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Elucidating the molecular basis of MSH2-deficient tumors by combined germline and somatic analysis.
Vargas-Parra, Gardenia M; González-Acosta, Maribel; Thompson, Bryony A; Gómez, Carolina; Fernández, Anna; Dámaso, Estela; Pons, Tirso; Morak, Monika; Del Valle, Jesús; Iglesias, Silvia; Velasco, Àngela; Solanes, Ares; Sanjuan, Xavier; Padilla, Natàlia; de la Cruz, Xavier; Valencia, Alfonso; Holinski-Feder, Elke; Brunet, Joan; Feliubadaló, Lídia; Lázaro, Conxi; Navarro, Matilde; Pineda, Marta; Capellá, Gabriel.
Affiliation
  • Vargas-Parra GM; Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, CIBERONC, Hospitalet de Llobregat, Spain.
  • González-Acosta M; Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, CIBERONC, Hospitalet de Llobregat, Spain.
  • Thompson BA; Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT.
  • Gómez C; Centre for Epidemiology and Biostatistics, School of Population and Global Health, University of Melbourne, Melbourne, Australia.
  • Fernández A; Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, CIBERONC, Hospitalet de Llobregat, Spain.
  • Dámaso E; Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, CIBERONC, Hospitalet de Llobregat, Spain.
  • Pons T; Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, CIBERONC, Hospitalet de Llobregat, Spain.
  • Morak M; Structural Biology and Biocomputing Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
  • Del Valle J; Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Ziemssenstr. Germany MGZ-Medizinisch Genetisches Zentrum, Munich, Germany.
  • Iglesias S; MGZ-Medizinisch Genetisches Zentrum, Munich, Germany.
  • Velasco À; Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, CIBERONC, Hospitalet de Llobregat, Spain.
  • Solanes A; Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, CIBERONC, Hospitalet de Llobregat, Spain.
  • Sanjuan X; Hereditary Cancer Program, Catalan Institute of Oncology, IdIBGI, Girona, Spain.
  • Padilla N; Hereditary Cancer Program, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain.
  • de la Cruz X; Pathology Department, Hospital Universitari de Bellvitge-IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.
  • Valencia A; Research Unit in Translational Bioinformatics, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.
  • Holinski-Feder E; Research Unit in Translational Bioinformatics, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.
  • Brunet J; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
  • Feliubadaló L; Structural Biology and Biocomputing Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
  • Lázaro C; Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Ziemssenstr. Germany MGZ-Medizinisch Genetisches Zentrum, Munich, Germany.
  • Navarro M; MGZ-Medizinisch Genetisches Zentrum, Munich, Germany.
  • Pineda M; Hereditary Cancer Program, Catalan Institute of Oncology, IdIBGI, Girona, Spain.
  • Capellá G; Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, CIBERONC, Hospitalet de Llobregat, Spain.
Int J Cancer ; 141(7): 1365-1380, 2017 10 01.
Article in En | MEDLINE | ID: mdl-28577310
ABSTRACT
In a proportion of patients presenting mismatch repair (MMR)-deficient tumors, no germline MMR mutations are identified, the so-called Lynch-like syndrome (LLS). Recently, MMR-deficient tumors have been associated with germline mutations in POLE and MUTYH or double somatic MMR events. Our aim was to elucidate the molecular basis of MSH2-deficient LS-suspected cases using a comprehensive analysis of colorectal cancer (CRC)-associated genes at germline and somatic level. Fifty-eight probands harboring MSH2-deficient tumors were included. Germline mutational analysis of MSH2 (including EPCAM deletions) and MSH6 was performed. Pathogenicity of MSH2 variants was assessed by RNA analysis and multifactorial likelihood calculations. MSH2 cDNA and methylation of MSH2 and MSH6 promoters were studied. Matched blood and tumor DNA were analyzed using a customized next generation sequencing panel. Thirty-five individuals were carriers of pathogenic or probably pathogenic variants in MSH2 and EPCAM. Five patients harbored 4 different MSH2 variants of unknown significance (VUS) and one had 2 novel MSH6 promoter VUS. Pathogenicity assessment allowed the reclassification of the 4 MSH2 VUS and 6 probably pathogenic variants as pathogenic mutations, enabling a total of 40 LS diagnostics. Predicted pathogenic germline variants in BUB1, SETD2, FAN1 and MUTYH were identified in 5 cases. Three patients had double somatic hits in MSH2 or MSH6, and another 2 had somatic alterations in other MMR genes and/or proofreading polymerases. In conclusion, our comprehensive strategy combining germline and somatic mutational status of CRC-associated genes by means of a subexome panel allows the elucidation of up to 86% of MSH2-deficient suspected LS tumors.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Colorectal Neoplasms, Hereditary Nonpolyposis / Germ-Line Mutation / DNA-Binding Proteins / MutS Homolog 2 Protein / DNA Mismatch Repair Limits: Humans Language: En Journal: Int J Cancer Year: 2017 Document type: Article Affiliation country:

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Colorectal Neoplasms, Hereditary Nonpolyposis / Germ-Line Mutation / DNA-Binding Proteins / MutS Homolog 2 Protein / DNA Mismatch Repair Limits: Humans Language: En Journal: Int J Cancer Year: 2017 Document type: Article Affiliation country: