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  • 1. Campanella, Gianluca
    et al.
    Gunter, Marc J.
    Polidoro, Silvia
    Krogh, Vittorio
    Palli, Domenico
    Panico, Salvatore
    Sacerdote, Carlotta
    Tumino, Rosario
    Fiorito, Giovanni
    Guarrera, Simonetta
    Iacoviello, Licia
    Bergdahl, Ingvar A.
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Lenner, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    de Kok, Theo M. C. M.
    Georgiadis, Panagiotis
    Kleinjans, Jos C. S.
    Kyrtopoulos, Soterios A.
    Bueno-de-Mesquita, H. Bas
    Lillycrop, Karen A.
    May, Anne M.
    Onland-Moret, N. Charlotte
    Murray, Robert
    Riboli, Elio
    Verschuren, Monique
    Lund, Eiliv
    Mode, Nicolle
    Sandanger, Torkjel M.
    Fiano, Valentina
    Trevisan, Morena
    Matullo, Giuseppe
    Froguel, Philippe
    Elliott, Paul
    Vineis, Paolo
    Chadeau-Hyam, Marc
    Epigenome-wide association study of adiposity and future risk of obesity-related diseases2018In: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 42, no 12, p. 2022-2035Article in journal (Refereed)
    Abstract [en]

    Background: Obesity is an established risk factor for several common chronic diseases such as breast and colorectal cancer, metabolic and cardiovascular diseases; however, the biological basis for these relationships is not fully understood. To explore the association of obesity with these conditions, we investigated peripheral blood leucocyte (PBL) DNA methylation markers for adiposity and their contribution to risk of incident breast and colorectal cancer and myocardial infarction.

    Methods: DNA methylation profiles (Illumina Infinium® HumanMethylation450 BeadChip) from 1941 individuals from four population-based European cohorts were analysed in relation to body mass index, waist circumference, waist-hip and waist-height ratio within a meta-analytical framework. In a subset of these individuals, data on genome-wide gene expression level, biomarkers of glucose and lipid metabolism were also available. Validation of methylation markers associated with all adiposity measures was performed in 358 individuals. Finally, we investigated the association of obesity-related methylation marks with breast, colorectal cancer and myocardial infarction within relevant subsets of the discovery population.

    Results: We identified 40 CpG loci with methylation levels associated with at least one adiposity measure. Of these, one CpG locus (cg06500161) in ABCG1 was associated with all four adiposity measures (P = 9.07×10−8 to 3.27×10−18) and lower transcriptional activity of the full-length isoform of ABCG1 (P = 6.00×10−7), higher triglyceride levels (P = 5.37×10−9) and higher triglycerides-to-HDL cholesterol ratio (P = 1.03×10−10). Of the 40 informative and obesity-related CpG loci, two (in IL2RB and FGF18) were significantly associated with colorectal cancer (inversely, P < 1.6×10−3) and one intergenic locus on chromosome 1 was inversely associated with myocardial infarction (P < 1.25×10−3), independently of obesity and established risk factors.

    Conclusion: Our results suggest that epigenetic changes, in particular altered DNA methylation patterns, may be an intermediate biomarker at the intersection of obesity and obesity-related diseases, and could offer clues as to underlying biological mechanisms.

  • 2. Campanella, Gianluca
    et al.
    Gunter, Marc J.
    Polidoro, Silvia
    Krogh, Vittorio
    Palli, Domenico
    Panico, Salvatore
    Sacerdote, Carlotta
    Tumino, Rosario
    Fiorito, Giovanni
    Guarrera, Simonetta
    Iacoviello, Licia
    Bergdahl, Ingvar
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Lenner, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    de Kok, Theo M. C. M.
    Georgiadis, Panagiotis
    Kleinjans, Jos C. S.
    Kyrtopoulos, Soterios A.
    Bueno-de-Mesquita, H. Bas
    Lillycrop, Karen A.
    May, Anne M.
    Onland-Moret, N. Charlotte
    Murray, Robert
    Riboli, Elio
    Verschuren, Monique
    Lund, Eiliv
    Mode, Nicolle
    Sandanger, Torkjel M.
    Fiano, Valentina
    Trevisan, Morena
    Matullo, Giuseppe
    Froguel, Philippe
    Elliott, Paul
    Vineis, Paolo
    Chadeau-Hyam, Marc
    Epigenome-wide association study of adiposity and future risk of obesity-related diseases2018In: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 42, no 12, p. 2022-2035Article in journal (Refereed)
    Abstract [en]

