2. Academic Validation
  3. Exome Sequencing Identifies Biallelic MSH3 Germline Mutations as a Recessive Subtype of Colorectal Adenomatous Polyposis

Exome Sequencing Identifies Biallelic MSH3 Germline Mutations as a Recessive Subtype of Colorectal Adenomatous Polyposis

  • Am J Hum Genet. 2016 Aug 4;99(2):337-51. doi: 10.1016/j.ajhg.2016.06.015.
Ronja Adam 1,  Isabel Spier 1,  Bixiao Zhao 2,  Michael Kloth 3,  Jonathan Marquez 2,  Inga Hinrichsen 4,  Jutta Kirfel 5,  Aylar Tafazzoli 6,  Sukanya Horpaopan 7,  Siegfried Uhlhaas 8,  Dietlinde Stienen 8,  Nicolaus Friedrichs 3,  Janine Altmüller 9,  Andreas Laner 10,  Stefanie Holzapfel 1,  Sophia Peters 8,  Katrin Kayser 8,  Holger Thiele 11,  Elke Holinski-Feder 10,  Giancarlo Marra 12,  Glen Kristiansen 5,  Markus M Nöthen 6,  Reinhard Büttner 3,  Gabriela Möslein 13,  Regina C Betz 6,  Angela Brieger 4,  Richard P Lifton 2,  Stefan Aretz 14
Affiliations

Affiliations

  • 1 Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany; Center for Hereditary Tumor Syndromes, University of Bonn, 53127 Bonn, Germany.
  • 2 Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520-8005, USA.
  • 3 Institute of Pathology, University of Cologne, 50937 Cologne, Germany.
  • 4 Medical Clinic 1, Biomedical Research Laboratory, Goethe-University Frankfurt, 60590 Frankfurt, Germany.
  • 5 Institute of Pathology, University of Bonn, 53127 Bonn, Germany.
  • 6 Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, 53127 Bonn, Germany.
  • 7 Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany; Department of Anatomy, Faculty of Medical Science, Naresuan University, Phitsanulok, Chiang Mai 50200, Thailand.
  • 8 Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany.
  • 9 Cologne Center for Genomics, University of Cologne, 50937 Cologne, Germany; Institute of Human Genetics, University of Cologne, 50937 Cologne, Germany.
  • 10 Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-University, 80336 Munich, Germany; Medical Genetics Center, 80335 Munich, Germany.
  • 11 Cologne Center for Genomics, University of Cologne, 50937 Cologne, Germany.
  • 12 Institute of Molecular Cancer Research, University of Zurich, CH-8057 Zurich, Switzerland.
  • 13 HELIOS Klinikum Wuppertal, University of Witten/Herdecke, 42283 Wuppertal, Germany.
  • 14 Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany; Center for Hereditary Tumor Syndromes, University of Bonn, 53127 Bonn, Germany. Electronic address: [email protected].
PMID: 27476653 DOI: 10.1016/j.ajhg.2016.06.015
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.

Keywords

adenomatous polyposis; candidate genes; exome sequencing; familial colorectal cancer; hereditary tumor syndromes; massive parallel sequencing; mismatch repair.

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