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1.
Cancer Epidemiol Biomarkers Prev ; 28(7): 1228-1237, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31263055

RESUMO

BACKGROUND: Lung cancer remains the leading cause of cancer mortality with relatively few prognostic biomarkers. We investigated associations with overall survival for telomere length (TL) and genetic variation in chromosome 5p15.33, an established telomere maintenance locus. METHODS: Leukocyte TL was measured after diagnosis in 807 patients with non-small cell lung cancer (NSCLC) from the Princess Margaret Cancer Center in Toronto and assessed prospectively in 767 NSCLC cases from the Copenhagen City Heart Study and the Copenhagen General Population Study. Associations with all-cause mortality were tested for 723 variants in 5p15.33, genotyped in 4,672 NSCLC cases. RESULTS: Short telomeres (≤10th percentile) were associated with poor prognosis for adenocarcinoma in both populations: TL measured 6 months after diagnosis [HR = 1.65; 95% confidence intervals (CI), 1.04-2.64] and for those diagnosed within 5 years after blood sampling (HR = 2.42; 95% CI, 1.37-4.28). Short TL was associated with mortality in never smokers with NSCLC (HR = 10.29; 95% CI, 1.86-56.86) and adenocarcinoma (HR = 11.31; 95% CI, 1.96-65.24). Analyses in 5p15.33 identified statistically significant prognostic associations for rs56266421-G in LPCAT1 (HR = 1.86; 95% CI, 1.38-2.52; P = 4.5 × 10-5) in stage I-IIIA NSCLC, and for the SLC6A3 gene with OS in females with NSCLC (P = 1.6 × 10-3). CONCLUSIONS: Our findings support the potential clinical utility of TL, particularly for adenocarcinoma patients, while associations in chromosome 5p15.33 warrant further exploration. IMPACT: This is the largest lung cancer study of leukocyte TL and OS, and the first to examine the impact of the timing of TL measurement. Our findings suggest that extremely short telomeres are indicative of poor prognosis in NSCLC.

2.
PLoS One ; 14(5): e0217398, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31150433

RESUMO

BACKGROUND: While physical activity reduces risk of developing myocardial infarction (MI), it is unknown whether a history of physical activity is also protective of fatal arrhythmia and case-fatality in patients who have suffered an acute MI. METHODS: 104,801 individuals included in 2003-2014 in the Copenhagen General Population Study (CGPS), a prospective population-based study with self-reported leisure time physical activity (LTPA) in three categories measured at baseline, were followed until 2014 through national registries. The 1,517 individuals who suffered a first time MI during follow-up constituted the study population. Outcomes were fatal MI, defined as date of death same as date of MI (including out-of-hospital deaths) and 28-day fatality. Through multivariable analyses the association between baseline LTPA and outcomes were assessed adjusted for CVD risk factors. RESULTS: Of 1,517 MI events, 117 (7.7%) were fatal and another 79 (5.6%) lead to death within 28 days. Median time from baseline to MI was 3.6 years (IQR 1.7-5.8). LTPA was associated with lower risk of fatal MI with odds ratios of 0.40 (95% CI: 0.22-0.73) for light and 0.41 (0.22-0.76) for moderate/high LTPA after multivariable adjustment with sedentary LTPA as reference. Age, alcohol-intake, education and smoking were identified as other predictors for fatal MI. We found no association between LTPA and 28-day case fatality. CONCLUSIONS: Among individuals with MI, those that have engaged in any light or moderate physical activity were more likely to survive their MI. Results are consistent with effect of exercise preconditioning on risk of fatal arrhythmia.

