title: The MLH1 c.1852_1853delinsGC (p.K618A) variant in colorectal cancer: genetic association study in 18,723 individuals.
abstract: Colorectal cancer is one of the most frequent neoplasms and an important cause of mortality in the developed world. Mendelian syndromes account for about 5% of the total burden of CRC, being Lynch syndrome and familial adenomatous polyposis the most common forms. Lynch syndrome tumors develop mainly as a consequence of defective DNA mismatch repair associated with germline mutations in MLH1, MSH2, MSH6 and PMS2. A significant proportion of variants identified by screening these genes correspond to missense or noncoding changes without a clear pathogenic consequence, and they are designated as "variants of uncertain significance", being the c.1852_1853delinsGC (p.K618A) variant in the MLH1 gene a clear example. The implication of this variant as a low-penetrance risk variant for CRC was assessed in the present study by performing a case-control study within a large cohort from the COGENT consortium-COST Action BM1206 including 18,723 individuals (8,055 colorectal cancer cases and 10,668 controls) and a case-only genotype-phenotype correlation with several clinical and pathological characteristics restricted to the Epicolon cohort. Our results showed no involvement of this variant as a low-penetrance variant for colorectal cancer genetic susceptibility and no association with any clinical and pathological characteristics including family history for this neoplasm or Lynch syndrome.
authors.affiliation: Department of Gastroenterology, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Catalonia, Spain; Department of Gastroenterology, Hospital del Mar-IMIM (Hospital del Mar Medical Research Centre), Pompeu Fabra University, Barcelona, Catalonia, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Abulí
authors.affiliation: Gastroenterology Department, Hospital Donostia, Networked Biomedical Research Centre for Hepatic and Digestive Diseases (CIBEREHD), Basque Country University, San Sebastián, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Bujanda
authors.affiliation: Department of Gastroenterology, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Catalonia, Spain.
authors.forename: Jenifer
authors.initials: J
authors.lastname: Muñoz
authors.affiliation: Department of Medine I, University Hospital Dresden, Dresden, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Buch
authors.affiliation: Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Clemens
authors.initials: C
authors.lastname: Schafmayer
authors.affiliation: IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Valeria Maiorana
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Veneroni
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Tom
authors.initials: T
authors.lastname: van Wezel
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Helga
authors.initials: H
authors.lastname: Westers
authors.affiliation: Department of Gastroenterology, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Catalonia, Spain.
authors.forename: Clara
authors.initials: C
authors.lastname: Esteban-Jurado
authors.affiliation: Department of Gastroenterology, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Catalonia, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Ocaña
authors.affiliation: Department of Gastroenterology, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Catalonia, Spain.
authors.forename: Josep M
authors.initials: JM
authors.lastname: Piqué
authors.affiliation: Department of Gastroenterology, Hospital del Mar-IMIM (Hospital del Mar Medical Research Centre), Pompeu Fabra University, Barcelona, Catalonia, Spain.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Andreu
authors.affiliation: Department of Gastroenterology, Hospital General d'Alacant, Alicante, Spain.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Jover
authors.affiliation: Galician Public Foundation of Genomic Medicine (FPGMX), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Genomics Medicine Group, Hospital Clínico, Santiago de Compostela, University of Santiago de Compostela, Galicia, Spain; Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
authors.forename: Angel
authors.initials: A
authors.lastname: Carracedo
authors.affiliation: Section of Digestive Diseases and Nutrition, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Xicola
authors.affiliation: Section of Digestive Diseases and Nutrition, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors.forename: Xavier
authors.initials: X
authors.lastname: Llor
authors.affiliation: Department of Gastroenterology, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Catalonia, Spain.
authors.forename: Antoni
authors.initials: A
authors.lastname: Castells
authors.affiliation: Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh and MRC Human Genetics Unit, Edinburgh, United Kingdom.