    Background Obesity is an established risk factor for several common chronic diseases such as breast and colorectal cancer, metabolic and cardiovascular diseases; however, the biological basis for these relationships is not fully understood. To explore the association of obesity with these conditions, we investigated peripheral blood leucocyte (PBL) DNA methylation markers for adiposity and their contribution to risk of incident breast and colorectal cancer and myocardial infarction. Methods DNA methylation profiles (Illumina Infinium® HumanMethylation450 BeadChip) from 1941 individuals from four population-based European cohorts were analysed in relation to body mass index, waist circumference, waist-hip and waistheight ratio within a meta-analytical framework. In a subset of these individuals, data on genome-wide gene expression level, biomarkers of glucose and lipid metabolism were also available. Validation of methylation markers associated with all adiposity measures was performed in 358 individuals. Finally, we investigated the association of obesity-related methylation marks with breast, colorectal cancer and myocardial infarction within relevant subsets of the discovery population. Results We identified 40 CpG loci with methylation levels associated with at least one adiposity measure. Of these, one CpG locus (cg06500161) in ABCG1 was associated with all four adiposity measures (P=9.07×10−8 to 3.27×10−18) and lower transcriptional activity of the full-length isoform of ABCG1 (P=6.00×10−7), higher triglyceride levels (P=5.37×10−9) and higher triglycerides-to-HDL cholesterol ratio (P=1.03×10−10). Of the 40 informative and obesity-related CpG loci, two (in IL2RB and FGF18) were significantly associated with colorectal cancer (inversely, P<1.6×10−3) and one intergenic locus on chromosome 1 was inversely associated with myocardial infarction (P<1.25×10−3), independently of obesity and established risk factors. Conclusion Our results suggest that epigenetic changes, in particular altered DNA methylation patterns, may be an intermediate biomarker at the intersection of obesity and obesity-related diseases, and could offer clues as to underlying biological mechanisms.

  • 3. Kaaks, Rudolf
    et al.
    Fortner, Renée Turzanski
    Hüsing, Anika
    Barrdahl, Myrto
    Hopper, Marika
    Johnson, Theron
    Tjønneland, Anne
    Hansen, Louise
    Overvad, Kim
    Fournier, Agnès
    Boutron-Ruault, Marie-Christine
    Kvaskoff, Marina
    Dossus, Laure
    Johansson, Mattias
    Boeing, Heiner
    Trichopoulou, Antonia
    Benetou, Vassiliki
    La Vecchia, Carlo
    Sieri, Sabina
    Mattiello, Amalia
    Palli, Domenico
    Tumino, Rosario
    Matullo, Giuseppe
    Onland-Moret, N. Charlotte
    Gram, Inger T.
    Weiderpass, Elisabete
    Sánchez, Maria-Jose
    Navarro Sanchez, Carmen
    Duell, Eric J.
    Ardanaz, Eva
    Larranaga, Nerea
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Jirström, Karin
    Nodin, Björn
    Travis, Ruth C.
    Riboli, Elio
    Merritt, Melissa
    Aune, Dagfinn
    Terry, Kathryn
    Cramer, Daniel W.
    Anderson, Karen S.
    Tumor-associated autoantibodies as early detection markers for ovarian cancer?: A prospective evaluation2018In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 143, no 3, p. 515-526Article in journal (Refereed)
    Abstract [en]

    Immuno-proteomic screening has identified several tumor-associated autoantibodies (AAb) that may have diagnostic capacity for invasive epithelial ovarian cancer, with AAbs to P53 proteins and cancer-testis antigens (CTAGs) as prominent examples. However, the early detection potential of these AAbs has been insufficiently explored in prospective studies. We performed ELISA measurements of AAbs to CTAG1A, CTAG2, P53 and NUDT11 proteins, for 194 patients with ovarian cancer and 705 matched controls from the European EPIC cohort, using serum samples collected up to 36 months prior to diagnosis under usual care. CA125 was measured using electrochemo-luminiscence. Diagnostic discrimination statistics were calculated by strata of lead-time between blood collection and diagnosis. With lead times 6 months, ovarian cancer detection sensitivity at 0.98 specificity (SE98) varied from 0.19 [95% CI 0.08-0.40] for CTAG1A, CTAG2 and NUDT1 to 0.23 [0.10-0.44] for P53 (0.33 [0.11-0.68] for high-grade serous tumors). However, at longer lead-times, the ability of these AAb markers to distinguish future ovarian cancer cases from controls declined rapidly; at lead times >1 year, SE98 estimates were close to zero (all invasive cases, range: 0.01-0.11). Compared to CA125 alone, combined logistic regression scores of AAbs and CA125 did not improve detection sensitivity at equal level of specificity. The added value of these selected AAbs as markers for ovarian cancer beyond CA125 for early detection is therefore limited. What's new? Could autoantibodies against tumor antigens provide an early warning system for ovarian cancer? These authors tested how well certain antibodies detected ovarian cancer. They selected four candidate antibodies, to p53, CTAG1A, CTAG2 and NUDT11 proteins, which appear in elevated levels in cancer patients. None of them performed well as a herald of burgeoning cancer. They did not perform any better than the best currently available biomarker, CA125, and as lead times increased past 6 months prediagnosis, the effectiveness diminished. Surprisingly, elevated antibodies appeared in quite a few of the control samples, suggesting they might not be as cancer-specific as expected.

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