title: Homozygosity of MSH2 c.1906G-->C germline mutation is associated with childhood colon cancer, astrocytoma and signs of Neurofibromatosis type I.
abstract: Hereditary non-polyposis colorectal cancer is a cancer predisposition syndrome known to be caused by heterozygous germline mutations in DNA mismatch repair genes (MMR) most commonly hMLH1, hMSH2, hMSH6. Heterozygous mutations in one of these genes confer an increased risk, mainly for colon and endometrial cancer. Recently, several publications identified that biallelic mutations in the MMR genes are associated with a more severe phenotype, including childhood malignancies and signs of neurofibromatosis type I (NF1). We report on a non-consanguineous Ashkenazi Jewish family with two affected siblings with features of NF1, colon cancer and astrocytoma at age 13 and 14. Their mother developed endometrial cancer at age 54. Their father had leukoplakia of the vocal cords with a family history of pancreatic cancer. Molecular and pathology studies were done on the tumor tissue and on genomic DNA of family members. Tumor testing demonstrated a high degree of microsatellite instability (MSI analysis), expression of MLH1 and absence of expression of both MSH2 and MSH6 proteins. A biallelic c.1906G > C (p.A636P) mutation in the hMSH2 gene was detected in the blood of one affected child. Parental genetic testing showed that each parent was heterozygote for the mutation. The c.1906G > C mutation is a founder mutation in the Ashkenazi Jewish population. To our knowledge this is the first report of homozygosity for this founder mutation.
authors.affiliation: Schneider Children's Medical Center of Israel and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Helen
authors.initials: H
authors.lastname: Toledano
authors.forename: Yael
authors.initials: Y
authors.lastname: Goldberg
authors.forename: Inbal
authors.initials: I
authors.lastname: Kedar-Barnes
authors.forename: Hagit
authors.initials: H
authors.lastname: Baris
authors.forename: Rinnat M
authors.initials: RM
authors.lastname: Porat
authors.forename: Chen
authors.initials: C
authors.lastname: Shochat
authors.forename: Dani
authors.initials: D
authors.lastname: Bercovich
authors.forename: Eli
authors.initials: E
authors.lastname: Pikarsky
authors.forename: Israela
authors.initials: I
authors.lastname: Lerer
authors.forename: Isaac
authors.initials: I
authors.lastname: Yaniv
authors.forename: Dvorah
authors.initials: D
authors.lastname: Abeliovich
authors.forename: Tamar
authors.initials: T
authors.lastname: Peretz
mesh_terms: D000293:Adolescent; D001254:Astrocytoma / Q000235:genetics*; D002648:Child; D003110:Colonic Neoplasms / Q000235:genetics*; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D018095:Germ-Line Mutation; D006720:Homozygote; D006801:Humans; D008297:Male; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D009456:Neurofibromatosis 1 / Q000235:genetics*; D010375:Pedigree
chemical_list: D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; D051718:MutS Homolog 2 Protein