Universität zu Köln

Adam, Ronja, Spier, Isabel, Zhao, Bixiao ORCID: 0000-0002-1775-1690, Kloth, Michael, Marquez, Jonathan, Hinrichsen, Inga, Kirfel, Jutta, Tafazzoli, Aylar, Horpaopan, Sukanya, Uhlhaas, Siegfried, Stienen, Dietlinde, Friedrichs, Nicolaus, Altmueller, Janine, Laner, Andreas, Holzapfel, Stefanie, Peters, Sophia, Kayser, Katrin, Thiele, Holger, Holinski-Feder, Elke, Marra, Giancarlo, Kristiansen, Glen, Noethen, Markus M., Buettner, Reinhard, Moeslein, Gabriela, Betz, Regina C., Brieger, Angela, Lifton, Richard P. and Aretz, Stefan ORCID: 0000-0002-5228-1890 (2016). Exome Sequencing Identifies Biallelic MSH3 Germline Mutations as a Recessive Subtype of Colorectal Adenomatous Polyposis. Am. J. Hum. Genet., 99 (2). S. 337 - 352. CAMBRIDGE: CELL PRESS. ISSN 1537-6605

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Abstract

In similar to 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Adam, Ronja UNSPECIFIED UNSPECIFIED UNSPECIFIED Spier, Isabel UNSPECIFIED UNSPECIFIED UNSPECIFIED Zhao, Bixiao UNSPECIFIED orcid.org/0000-0002-1775-1690 UNSPECIFIED Kloth, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Marquez, Jonathan UNSPECIFIED UNSPECIFIED UNSPECIFIED Hinrichsen, Inga UNSPECIFIED UNSPECIFIED UNSPECIFIED Kirfel, Jutta UNSPECIFIED UNSPECIFIED UNSPECIFIED Tafazzoli, Aylar UNSPECIFIED UNSPECIFIED UNSPECIFIED Horpaopan, Sukanya UNSPECIFIED UNSPECIFIED UNSPECIFIED Uhlhaas, Siegfried UNSPECIFIED UNSPECIFIED UNSPECIFIED Stienen, Dietlinde UNSPECIFIED UNSPECIFIED UNSPECIFIED Friedrichs, Nicolaus UNSPECIFIED UNSPECIFIED UNSPECIFIED Altmueller, Janine UNSPECIFIED UNSPECIFIED UNSPECIFIED Laner, Andreas UNSPECIFIED UNSPECIFIED UNSPECIFIED Holzapfel, Stefanie UNSPECIFIED UNSPECIFIED UNSPECIFIED Peters, Sophia UNSPECIFIED UNSPECIFIED UNSPECIFIED Kayser, Katrin UNSPECIFIED UNSPECIFIED UNSPECIFIED Thiele, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED Holinski-Feder, Elke UNSPECIFIED UNSPECIFIED UNSPECIFIED Marra, Giancarlo UNSPECIFIED UNSPECIFIED UNSPECIFIED Kristiansen, Glen UNSPECIFIED UNSPECIFIED UNSPECIFIED Noethen, Markus M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Buettner, Reinhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Moeslein, Gabriela UNSPECIFIED UNSPECIFIED UNSPECIFIED Betz, Regina C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Brieger, Angela UNSPECIFIED UNSPECIFIED UNSPECIFIED Lifton, Richard P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Aretz, Stefan UNSPECIFIED orcid.org/0000-0002-5228-1890 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-266806
DOI:	10.1016/j.ajhg.2016.06.015
Journal or Publication Title:	Am. J. Hum. Genet.
Volume:	99
Number:	2
Page Range:	S. 337 - 352
Date:	2016
Publisher:	CELL PRESS
Place of Publication:	CAMBRIDGE
ISSN:	1537-6605
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MISMATCH REPAIR FUNCTION; MICROSATELLITE INSTABILITY; LYNCH-SYNDROME; TETRANUCLEOTIDE REPEATS; CANCER PREDISPOSITION; GENETIC INSTABILITY; PROTEIN EXPRESSION; CANDIDATE GENES; RARE VARIANTS; COLON-CANCER Multiple languages Genetics & Heredity Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/26680