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Int J Mol Epidemiol Genet 2011;2(1):36-50.
Original Article
Polymorphisms in CTNNBL1 in relation to colorectal cancer with evolutionary
implications
Stefanie Huhn, Dierk Ingelfinger, Justo Lorenzo Bermejo, Barbara Pardini, Alessio Naccarati, Verena Steinke, Nils Rahner, Elke
Holinski-Feder, Monika Morak, Hans K. Schackert, Heike Görgens, Christian P Pox, Timm Goecke, Matthias Kloor, Markus
Loeffler, Reinhard Büttner, Ludmila Vodickova, Jan Novotny, Kubilay Demir, Cristina-Maria Cruciat, Rebecca Renneberg,
Wolfgang Huber, Christof Niehrs, Michael Boutros, Peter Propping, Pavel Vodička, Kari Hemminki, Asta Försti
Stefanie Huhn; Department of Molecular Genetic Epidemiology; German Cancer Research, Center (DKFZ); Heidelberg;
Germany;
Dierk Ingelfinger; Division of Signaling and Functional Genomics; German Cancer Research, Center (DKFZ) and University of
Heidelberg; Germany; dierk.ingelfinger@medma.uni-heidelberg.de
Justo Lorenzo Bermejo; Department of Molecular Genetic Epidemiology; German Cancer, Research Center (DKFZ);
Heidelberg; Germany; Institute of Medical Biometry and Informatics; University Hospital Heidelberg; Germany;
Barbara Pardini; Department of Molecular Biology of Cancer at the Institute of Experimental Medicine; Academy of Sciences of
the Czech Republic; Prague; Czech Republic;
Alessio Naccarati; Department of Molecular Biology of Cancer at the Institute of Experimental Medicine; Academy of Sciences of
the Czech Republic; Prague;
Verena Steinke; Institute of Human Genetics; Rheinische Friedrich-Wilhelms-Universität; Bonn; Germany;
Nils Rahner; Institute of Human Genetics; Rheinische Friedrich-Wilhelms-Universität Bonn; Germany;
Elke Holinski-Feder; Department of Internal Medicine, Campus Innenstadt; University Hospital of the Ludwig-Maximilians-
University Munich; Germany;
Monika Morak; Department of Internal Medicine, Campus Innenstadt; University Hospital of the Ludwig-Maximilians-University
Munich; Germany;
Hans K. Schackert; Department of Surgical Research at the Universitätsklinikum Carl Gustav Carus; Technische Universität
Dresden; Germany;
Heike Görgens; Department of Surgical Research at the Universitätsklinikum Carl Gustav Carus; Technische Universität
Dresden; Germany;
Christian P Pox; Medical Department at the Knappschaftskrankenhaus Bochum; Ruhr University Bochum; Germany;
Timm Goecke; Institute of Human Genetics and Anthropology; Heinrich-Heine-Universität Düsseldorf; Germany;
Matthias Kloor; Department of Applied Tumour Biology at the Institute of Pathology; Ruprecht-Karls-Universität Heidelberg;
Germany;
Markus Loeffler; Faculty of Medicine, Institute of Medical Informatics, Statistics and Epidemiology; University of Leipzig; Germany;
Reinhard Büttner; Institute of Pathology; Rheinische Friedrich-Wilhelms-Universität Bonn; Germany; reinhard.
Ludmila Vodickova; a Department of Molecular Biology of Cancer at the Institute of Experimental Medicine; Academy of
Sciences of the Czech Republic; Prague; Czech Republic; Department of Toxicogenomics; National Institute of Public Health;
Prague; Czech Republic
Jan Novotny; Department of Oncology; General Teaching Hospital; Prague; Czech Republic;
Kubilay Demir; Division Signaling and Functional Genomics; German Cancer Research Center (DKFZ) and University of
Heidelberg Heidelberg; Germany;
Cristina-Maria Cruciat; Division of Molecular Embryology; German Cancer Research Center (DKFZ); Heidelberg; Germany;
Rebecca Renneberg;
Wolfgang Huber; EMBL European Bioinformatics Institute; Cambridge; UK;
Christof Niehrs; Division of Molecular Embryology, German Cancer Research Center (DKFZ), Heidelberg; Germany;
Michael Boutros; Division Signaling and Functional Genomics; German Cancer Research Center (DKFZ) and University of
Heidelberg; Germany;
Peter Propping; Institute of Human Genetics; Rheinische Friedrich-Wilhelms-Universität Bonn; Germany;
Pavel Vodicka; Department of Molecular Biology of Cancer at the Institute of Experimental Medicine; Academy of Sciences of the
Czech Republic; Prague; Czech Republic;
Kari Hemminki; Department of Molecular Genetic Epidemiology; German Cancer Research Center (DKFZ); Heidelberg;
Germany; Center of Primary Health Care Research at the Clinical Research Center; Lund University; Malmö; Sweden;
Asta Försti; Department of Molecular Genetic Epidemiology; German Cancer Research Center (DKFZ); Heidelberg; Germany;
Center of Primary Health Care Research at the Clinical Research Center; Lund University; Malmö; Sweden
Received November 8, 2010; accepted November, 2010; Epub December, 2010; published January 1, 2011
Abstract: Colorectal cancer (CRC) is a complex disease related to environmental and genetic risk factors. Several studies
have shown that susceptibility to complex diseases can be mediated by ancestral alleles. Using RNAi screening, CTNNBL1
was identified as a putative regulator of the Wnt signaling pathway, which plays a key role in colorectal carcinogenesis.