3.
Arterioscler Thromb Vasc Biol ; 39(5): 965-977, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30866659

RESUMO

Objective- Whether tobacco smoking causally affects white and red blood cells and thrombocyte counts is unknown. Using a Mendelian randomization approach, we tested the hypothesis that smoking causes increases in these blood cell indices. Approach and Results- We included 104 607 white Danes aged 20 to 100 years from the Copenhagen General Population Study with information on blood cell indices, smoking habits, and CHRNA3 (alpha 3 nicotinic cholinergic receptor) rs1051730 genotype, where the T allele causes higher tobacco consumption; 41 759 were former smokers and 17 852 current smokers. In multivariable adjusted observational analyses and compared with never smokers, white blood cells were associated with up to 19% increases, thrombocytes with up to 4.7% increases, and red blood cell indices with up to 2.3% increases in former and current smokers. All associations were dose dependent, with tobacco consumption but for white blood cells and thrombocytes also dependent on smoking cessation time in former smokers; highest increases were for <1-year smoking cessation and lowest increases for >10-year smoking cessation. In age- and sex-adjusted genetic analyses, percent differences per T allele increase in current smokers were 1.15% (95% CI, 0.61%-1.68%) for leukocytes, 1.07% (0.38%-1.76%) for neutrophils, 1.34% (0.66%-2.02%) for lymphocytes, 1.50% (0.83%-2.18%) for monocytes, -0.60% (-1.91% to 0.74%) for eosinophils, 0.17% (-0.94% to 1.29%) for basophils, 0.38% (-0.17% to 0.93%) for thrombocytes, 0.04% (-0.14% to 0.23%) for erythrocytes, 0.34% (0.17% to 0.50%) for hematocrit, 0.26% (0.09% to 0.43%) for hemoglobin, and 0.29% (0.18% to 0.41%) for mean corpuscular volume. Conclusions- Smoking causes increased blood leukocytes, neutrophils, lymphocytes, and monocytes, as well as increased hematocrit, hemoglobin, and mean corpuscular volume. The observational smoking relationships were long term for white blood cells and short term for red blood cell indices.

4.
PLoS One ; 14(2): e0211745, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30730943

RESUMO

BACKGROUND: Prior studies have shown that AHRR (cg05575921) hypomethylation may be a marker of smoking, lung cancer risk and potentially lung cancer survival (in some lung cancer subtypes). It is unknown if AHRR (cg05575921) hypomethylation is associated with reduced survival among lung cancer patients. METHODS: In bisulfite treated leukocyte DNA from 465 lung cancer patients from the Copenhagen prospective lung cancer study, we measured AHRR (cg05575921) methylation. 380 died during max follow-up of 4.4 years. Cox proportional hazard models were used to analyze survival as a function of AHRR (cg05575921) methylation. RESULTS: We observed the expected inverse correlation between cumulative smoking and AHRR methylation, as methylation (%) decreased (Coefficient -0.03; 95% confidence interval, -0.04- -0.02, p = 8.6x10-15) for every pack-year. Cumulative smoking > 60 pack-years was associated with reduced survival (hazard ratio and 95% confidence interval 1.48; 1.05-2.09), however, AHRR (cg05575921) methylation was not associated with survival when adjusted for sex, body mass index, smoking status, ethnicity, performance status, TNM Classification, and histology type of lung cancer. CONCLUSION: AHRR (cg05575921) methylation is linked to smoking but does not provide independent prognostic information in lung cancer patients.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/sangue , Biomarcadores Tumorais/sangue , Metilação de DNA , DNA de Neoplasias/sangue , Leucócitos/metabolismo , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/mortalidade , Proteínas de Neoplasias/sangue , Proteínas Repressoras/sangue , Idoso , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Biomarcadores Tumorais/genética , DNA de Neoplasias/genética , Intervalo Livre de Doença , Feminino , Humanos , Leucócitos/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Estudos Prospectivos , Proteínas Repressoras/genética , Fumar/sangue , Fumar/genética , Fumar/mortalidade , Taxa de Sobrevida
5.
Int J Cancer ; 2018 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-30499135

