coronary artery disease and/or low-density lipoprotein-cholesterol. These findings demonstrate the benefit of evaluating genotype-phenotype associations in multiple race/ethnicity groups and looking for pleiotropic relationships among SNPs previously associated with related phenotypes.


Assuntos
Proteína C-Reativa/metabolismo , Inflamação/genética , Adulto , Grupo com Ancestrais do Continente Africano/genética , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Feminino , Variação Genética , Estudo de Associação Genômica Ampla , Hispano-Americanos/genética , Humanos , Índios Norte-Americanos/genética , Inflamação/sangue , Inflamação/epidemiologia , Inflamação/etnologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estados Unidos/epidemiologia , Adulto Jovem
20.
Gut ; 63(5): 800-7, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-23935004

RESUMO

OBJECTIVE: Genome-wide association studies have identified a large number of single nucleotide polymorphisms (SNPs) associated with a wide array of cancer sites. Several of these variants demonstrate associations with multiple cancers, suggesting pleiotropic effects and shared biological mechanisms across some cancers. We hypothesised that SNPs previously associated with other cancers may additionally be associated with colorectal cancer. In a large-scale study, we examined 171 SNPs previously associated with 18 different cancers for their associations with colorectal cancer. DESIGN: We examined 13 338 colorectal cancer cases and 40 967 controls from three consortia: Population Architecture using Genomics and Epidemiology (PAGE), Genetic Epidemiology of Colorectal Cancer (GECCO), and the Colon Cancer Family Registry (CCFR). Study-specific logistic regression results, adjusted for age, sex, principal components of genetic ancestry, and/or study specific factors (as relevant) were combined using fixed-effect meta-analyses to evaluate the association between each SNP and colorectal cancer risk. A Bonferroni-corrected p value of 2.92×10(-4) was used to determine statistical significance of the associations. RESULTS: Two correlated SNPs--rs10090154 and rs4242382--in Region 1 of chromosome 8q24, a prostate cancer susceptibility region, demonstrated statistically significant associations with colorectal cancer risk. The most significant association was observed with rs4242382 (meta-analysis OR=1.12; 95% CI 1.07 to 1.18; p=1.74×10(-5)), which also demonstrated similar associations across racial/ethnic populations and anatomical sub-sites. CONCLUSIONS: This is the first study to clearly demonstrate Region 1 of chromosome 8q24 as a susceptibility locus for colorectal cancer; thus, adding colorectal cancer to the list of cancer sites linked to this particular multicancer risk region at 8q24.


Assuntos
Neoplasias Colorretais/genética , Pleiotropia Genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Idoso , Cromossomos Humanos Par 8 , Feminino , Marcadores Genéticos , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise de Componente Principal , Sistema de Registros , Fatores de Risco
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