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Sökning: WFRF:(Mellemgaard A.)

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  • McKay, James D., et al. (författare)
  • Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes
  • 2017
  • Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 49:7, s. 1126-1132
  • Tidskriftsartikel (refereegranskat)abstract
    • Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genomewide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer.
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3.
  • Ji, Xuemei, et al. (författare)
  • Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk
  • 2018
  • Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 9, s. 1-15
  • Tidskriftsartikel (refereegranskat)abstract
    • Genome-wide association studies (GWAS) identified the chromosome 15q25.1 locus as a leading susceptibility region for lung cancer. However, the pathogenic pathways, through which susceptibility SNPs within chromosome 15q25.1 affects lung cancer risk, have not been explored. We analyzed three cohorts with GWAS data consisting 42,901 individuals and lung expression quantitative trait loci (eQTL) data on 409 individuals to identify and validate the underlying pathways and to investigate the combined effect of genes from the identified susceptibility pathways. The KEGG neuroactive ligand receptor interaction pathway, two Reactome pathways, and 22 Gene Ontology terms were identified and replicated to be significantly associated with lung cancer risk, with P values less than 0.05 and FDR less than 0.1. Functional annotation of eQTL analysis results showed that the neuroactive ligand receptor interaction pathway and gated channel activity were involved in lung cancer risk. These pathways provide important insights for the etiology of lung cancer.
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4.
  • Ji, Xuemei, et al. (författare)
  • Protein-altering germline mutations implicate novel genes related to lung cancer development
  • 2020
  • Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio=8.82, P=1.18x10(-15)) and replication (adjusted OR=2.93, P=2.22x10(-3)) that is more pronounced in females (adjusted OR=6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR=2.61, P=7.98x10(-22)) and replication datasets (adjusted OR=1.55, P=0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930. Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk. In lung cancer, relatively few germline mutations are known to impact risk. Here the authors looked at rare variants in 39,146 individuals and find novel germline mutations associated with risk, as well as implicating ATM and a new candidate gene for lung cancer risk.
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  • Wolk, A., et al. (författare)
  • International renal cell cancer study. VII. Role of diet
  • 1996
  • Ingår i: International Journal of Cancer. - Hoboken, USA : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 65:1, s. 67-73
  • Tidskriftsartikel (refereegranskat)abstract
    • We investigated the role of diet in the etiology of renal cell cancer (RCC) in a multi-center, population-based case-control study conducted in Australia, Denmark, Sweden and the United States, using a shared protocol. A total of 1,185 incident histopathologically confirmed cases (698 men, 487 women) and 1,526 controls (915 men, 611 women) frequency-matched to cases by sex and age were included in the analyses. The association between RCC and diet was estimated by relative risks (RR) and 95% confidence intervals (CI) adjusted for age, sex, study center, body mass index and smoking. A statistically significant positive association was observed for total energy intake (RR = 1.7, 95% CI = 1.4-2.2 for the highest vs. lowest quartile, p value for trend < 0.00001), while the hypothesis that protein and fat are risk factors independent of energy was not supported. Fried meats were associated with increased RCC risk, while vegetables and fruits were protective, with the strongest effect observed for the highest quartile of consumption of orange/dark green vegetables but not vitamin C or beta carotene. Increased risk was associated with low intake (lowest decile) of vitamin E and magnesium. We observed an apparent protective effect of alcohol confined to women and probably due to chance. Our findings indicate an important role of nutrition in the development of RCC. The apparent positive association of energy intake with risk of RCC needs further investigation in a prospective cohort study to exclude the possible impact of differences in recall between cases and controls.
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9.
  • Lindblad, Per, 1953-, et al. (författare)
  • International renal-cell cancer study. V. Reproductive factors, gynecologic operations and exogenous hormones
  • 1995
  • Ingår i: International Journal of Cancer. - Hoboken, USA : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 61:2, s. 192-198
  • Tidskriftsartikel (refereegranskat)abstract
    • The relationships between reproductive factors, exogenous hormones and renal-cell cancer were examined in an international, multicenter, population-based, case-control study undertaken in 1989-1991. Data from 5 centers situated in Australia, Denmark, Germany, Sweden and the United States included for analysis 608 women with renal-cell cancer and 766 female controls. A significant trend in risk (p = 0.002) was associated with number of births, with an 80% excess risk for 6 or more births [RR = 1.8, 95% confidence interval (CI) = 1.1 to 2.9] compared with one birth. A decreasing risk was seen for increasing age at first birth, although this was confounded by body-mass index and number of births. A suggestive reduction of risk was also seen for increasing age at menarche. Age at menopause was unrelated to risk of renal-cell cancer. An increased risk was observed for women having had both a hysterectomy and an oophorectomy. Use of oral contraceptives in non-smoking women reduced the risk of renal-cell cancer (RR = 0.5, 95% CI = 0.4 to 0.8); this reduction increased with longer duration of use. No association was observed for estrogen replacement therapy. Our results indicate that certain hormonal and reproductive variables may be related to risk of renal-cell cancer and deserve further investigation, both epidemiologically and experimentally.
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10.
  • Lindblad, Per, 1953-, et al. (författare)
  • Risk of kidney cancer among patients using analgesics and diuretics : a population-based cohort study
  • 1993
  • Ingår i: International Journal of Cancer. - Ne York, USA : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 55:1, s. 5-9
  • Tidskriftsartikel (refereegranskat)abstract
    • The aim of this study was to determine the risk of kidney cancer in 2 cohorts defined on the basis of hospital discharge diagnoses associated with analgesic or diuretic use during the period 1965 to 1983. Patients were followed up through 1984 for cancer incidence. After excluding cancers in the first year of observation, 161 kidney cancers were observed vs. 138 expected among 54,662 patients in the analgesics cohort. The relative risk was higher for women than for men. When examined by sub-site within the kidney, risk for cancer of the renal pelvis was similar in magnitude to that for the renal parenchyma. Among 115,616 patients in the diuretics cohort, 278 kidney cancers occurred vs. 209 expected. The risk for women was higher than for men. This elevation in risk was confined to cancer of the renal parenchyma, with no significantly increased risk seen for cancer of the renal pelvis. Although we observed little excess risk among members of the analgesics cohort, the significantly elevated risk among patients using diuretics supports a number of recent studies, but inability to adjust for confounding factors such as obesity preclude drawing any conclusion regarding diuretics. Further research is warranted to assess in detail the relationship between diuretic use and cancer of the renal parenchyma.
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