RESUMO

Vitamin B supplementation can have side effects for human health, including cancer risk. We aimed to elucidate the role of vitamin B12 in lung cancer aetiology via direct measurements of pre-diagnostic circulating vitamin B12 concentrations in a nested case-control study, complemented with a Mendelian randomization (MR) approach in an independent case-control sample. We used pre-diagnostic biomarker data from 5,183 case-control pairs nested within 20 prospective cohorts, and genetic data from 29,266 cases and 56,450 controls. Exposures included directly measured circulating vitamin B12 in pre-diagnostic blood samples from the nested case-control study, and 8 single nucleotide polymorphisms associated with vitamin B12 concentrations in the MR study. Our main outcome of interest was increased risk for lung cancer, overall and by histological subtype, per increase in circulating vitamin B12 concentrations. We found circulating vitamin B12 to be positively associated with overall lung cancer risk in a dose response fashion (odds ratio for a doubling in B12 [ORlog2B12 ] = 1.15, 95% confidence interval (95%CI) = 1.06-1.25). The MR analysis based on 8 genetic variants also indicated that genetically determined higher vitamin B12 concentrations were positively associated with overall lung cancer risk (OR per 150 pmol/L standard deviation increase in B12 [ORSD ]= 1.08, 95%CI= 1.00-1.16). Considering the consistency of these two independent and complementary analyses, these findings support the hypothesis that high vitamin B12 status increases the risk of lung cancer. This article is protected by copyright. All rights reserved.

6.
J Clin Pathol ; 2018 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-30514740

RESUMO

AIMS: The JAK2 V617F mutation is highly recurrent in many of the myeloproliferative neoplasms, a molecular variant that can be easily detected using sensitive and minimally invasive techniques. Given the ease of JAK2 V617F testing, this test may be improperly requested for the purposes of patient 'screening' and to optimise laboratory resource utilisation, it behooves clinicians and laboratorians to perform JAK2 V617F testing only when most appropriate. METHODS: To assist with the screening of patients being considered for JAK2 V617F testing, we developed a clinical decision rule, "JAK2-tree", which can be easily applied to basic CBC parameters (haemoglobin, platelet and white blood cell counts). RESULTS: We tested JAK2-tree on two independent datasets, one an unselected population-based sample (the Copenhagen General Population Study) and the other an historical clinical laboratory referral set, with sensitivities for JAK2 V617F detection of 91% and 94%, respectively. As applied to the historical laboratory referral dataset, moreover, the JAK2-tree algorithm would have reduced JAK2 V617F testing volume over the period of evaluation by 15%. CONCLUSIONS: Our work supports a simple decision-tree-based screening approach to optimize the selection of patients most appropriate for JAK2 V617F testing.

7.
PLoS Med ; 15(11): e1002685, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30383787

RESUMO

BACKGROUND: Neutropenia increases the risk of infection, but it is unknown if this also applies to lymphopenia. We therefore tested the hypotheses that lymphopenia is associated with increased risk of infection and infection-related death in the general population. METHODS AND FINDINGS: Of the invited 220,424 individuals, 99,191 attended examination. We analyzed 98,344 individuals from the Copenhagen General Population Study (Denmark), examined from November 25, 2003, to July 9, 2013, and with available blood lymphocyte count at date of examination. During a median of 6 years of follow-up, they developed 8,401 infections and experienced 1,045 infection-related deaths. Due to the completeness of the Danish civil and health registries, none of the 98,344 individuals were lost to follow-up, and those emigrating (n = 385) or dying (n = 5,636) had their follow-up truncated at the day of emigration or death. At date of examination, mean age was 58 years, and 44,181 (44.9%) were men. Individuals with lymphopenia (lymphocyte count < 1.1 × 109/l, n = 2,352) compared to those with lymphocytes in the reference range (1.1-3.7 × 109/l, n = 93,538) had multivariable-adjusted hazard ratios of 1.41 (95% CI 1.28-1.56) for any infection, 1.31 (1.14-1.52) for pneumonia, 1.44 (1.15-1.79) for skin infection, 1.26 (1.02-1.56) for urinary tract infection, 1.51 (1.21-1.89) for sepsis, 1.38 (1.01-1.88) for diarrheal disease, 2.15 (1.16-3.98) for endocarditis, and 2.26 (1.21-4.24) for other infections. The corresponding hazard ratio for infection-related death was 1.70 (95% CI 1.37-2.10). Analyses were adjusted for age, sex, smoking status, cumulative smoking, alcohol intake, body mass index, plasma C-reactive protein, blood neutrophil count, recent infection, Charlson comorbidity index, autoimmune diseases, medication use, and immunodeficiency/hematologic disease. The findings were robust in all stratified analyses and also when including only events later than 2 years after first examination. However, due to the observational design, the study cannot address questions of causality, and our analyses might theoretically have been affected by residual confounding and reverse causation. In principle, fluctuating lymphocyte counts over time might also have influenced analyses, but lymphocyte counts in 5,181 individuals measured 10 years after first examination showed a regression dilution ratio of 0.68. CONCLUSIONS: Lymphopenia was associated with increased risk of hospitalization with infection and increased risk of infection-related death in the general population. Notably, causality cannot be deduced from our data.

