title: Biallelic MUTYH mutations can mimic Lynch syndrome.
abstract: The hallmarks of Lynch syndrome (LS) include a positive family history of colorectal cancer (CRC), germline mutations in the DNA mismatch repair (MMR) genes, tumours with high microsatellite instability (MSI-H) and loss of MMR protein expression. However, in ∼10-15% of clinically suspected LS cases, MMR mutation analyses cannot explain MSI-H and abnormal immunohistochemistry (IHC) results. The highly variable phenotype of MUTYH-associated polyposis (MAP) can overlap with the LS phenotype, but is inherited recessively. We analysed the MUTYH gene in 85 'unresolved' patients with tumours showing IHC MMR-deficiency without detectable germline mutation. Biallelic p.(Tyr179Cys) MUTYH germline mutations were found in one patient (frequency 1.18%) with CRC, urothelial carcinoma and a sebaceous gland carcinoma. LS was suspected due to a positive family history of CRC and because of MSI-H and MSH2-MSH6 deficiency on IHC in the sebaceous gland carcinoma. Sequencing of this tumour revealed two somatic MSH2 mutations, thus explaining MSI-H and IHC results, and mimicking LS-like histopathology. This is the first report of two somatic MSH2 mutations leading to an MSI-H tumour lacking MSH2-MSH6 protein expression in a patient with MAP. In addition to typical transversion mutations in KRAS and APC, MAP can also induce tumourigenesis via the MSI-pathway.
authors: 1] Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Munich, Germany [2] MGZ - Medizinisch Genetisches Zentrum, Munich, Germany.
authors: Monika
authors: M
authors: Morak
authors: Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Munich, Germany.
authors: Barbara
authors: B
authors: Heidenreich
authors: Institute of Pathology, Technical University of Munich, Munich, Germany.
authors: Gisela
authors: G
authors: Keller
authors: Human Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors: Heather
authors: H
authors: Hampel
authors: MGZ - Medizinisch Genetisches Zentrum, Munich, Germany.
authors: Andreas
authors: A
authors: Laner
authors: Human Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors: Albert
authors: A
authors: de la Chapelle
authors: 1] Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Munich, Germany [2] MGZ - Medizinisch Genetisches Zentrum, Munich, Germany.
authors: Elke
authors: E
authors: Holinski-Feder
mesh_terms: D000328:Adult; D000483:Alleles; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D045647:DNA Glycosylases / Q000235:genetics* / Q000378:metabolism; D053843:DNA Mismatch Repair / Q000235:genetics; D004252:DNA Mutational Analysis; D004260:DNA Repair / Q000235:genetics; D005091:Exons; D005260:Female; D018095:Germ-Line Mutation; D006720:Homozygote; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D010375:Pedigree
chemical_list: D045647:DNA Glycosylases; C061738:mutY adenine glycosylase