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

Item Type:	Article
Title:	Exome sequencing identifies biallelic MSH3 germline mutations as a recessive subtype of colorectal adenomatous polyposis
Creators Name:	Adam, R. and Spier, I. and Zhao, B. and Kloth, M. and Marquez, J. and Hinrichsen, I. and Kirfel, J. and Tafazzoli, A. and Horpaopan, S. and Uhlhaas, S. and Stienen, D. and Friedrichs, N. and Altmüller, J. and Laner, A. and Holzapfel, S. and Peters, S. and Kayser, K. and Thiele, H. and Holinski-Feder, E. and Marra, G. and Kristiansen, G. and Nöthen, M.M. and Büttner, R. and Möslein, G. and Betz, R.C. and Brieger, A. and Lifton, R.P. and Aretz, S.
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:	Familial Colorectal Cancer, Adenomatous Polyposis, Candidate Genes, Mismatch Repair, Exome Sequencing, Massive Parallel Sequencing, Hereditary Tumor Syndromes
Source:	American Journal of Human Genetics
ISSN:	0002-9297
Publisher:	Cell Press
Volume:	99
Number:	2
Page Range:	337-51
Date:	4 August 2016
Official Publication:	https://doi.org/10.1016/j.ajhg.2016.06.015
PubMed:	View item in PubMed

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