8.
Nat Commun ; 9(1): 3927, 2018 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-30254314

RESUMO

Lung cancer has several genetic associations identified within the major histocompatibility complex (MHC); although the basis for these associations remains elusive. Here, we analyze MHC genetic variation among 26,044 lung cancer patients and 20,836 controls densely genotyped across the MHC, using the Illumina Illumina OncoArray or Illumina 660W SNP microarray. We impute sequence variation in classical HLA genes, fine-map MHC associations for lung cancer risk with major histologies and compare results between ethnicities. Independent and novel associations within HLA genes are identified in Europeans including amino acids in the HLA-B*0801 peptide binding groove and an independent HLA-DQB1*06 loci group. In Asians, associations are driven by two independent HLA allele sets that both increase risk in HLA-DQB1*0401 and HLA-DRB1*0701; the latter better represented by the amino acid Ala-104. These results implicate several HLA-tumor peptide interactions as the major MHC factor modulating lung cancer susceptibility.

9.
Int J Epidemiol ; 2018 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-30059977

RESUMO

Background: Evidence from observational studies of telomere length (TL) has been conflicting regarding its direction of association with cancer risk. We investigated the causal relevance of TL for lung and head and neck cancers using Mendelian Randomization (MR) and mediation analyses. Methods: We developed a novel genetic instrument for TL in chromosome 5p15.33, using variants identified through deep-sequencing, that were genotyped in 2051 cancer-free subjects. Next, we conducted an MR analysis of lung (16 396 cases, 13 013 controls) and head and neck cancer (4415 cases, 5013 controls) using eight genetic instruments for TL. Lastly, the 5p15.33 instrument and distinct 5p15.33 lung cancer risk loci were evaluated using two-sample mediation analysis, to quantify their direct and indirect, telomere-mediated, effects. Results: The multi-allelic 5p15.33 instrument explained 1.49-2.00% of TL variation in our data (p = 2.6 × 10-9). The MR analysis estimated that a 1000 base-pair increase in TL increases risk of lung cancer [odds ratio (OR) = 1.41, 95% confidence interval (CI): 1.20-1.65] and lung adenocarcinoma (OR = 1.92, 95% CI: 1.51-2.22), but not squamous lung carcinoma (OR = 1.04, 95% CI: 0.83-1.29) or head and neck cancers (OR = 0.90, 95% CI: 0.70-1.05). Mediation analysis of the 5p15.33 instrument indicated an absence of direct effects on lung cancer risk (OR = 1.00, 95% CI: 0.95-1.04). Analysis of distinct 5p15.33 susceptibility variants estimated that TL mediates up to 40% of the observed associations with lung cancer risk. Conclusions: Our findings support a causal role for long telomeres in lung cancer aetiology, particularly for adenocarcinoma, and demonstrate that telomere maintenance partially mediates the lung cancer susceptibility conferred by 5p15.33 loci.