Recently, single nucleotide polymorphisms (SNPs) in CTNNBL1 have been associated with obesity, a known risk factor for
CRC. We investigated whether genetic variation in CTNNBL1 affects susceptibility to CRC and tested for signals of recent
selection. We applied a tagging SNP approach that cover all known common variation in CTNNBL1 (allele frequency >5%; r²>0.
8). A case-control study was carried out using two well-characterized study populations: a hospital-based Czech population
composed of 751 sporadic cases and 755 controls and a family/early onset-based German population (697 cases and 644
controls). Genotyping was performed using allele specific PCR based TaqMan® assays (Applied Biosystems, Weiterstadt,
Germany). In the Czech cohort, containing sporadic cases, the ancestral alleles of three SNPs showed evidence of association
with CRC: rs2344481 (OR 1.44, 95%CI 1.06-1.95, dominant model), rs2281148 (OR 0.59, 95%CI 0.36-0.96, dominant model)
and rs2235460 (OR 1.38, 95%CI 1.01-1.89, AA vs. GG). The associations were less prominent in the family/early onset-based
German cohort. Data derived from several databases and statistical tests consistently pointed to a likely shaping of CTNNBL1
by positive selection. Further studies are needed to identify the actual function of CTNNBL1 and to validate the association
results in other populations.(IJMEG1011004).
Keywords: Colorectal cancer, case-control study, ancestral-susceptibility model, selective pressure, CTNNBL1
Full Text PDF
Address all correspondence to:
Stefanie Huhn
Department of Molecular Genetic Epidemiology
German Cancer Research Center (DKFZ)
Heidelberg; Germany.
Tel: +49 6221 42 1811, Fax: +49 6221 42 1810
E-mail: s.huhn@dkfz.de
Original Article
Polymorphisms in CTNNBL1 in relation to colorectal cancer with evolutionary
implications
Stefanie Huhn, Dierk Ingelfinger, Justo Lorenzo Bermejo, Barbara Pardini, Alessio Naccarati, Verena Steinke, Nils Rahner, Elke
Holinski-Feder, Monika Morak, Hans K. Schackert, Heike Görgens, Christian P Pox, Timm Goecke, Matthias Kloor, Markus
Loeffler, Reinhard Büttner, Ludmila Vodickova, Jan Novotny, Kubilay Demir, Cristina-Maria Cruciat, Rebecca Renneberg,
Wolfgang Huber, Christof Niehrs, Michael Boutros, Peter Propping, Pavel Vodička, Kari Hemminki, Asta Försti
Stefanie Huhn; Department of Molecular Genetic Epidemiology; German Cancer Research, Center (DKFZ); Heidelberg;
Germany;
Dierk Ingelfinger; Division of Signaling and Functional Genomics; German Cancer Research, Center (DKFZ) and University of
Heidelberg; Germany; dierk.ingelfinger@medma.uni-heidelberg.de
Justo Lorenzo Bermejo; Department of Molecular Genetic Epidemiology; German Cancer, Research Center (DKFZ);
Heidelberg; Germany; Institute of Medical Biometry and Informatics; University Hospital Heidelberg; Germany;
Barbara Pardini; Department of Molecular Biology of Cancer at the Institute of Experimental Medicine; Academy of Sciences of
the Czech Republic; Prague; Czech Republic;
Alessio Naccarati; Department of Molecular Biology of Cancer at the Institute of Experimental Medicine; Academy of Sciences of
the Czech Republic; Prague;
Verena Steinke; Institute of Human Genetics; Rheinische Friedrich-Wilhelms-Universität; Bonn; Germany;
Nils Rahner; Institute of Human Genetics; Rheinische Friedrich-Wilhelms-Universität Bonn; Germany;
Elke Holinski-Feder; Department of Internal Medicine, Campus Innenstadt; University Hospital of the Ludwig-Maximilians-
University Munich; Germany;
Monika Morak; Department of Internal Medicine, Campus Innenstadt; University Hospital of the Ludwig-Maximilians-University
Munich; Germany;
Hans K. Schackert; Department of Surgical Research at the Universitätsklinikum Carl Gustav Carus; Technische Universität
Dresden; Germany;
Heike Görgens; Department of Surgical Research at the Universitätsklinikum Carl Gustav Carus; Technische Universität
Dresden; Germany;
Christian P Pox; Medical Department at the Knappschaftskrankenhaus Bochum; Ruhr University Bochum; Germany;
Timm Goecke; Institute of Human Genetics and Anthropology; Heinrich-Heine-Universität Düsseldorf; Germany;
Matthias Kloor; Department of Applied Tumour Biology at the Institute of Pathology; Ruprecht-Karls-Universität Heidelberg;
Germany;
Markus Loeffler; Faculty of Medicine, Institute of Medical Informatics, Statistics and Epidemiology; University of Leipzig; Germany;
Reinhard Büttner; Institute of Pathology; Rheinische Friedrich-Wilhelms-Universität Bonn; Germany; reinhard.
