Exome sequencing identifies biallelic MSH3 germline mutations as a recessive subtype of colorectal adenomatous polyposis

  • 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.

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Author:Ronja Adam, Isabel Spier, Bixiao Zhao, Michael Kloth, Jonathan Marquez, Inga HinrichsenGND, Jutta Kirfel, Aylar Tafazzoli, Sukanya Horpaopan, Siegfried Uhlhaas, Dietlinde Stienen, Nicolaus Friedrichs, Janine AltmüllerORCiDGND, Andreas Laner, Stefanie Holzapfel, Sophia Peters, Katrin Kayser, Holger ThieleORCiD, Elke Holinski-Feder, Giancarlo MarraORCiD, Glen Kristiansen, Markus Maria NöthenORCiDGND, Reinhard BüttnerORCiDGND, Gabriela Möslein, Regina Christine Betz, Angela BriegerORCiDGND, Richard P. Lifton, Stefan Aretz
URN:urn:nbn:de:hebis:30:3-440315
DOI:https://doi.org/10.1016/j.ajhg.2016.06.015
ISSN:0002-9297
ISSN:1537-6605
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/27476653
Parent Title (English):American journal of human genetics
Publisher:Elsevier ; Cell Press
Place of publication:New York, NY [u. a.]
Document Type:Article
Language:English
Date of Publication (online):2017/05/22
Year of first Publication:2016
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2017/05/22
Tag:adenomatous polyposis; candidate genes; exome sequencing; familial colorectal cancer; hereditary tumor syndromes; massive parallel sequencing; mismatch repair
Volume:99
Issue:2
Page Number:15
First Page:337
Last Page:351
Note:
© 2016 American Society of Human Genetics.
HeBIS-PPN:420978275
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoDeutsches Urheberrecht