10.
Br J Psychiatry ; 210(1): 31-38, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27810892

RESUMO

BACKGROUND: Depression has been cross-sectionally associated with short telomeres as a measure of biological age. However, the direction and nature of the association is currently unclear. AIMS: We examined whether short telomere length is associated with depression cross-sectionally as well as prospectively and genetically. METHOD: Telomere length and three polymorphisms, TERT, TERC and OBFC1, were measured in 67 306 individuals aged 20-100 years from the Danish general population and associated with register-based attendance at hospital for depression and purchase of antidepressant medication. RESULTS: Attendance at hospital for depression was associated with short telomere length cross-sectionally, but not prospectively. Further, purchase of antidepressant medication was not associated with short telomere length cross-sectionally or prospectively. Mean follow-up was 7.6 years (range 0.0-21.5). The genetic analyses suggested that telomere length was not causally associated with attendance at hospital for depression or with purchase of antidepressant medication. CONCLUSIONS: Short telomeres were not associated with depression in prospective or in causal, genetic analyses.


Assuntos
Depressão/genética , Transtorno Depressivo/genética , Análise da Randomização Mendeliana/métodos , Sistema de Registros , Encurtamento do Telômero/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Dinamarca , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
11.
Epidemiology ; 26(3): 353-61, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25695354

RESUMO

BACKGROUND: Alcohol consumption, increased body mass index (BMI), and hormone therapy are risk factors for postmenopausal breast cancer, but their combined effects are not well understood. Because hormone therapy is effective for the relief of menopausal symptoms, the identification of "high-risk" users is important for therapeutic reasons. We investigated interactions between hormone therapy use and alcohol-use/high BMI status in relation to invasive breast cancer risk, both overall and according to estrogen receptor (ER) status. METHODS: Two Danish prospective cohorts were pooled, including 30,789 women ages 50+ years (study period 1981 to 2009). Information on risk factors was obtained in baseline questionnaires. We performed analyses using the Aalen additive hazards model. Serum estradiol and testosterone measurements were obtained in a subsample of approximately 1000 women. RESULTS: During 392,938 person-years of follow-up, 1579 women developed invasive breast cancer. Among nonusers of hormone therapy, the risk of breast cancer was slightly increased with overweight/obesity and increasing alcohol consumption. Compared with normal-weight nonusers, the risk of breast cancer was higher in hormone therapy users across all BMI strata (P for interaction = 0.003). A markedly higher risk of breast cancer was also observed for alcohol combined with hormone therapy use compared with abstinent nonusers (P for interaction = 0.02). These effects were primarily restricted to ER-positive cases. Combined effects of hormone therapy/high BMI and hormone therapy/alcohol on serum estradiol and testosterone supported the hypothesis of a hormonal pathway linking these exposures to breast cancer. CONCLUSION: These analyses suggest an increased risk of breast cancer associated with hormone therapy use-a risk that may be particularly strong among women consuming alcohol.


Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Índice de Massa Corporal , Neoplasias da Mama/etiologia , Terapia de Reposição de Estrogênios/efeitos adversos , Neoplasias da Mama/induzido quimicamente , Neoplasias da Mama/epidemiologia , Dinamarca/epidemiologia , Estradiol/sangue , Feminino , Humanos , Pessoa de Meia-Idade , Obesidade/complicações , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco , Inquéritos e Questionários , Testosterona/sangue
12.
Cancer Epidemiol ; 34(2): 178-83, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20117066

