title: Exome Sequencing Identifies Biallelic MSH3 Germline Mutations as a Recessive Subtype of Colorectal Adenomatous Polyposis.
abstract: In ∼30% of families affected by colorectal adenomatous polyposis, no germline mutations have been identified in the previously implicated genes APC, MUTYH, POLE, POLD1, and NTHL1, although a hereditary etiology is likely. To uncover further genes with high-penetrance causative mutations, we performed exome sequencing of leukocyte DNA from 102 unrelated individuals with unexplained adenomatous polyposis. We identified two unrelated individuals with differing compound-heterozygous loss-of-function (LoF) germline mutations in the mismatch-repair gene MSH3. The impact of the MSH3 mutations (c.1148delA, c.2319-1G>A, c.2760delC, and c.3001-2A>C) was indicated at the RNA and protein levels. Analysis of the diseased individuals' tumor tissue demonstrated high microsatellite instability of di- and tetranucleotides (EMAST), and immunohistochemical staining illustrated a complete loss of nuclear MSH3 in normal and tumor tissue, confirming the LoF effect and causal relevance of the mutations. The pedigrees, genotypes, and frequency of MSH3 mutations in the general population are consistent with an autosomal-recessive mode of inheritance. Both index persons have an affected sibling carrying the same mutations. The tumor spectrum in these four persons comprised colorectal and duodenal adenomas, colorectal cancer, gastric cancer, and an early-onset astrocytoma. Additionally, we detected one unrelated individual with biallelic PMS2 germline mutations, representing constitutional mismatch-repair deficiency. Potentially causative variants in 14 more candidate genes identified in 26 other individuals require further workup. In the present study, we identified biallelic germline MSH3 mutations in individuals with a suspected hereditary tumor syndrome. Our data suggest that MSH3 mutations represent an additional recessive subtype of colorectal adenomatous polyposis.
authors.affiliation: Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany; Center for Hereditary Tumor Syndromes, University of Bonn, 53127 Bonn, Germany.
authors.forename: Ronja
authors.initials: R
authors.lastname: Adam
authors.affiliation: Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany; Center for Hereditary Tumor Syndromes, University of Bonn, 53127 Bonn, Germany.
authors.forename: Isabel
authors.initials: I
authors.lastname: Spier
authors.affiliation: Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520-8005, USA.
authors.forename: Bixiao
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Institute of Pathology, University of Cologne, 50937 Cologne, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Kloth
authors.affiliation: Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520-8005, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Marquez
authors.affiliation: Medical Clinic 1, Biomedical Research Laboratory, Goethe-University Frankfurt, 60590 Frankfurt, Germany.
authors.forename: Inga
authors.initials: I
authors.lastname: Hinrichsen
authors.affiliation: Institute of Pathology, University of Bonn, 53127 Bonn, Germany.
authors.forename: Jutta
authors.initials: J
authors.lastname: Kirfel
authors.affiliation: Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, 53127 Bonn, Germany.
authors.forename: Aylar
authors.initials: A
authors.lastname: Tafazzoli
authors.affiliation: Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany; Department of Anatomy, Faculty of Medical Science, Naresuan University, Phitsanulok, Chiang Mai 50200, Thailand.
authors.forename: Sukanya
authors.initials: S
authors.lastname: Horpaopan
authors.affiliation: Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany.
authors.forename: Siegfried
authors.initials: S
authors.lastname: Uhlhaas
authors.affiliation: Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany.
authors.forename: Dietlinde
authors.initials: D
authors.lastname: Stienen
authors.affiliation: Institute of Pathology, University of Cologne, 50937 Cologne, Germany.
authors.forename: Nicolaus
authors.initials: N
authors.lastname: Friedrichs
authors.affiliation: Cologne Center for Genomics, University of Cologne, 50937 Cologne, Germany; Institute of Human Genetics, University of Cologne, 50937 Cologne, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Altmüller
authors.affiliation: Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-University, 80336 Munich, Germany; Medical Genetics Center, 80335 Munich, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Laner
authors.affiliation: Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany; Center for Hereditary Tumor Syndromes, University of Bonn, 53127 Bonn, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Holzapfel
authors.affiliation: Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany.
authors.forename: Sophia
authors.initials: S
authors.lastname: Peters
authors.affiliation: Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Kayser
authors.affiliation: Cologne Center for Genomics, University of Cologne, 50937 Cologne, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.affiliation: Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-University, 80336 Munich, Germany; Medical Genetics Center, 80335 Munich, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Holinski-Feder
authors.affiliation: Institute of Molecular Cancer Research, University of Zurich, CH-8057 Zurich, Switzerland.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Marra
authors.affiliation: Institute of Pathology, University of Bonn, 53127 Bonn, Germany.
authors.forename: Glen
authors.initials: G
authors.lastname: Kristiansen
authors.affiliation: Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, 53127 Bonn, Germany.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.affiliation: Institute of Pathology, University of Cologne, 50937 Cologne, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Büttner
authors.affiliation: HELIOS Klinikum Wuppertal, University of Witten/Herdecke, 42283 Wuppertal, Germany.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Möslein
authors.affiliation: Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, 53127 Bonn, Germany.
authors.forename: Regina C
authors.initials: RC
authors.lastname: Betz
authors.affiliation: Medical Clinic 1, Biomedical Research Laboratory, Goethe-University Frankfurt, 60590 Frankfurt, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Brieger
authors.affiliation: Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520-8005, USA.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Lifton
authors.affiliation: Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany; Center for Hereditary Tumor Syndromes, University of Bonn, 53127 Bonn, Germany. Electronic address: stefan.aretz@uni-bonn.de.
authors.forename: Stefan
authors.initials: S
authors.lastname: Aretz
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000483:Alleles; D002675:Child, Preschool; D015179:Colorectal Neoplasms / Q000235:genetics*; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D005260:Female; D005808:Genes, Recessive / Q000235:genetics*; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2 / Q000235:genetics; D000074081:MutS Homolog 3 Protein; D010375:Pedigree
chemical_list: D004268:DNA-Binding Proteins; C078444:MSH3 protein, human; D000074081:MutS Homolog 3 Protein; C094934:PMS2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2
keywords: adenomatous polyposis; candidate genes; exome sequencing; familial colorectal cancer; hereditary tumor syndromes; massive parallel sequencing; mismatch repair