Universität zu Köln

Perne, Claudia, Peters, Sophia, Cartolano, Maria, Horpaopan, Sukanya, Grimm, Christina, Altmuller, Janine, Sommer, Anna K., Hillmer, Axel M., Thiele, Holger, Odenthal, Margarete, Moeslein, Gabriela, Adam, Ronja, Sivalingam, Sugirthan, Kirfel, Jutta, Schweiger, Michal R., Peifer, Martin, Spier, Isabel and Aretz, Stefan (2021). Variant profiling of colorectal adenomas from three patients of two families with MSH3-related adenomatous polyposis. PLoS One, 16 (11). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1932-6203

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Abstract

The spectrum of somatic genetic variation in colorectal adenomas caused by biallelic pathogenic germline variants in the MSH3 gene, was comprehensively analysed to characterise mutational signatures and identify potential driver genes and pathways of MSH3-related tumourigenesis. Three patients from two families with MSH3-associated polyposis were included. Whole exome sequencing of nine adenomas and matched normal tissue was performed. The amount of somatic variants in the MSH3-deficient adenomas and the pattern of single nucleotide variants (SNVs) was similar to sporadic adenomas, whereas the fraction of small insertions/deletions (indels) (21-42% of all small variants) was significantly higher. Interestingly, pathogenic somatic APC variants were found in all but one adenoma. The vast majority (12/13) of these were di-, tetra-, or penta-base pair (bp) deletions. The fraction of APC indels was significantly higher than that reported in patients with familial adenomatous polyposis (FAP) (p < 0.01) or in sporadic adenomas (p < 0.0001). In MSH3-deficient adenomas, the occurrence of APC indels in a repetitive sequence context was significantly higher than in FAP patients (p < 0.01). In addition, the MSH3-deficient adenomas harboured one to five (recurrent) somatic variants in 13 established or candidate driver genes for early colorectal carcinogenesis, including ACVR2A and ARID genes. Our data suggest that MSH3-related colorectal carcinogenesis seems to follow the classical APC-driven pathway. In line with the specific function of MSH3 in the mismatch repair (MMR) system, we identified a characteristic APC mutational pattern in MSH3-deficient adenomas, and confirmed further driver genes for colorectal tumourigenesis.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Perne, Claudia UNSPECIFIED UNSPECIFIED UNSPECIFIED Peters, Sophia UNSPECIFIED UNSPECIFIED UNSPECIFIED Cartolano, Maria UNSPECIFIED UNSPECIFIED UNSPECIFIED Horpaopan, Sukanya UNSPECIFIED UNSPECIFIED UNSPECIFIED Grimm, Christina UNSPECIFIED UNSPECIFIED UNSPECIFIED Altmuller, Janine UNSPECIFIED UNSPECIFIED UNSPECIFIED Sommer, Anna K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hillmer, Axel M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Thiele, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED Odenthal, Margarete UNSPECIFIED UNSPECIFIED UNSPECIFIED Moeslein, Gabriela UNSPECIFIED UNSPECIFIED UNSPECIFIED Adam, Ronja UNSPECIFIED UNSPECIFIED UNSPECIFIED Sivalingam, Sugirthan UNSPECIFIED UNSPECIFIED UNSPECIFIED Kirfel, Jutta UNSPECIFIED UNSPECIFIED UNSPECIFIED Schweiger, Michal R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Peifer, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Spier, Isabel UNSPECIFIED UNSPECIFIED UNSPECIFIED Aretz, Stefan UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-599538
DOI:	10.1371/journal.pone.0259185
Journal or Publication Title:	PLoS One
Volume:	16
Number:	11
Date:	2021
Publisher:	PUBLIC LIBRARY SCIENCE
Place of Publication:	SAN FRANCISCO
ISSN:	1932-6203
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language GERMLINE MUTATIONS; GENETIC INSTABILITY; TUMOR LOCATION; APC MUTATIONS; REPAIR; MSH3; DNA; IDENTIFICATION; SIGNATURE; CANCER Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/59953