RESUMO

BACKGROUND: CYP2C9 enzymes are important in the metabolism of procarcinogenic chemicals such as polycyclic aromatic hydrocarbons (PAHs) found in tobacco smoke. Two functional variants in the CYP2C9 gene (CYP2C9*2 and CYP2C9*3) are known to be associated with decreased enzyme activity towards tolbutamide and warfarin, while this has not been investigated for PAHs. We hypothesised that these two variants in the CYP2C9 gene influence risk of tobacco-related cancer. METHODS: In a prospective study of the general population (n=10 392) with 60 years of follow-up, the Copenhagen City Heart Study, we associated two variants of CYP2C9 (CYP2C9*2 and CYP2C9*3) with risk of tobacco-related cancer and all cancer. All results were re-tested in a cross-sectional study of the general population (n=36 856), the Copenhagen General Population Study. RESULTS: We found no association between any of the CYP2C9 genotypes and risk of tobacco-related cancer, individual tobacco-related cancers, or all cancer. For the combined carriers (any CYP2C9*2 or CYP2C9*3 heterozygotes or homozygotes) vs. non-carriers we had 90% statistical power to exclude measures of relative risks below/above 0.8/1.2 and 0.9/1.1 in the Copenhagen City Heart Study and below/above 0.8/1.3 and 0.9/1.1 in the Copenhagen General Population Study for tobacco-related cancer and all cancer, respectively. CONCLUSION: Genetic variations in CYP2C9 do not affect risk of tobacco-related cancers.


Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Neoplasias/genética , Fumar/efeitos adversos , Adulto , Idoso , Hidrocarboneto de Aril Hidroxilases/metabolismo , Cocarcinogênese , Estudos de Coortes , Citocromo P-450 CYP2C9 , Dinamarca/epidemiologia , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/enzimologia , Neoplasias/epidemiologia , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Fumar/epidemiologia , Fumar/genética , Fumar/metabolismo
13.
Cancer Epidemiol Biomarkers Prev ; 18(8): 2339-42, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19661094

RESUMO

PURPOSE: BRCA1 and BRCA2 are key tumor suppressors with a role in cellular DNA repair, genomic stability, and checkpoint control. Mutations in BRCA1 and BRCA2 often cause hereditary breast and ovarian cancer; however, missense polymorphisms in these genes pose a problem in genetic counseling, as their impact on risk of breast and ovarian cancer is unclear. EXPERIMENTAL DESIGN: We resequenced BRCA1 and BRCA2 in 194 women with a familial history of breast and/or ovarian cancer and identified nine possibly biologically relevant polymorphisms (BRCA1 Gln356Arg, Pro871Leu, Glu1038Gly, Ser1613Gly, and Met1652Ile. BRCA2 Asn289His, Asn372His, Asp1420Tyr, and Thr1915Met). [corrected] We evaluated risk of breast and/or ovarian cancer by these polymorphisms in a prospective study of 5,743 women from the general population followed for 39 years and in a case-control study of 1,201 breast cancer cases and 4,120 controls. RESULTS: We found no association between heterozygosity or homozygosity for any of the nine polymorphisms and risk of breast and/or ovarian cancer in either study. We had 80% power to exclude hazard/odds ratios for heterozygotes and/or homozygotes for all nine missense polymorphisms above 1.3 to 3.3 in the prospective study, and above 1.2 to 3.2 in the case-control study. CONCLUSIONS: Heterozygosity and homozygosity of any of the examined nine BRCA1 and BRCA2 missense polymorphisms cannot explain the increased risk of breast and/or ovarian cancer observed in families with hereditary breast and/or ovarian cancer. Therefore, genetic counseling of such families safely can disregard findings of these missense polymorphisms.


Assuntos
Neoplasias da Mama/genética , Genes BRCA1 , Genes BRCA2 , Predisposição Genética para Doença , Neoplasias Ovarianas/genética , Polimorfismo Genético , Neoplasias da Mama/epidemiologia , Feminino , Humanos , Incidência , Neoplasias Ovarianas/epidemiologia , Reação em Cadeia da Polimerase , Fatores de Risco
14.
J Clin Oncol ; 26(18): 3057-62, 2008 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-18565893