Ludmila Vodickova; a Department of Molecular Biology of Cancer at the Institute of Experimental Medicine; Academy of
Sciences of the Czech Republic; Prague; Czech Republic; Department of Toxicogenomics; National Institute of Public Health;
Prague; Czech Republic
Jan Novotny; Department of Oncology; General Teaching Hospital; Prague; Czech Republic;
Kubilay Demir; Division Signaling and Functional Genomics; German Cancer Research Center (DKFZ) and University of
Heidelberg Heidelberg; Germany;
Cristina-Maria Cruciat; Division of Molecular Embryology; German Cancer Research Center (DKFZ); Heidelberg; Germany;
Rebecca Renneberg;
Wolfgang Huber; EMBL European Bioinformatics Institute; Cambridge; UK;
Christof Niehrs; Division of Molecular Embryology, German Cancer Research Center (DKFZ), Heidelberg; Germany;
Michael Boutros; Division Signaling and Functional Genomics; German Cancer Research Center (DKFZ) and University of
Heidelberg; Germany;
Peter Propping; Institute of Human Genetics; Rheinische Friedrich-Wilhelms-Universität Bonn; Germany;
Pavel Vodicka; Department of Molecular Biology of Cancer at the Institute of Experimental Medicine; Academy of Sciences of the
Czech Republic; Prague; Czech Republic;
Kari Hemminki; Department of Molecular Genetic Epidemiology; German Cancer Research Center (DKFZ); Heidelberg;
Germany; Center of Primary Health Care Research at the Clinical Research Center; Lund University; Malmö; Sweden;
Asta Försti; Department of Molecular Genetic Epidemiology; German Cancer Research Center (DKFZ); Heidelberg; Germany;
Center of Primary Health Care Research at the Clinical Research Center; Lund University; Malmö; Sweden
Received November 8, 2010; accepted November, 2010; Epub December, 2010; published January 1, 2011
Abstract: Colorectal cancer (CRC) is a complex disease related to environmental and genetic risk factors. Several studies
have shown that susceptibility to complex diseases can be mediated by ancestral alleles. Using RNAi screening, CTNNBL1
was identified as a putative regulator of the Wnt signaling pathway, which plays a key role in colorectal carcinogenesis.
Recently, single nucleotide polymorphisms (SNPs) in CTNNBL1 have been associated with obesity, a known risk factor for
CRC. We investigated whether genetic variation in CTNNBL1 affects susceptibility to CRC and tested for signals of recent
selection. We applied a tagging SNP approach that cover all known common variation in CTNNBL1 (allele frequency >5%; r²>0.
8). A case-control study was carried out using two well-characterized study populations: a hospital-based Czech population
composed of 751 sporadic cases and 755 controls and a family/early onset-based German population (697 cases and 644
controls). Genotyping was performed using allele specific PCR based TaqMan® assays (Applied Biosystems, Weiterstadt,
Germany). In the Czech cohort, containing sporadic cases, the ancestral alleles of three SNPs showed evidence of association
with CRC: rs2344481 (OR 1.44, 95%CI 1.06-1.95, dominant model), rs2281148 (OR 0.59, 95%CI 0.36-0.96, dominant model)
and rs2235460 (OR 1.38, 95%CI 1.01-1.89, AA vs. GG). The associations were less prominent in the family/early onset-based
German cohort. Data derived from several databases and statistical tests consistently pointed to a likely shaping of CTNNBL1
by positive selection. Further studies are needed to identify the actual function of CTNNBL1 and to validate the association
results in other populations.(IJMEG1011004).
Keywords: Colorectal cancer, case-control study, ancestral-susceptibility model, selective pressure, CTNNBL1
Full Text PDF
Address all correspondence to:
Stefanie Huhn
Department of Molecular Genetic Epidemiology
German Cancer Research Center (DKFZ)
Heidelberg; Germany.
Tel: +49 6221 42 1811, Fax: +49 6221 42 1810
E-mail: s.huhn@dkfz.de