authors.forename: Malcolm
authors.initials: M
authors.lastname: Dunlop
authors.affiliation: Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Robert
authors.initials: R
authors.lastname: Hofstra
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
authors.forename: Annika
authors.initials: A
authors.lastname: Lindblom
authors.affiliation: Departments of Human Genetics and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Juul
authors.initials: J
authors.lastname: Wijnen
authors.affiliation: IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Peterlongo
authors.affiliation: Department of Medine I, University Hospital Dresden, Dresden, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Hampe
authors.affiliation: Galician Public Foundation of Genomic Medicine (FPGMX), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Genomics Medicine Group, Hospital Clínico, Santiago de Compostela, University of Santiago de Compostela, Galicia, Spain.
authors.forename: Clara
authors.initials: C
authors.lastname: Ruiz-Ponte
authors.affiliation: Department of Gastroenterology, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Catalonia, Spain.
authors.forename: Sergi
authors.initials: S
authors.lastname: Castellví-Bel
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000251:Adenosine Triphosphatases / Q000235:genetics; D019943:Amino Acid Substitution; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D018095:Germ-Line Mutation; D006801:Humans; D054643:INDEL Mutation; D008297:Male; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; C497172:MSH2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D045643:DNA Repair Enzymes
references.citation: Gastroenterology. 2013 Apr;144(4):799-807.e24
references.pmid: 23266556
references.citation: Cancer Epidemiol Biomarkers Prev. 2009 Nov;18(11):3062-7
references.pmid: 19843678
references.citation: Mutagenesis. 2012 Mar;27(2):143-51
references.pmid: 22294761
references.citation: Hum Genet. 1999 Nov;105(5):437-41
references.pmid: 10598809
references.citation: Int J Cancer. 2002 Apr 10;98(5):774-9
references.pmid: 11920650
references.citation: PLoS One. 2013 Sep 06;8(9):e72091
references.pmid: 24039736
references.citation: Nat Genet. 2014 Feb;46(2):107-115
references.pmid: 24362816
references.citation: Nat Genet. 2010 Nov;42(11):973-7
references.pmid: 20972440
references.citation: PLoS Genet. 2011 Jun;7(6):e1002105
references.pmid: 21655089
references.citation: Genet Med. 2011 Feb;13(2):115-24
references.pmid: 21239990
references.citation: Clin Cancer Res. 2013 May 1;19(9):2432-41
references.pmid: 23403630
references.citation: Br J Cancer. 2010 Jan 19;102(2):447-54
references.pmid: 19920828
references.citation: Nat Genet. 2013 Feb;45(2):191-6
references.pmid: 23263487
references.citation: Br J Cancer. 2012 Sep 4;107(6):1001-8
references.pmid: 22878375
references.citation: Hum Mutat. 2011 May;32(5):557-63
references.pmid: 21520333
references.citation: BMC Med Genet. 2011 Jan 19;12:12
references.pmid: 21247423
references.citation: Hum Mutat. 2012 Dec;33(12):1617-25
references.pmid: 22833534
references.citation: Cancer Res. 2007 May 15;67(10):4595-604
references.pmid: 17510385
references.citation: Nat Rev Genet. 2009 Jun;10(6):353-8
references.pmid: 19434079
references.citation: Hum Mutat. 2008 Jun;29(6):852-60
references.pmid: 18383312
references.citation: Hum Mutat. 2008 Dec;29(12):1412-24
references.pmid: 18561205
references.citation: BMC Med Genet. 2008 Jun 11;9:52
references.pmid: 18547406
references.citation: Am J Hum Genet. 2005 May;76(5):887-93
references.pmid: 15789306
references.citation: BMC Genomics. 2013 Jan 26;14:55
references.pmid: 23350875
references.citation: JAMA. 2005 Apr 27;293(16):1986-94
references.pmid: 15855432
references.citation: Nat Genet. 2012 May 27;44(7):770-6
references.pmid: 22634755
references.citation: Am J Hum Genet. 2007 Sep;81(3):559-75
references.pmid: 17701901
references.citation: J Mol Diagn. 2012 May-Jun;14(3):264-73
references.pmid: 22426235
references.citation: Gastroenterology. 2010 Jun;138(6):2044-58
references.pmid: 20420945