RESUMO

PURPOSE: Truncating and missense mutations in the ATM gene, which cause insufficient DNA damage surveillance, allow damaged cells to proceed into mitosis, which eventually results in increased cancer susceptibility. We tested the hypotheses that ATM Ser49Cys and ATM Ser707Pro heterozygosity increase the risk of cancer overall, of breast cancer, and of 26 other cancer subtypes in the general population. PATIENTS AND METHODS: We genotyped 10,324 individuals from the Danish general population who were observed prospectively for 36 years, during which 2,056 developed cancer. RESULTS: Multifactorially adjusted hazard ratios for ATM Ser49Cys heterozygotes versus noncarriers were 1.2 (95% CI, 0.9 to 1.5) for cancer overall, 0.8 (95% CI, 0.3 to 2.0) for breast cancer, 4.8 (95% CI, 2.2 to 11) for melanoma, 2.3 (95% CI, 1.1 to 5.0) for prostate cancer, and 3.4 (95% CI, 1.1 to 11) for cancer of the oral cavity/pharynx. Multifactorially adjusted hazard ratios for ATM Ser707Pro heterozygotes versus noncarriers were 0.8 (95% CI, 0.6 to 1.2) for cancer overall, 0.6 (95% CI, 0.2 to 1.6) for breast cancer, 10 (95% CI, 1.1 to 93) for thyroid/other endocrine tumors, and 2.7 (95% CI, 1.0 to 7.6) for cancer of corpus uteri. CONCLUSION: ATM missense mutations do not increase the risk of cancer overall or of breast cancer in the general population; however, we observed in exploratory analyses that ATM missense mutations may be associated with an increased risk of other cancer subtypes. As we did multiple comparisons, some of these findings could represent chance findings rather than real phenomena.


Assuntos
Proteínas de Ciclo Celular/genética , Proteínas de Ligação a DNA/genética , Mutação de Sentido Incorreto , Neoplasias/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Supressoras de Tumor/genética , Adulto , Proteínas Mutadas de Ataxia Telangiectasia , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Dinamarca/epidemiologia , Feminino , Predisposição Genética para Doença , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Estudos Prospectivos
15.
J Clin Oncol ; 26(4): 542-8, 2008 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-18172190

RESUMO

PURPOSE: CHEK2*1100delC heterozygosity may be associated with an increased risk of breast cancer; however, it is unclear whether the evidence is sufficient to recommend genotyping in clinical practice. PATIENTS AND METHODS: We identified studies on CHEK2*1100delC heterozygosity and the risk of unselected, early-onset, and familial breast cancer through comprehensive, computer-based searches of PubMed, EMBASE, and Web of Science. Aggregated risk estimates were compared with previous estimates for BRCA1 and BRCA2 mutation heterozygotes. RESULTS: By using fixed-effect models for CHEK2*1100delC heterozygotes versus noncarriers, we found aggregated odds ratios of 2.7 (95% CI, 2.1 to 3.4) for unselected breast cancer, 2.6 (95% CI, 1.3 to 5.5) for early-onset breast cancer, and 4.8 (95% CI, 3.3 to 7.2) for familial breast cancer. For familial breast cancer, this corresponds to a cumulative risk of breast cancer at age 70 years in CHEK2*1100delC heterozygotes of 37% (95% CI, 26% to 56%), which compares with similar previous estimates of 57% (95% CI, 47% to 66%) for BRCA1 mutation heterozygotes and 49% (95% CI, 40% to 57%) for BRCA2 mutation heterozygotes. CONCLUSION: These meta-analyses emphasize that CHEK2*1100delC is an important breast cancer-predisposing gene, which increases the risk three- to five-fold. Because the cumulative risk of breast cancer at age 70 years among familial patient cases for CHEK2*1100delC heterozygotes is almost as high as that for BRCA1 and BRCA2 mutation heterozygotes, genotyping for CHEK2*1100delC should be considered together with BRCA1 and BRCA2 mutation screening in women with a family history of breast cancer.


Assuntos
Neoplasias da Mama/genética , Triagem de Portadores Genéticos , Testes Genéticos , Mutação , Proteínas Serina-Treonina Quinases/genética , Idoso , Proteínas Reguladoras de Apoptose , Proteína BRCA1/genética , Proteína BRCA2/genética , Estudos de Casos e Controles , Quinase do Ponto de Checagem 2 , Feminino , Predisposição Genética para Doença/genética , Genótipo , Humanos , Medição de Risco
16.
J Exp Med ; 204(6): 1295-301, 2007 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-17535973

RESUMO

p53 is an important tumor suppressor, normally preventing cancer development via apoptosis. A genomic Arg72Pro substitution in the p53 protein has important influence on cell death via apoptosis, which could be beneficial. We therefore tested the hypotheses that this polymorphism influences longevity, survival after a cancer diagnosis, and risk of cancer in the general population. We examined a cohort of 9,219 participants ages 20-95 from the Danish general population with 100% follow-up. The overall 12-yr survival was increased in p53 Arg/Pro heterozygotes with 3% (P = 0.003) and in Pro/Pro homozygotes with 6% (P = 0.002) versus Arg/Arg homozygotes, corresponding to an increase in median survival of 3 yr for Pro/Pro versus Arg/Arg homozygotes. We also demonstrated an increased survival after the development of cancer, or even after the development of other life-threatening diseases, for Pro/Pro versus Arg/Arg homozygotes. The Arg72Pro substitution did not associate with decreased risk of cancer. In conclusion, in this large cohort from the general population, we show that a well-known functional single nucleotide polymorphism in the tumor suppressor p53 protein leads to increased longevity, but not to decreased risk of cancer. The increased longevity may be due to increased survival after a diagnosis of cancer or other life-threatening diseases.


Assuntos
Longevidade/genética , Neoplasias/genética , Neoplasias/mortalidade , Polimorfismo de Nucleotídeo Único/genética , Proteína Supressora de Tumor p53/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Primers do DNA , Dinamarca , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Estudos Prospectivos , Medição de Risco , Taxa de Sobrevida
17.
J Clin Oncol ; 25(1): 57-63, 2007 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-16880452

RESUMO

PURPOSE: CHEK2*1100delC heterozygosity has been associated with increased risk of breast, prostate, and colorectal cancer in case-control studies. We tested the hypothesis that CHEK2*1100delC heterozygosity in the general population increases the risk of cancer in general, and breast, prostate, and colorectal cancer in particular. PATIENTS AND METHODS: We performed a prospective study of 9,231 individuals from the Danish general population, who were observed for 34 years, and we performed a case-control study including 1,101 cases of breast cancer and 4,665 controls. RESULTS: Of the general population, 0.5% were heterozygotes and 99.5% were noncarriers. In the prospective study, multifactorially adjusted hazard ratios by CHEK2*1100delC heterozygosity versus noncarriers were 1.2 (95% CI, 0.7 to 2.1) for all cancers, 3.2 (95% CI, 1.0 to 9.9) for breast cancer, 2.3 (95% CI, 0.6 to 9.5) for prostate cancer, and 1.6 (95% CI, 0.4 to 6.5) for colorectal cancer. In the case-control study, age-matched odds ratio for breast cancer by CHEK2*1100delC heterozygosity versus noncarriers was 2.6 (95% CI, 1.3 to 5.4). The absolute 10-year risk of breast cancer in CHEK2*1100delC heterozygotes amounted to 24% in women older than 60 years undergoing hormone replacement therapy, with a body mass index of 25 kg/m2 or higher. CONCLUSION: CHEK2*1100delC heterozygosity is associated with a three-fold risk of breast cancer in women in the general population.


Assuntos
Neoplasias da Mama/genética , Neoplasias Colorretais/genética , Predisposição Genética para Doença , Polimorfismo Genético , Neoplasias da Próstata/genética , Proteínas Serina-Treonina Quinases/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Quinase do Ponto de Checagem 2 , Dinamarca , Feminino , Deleção de Genes , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Risco
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