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:
CreatorsEmailORCIDORCID Put Code
Perne, ClaudiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peters, SophiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cartolano, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Horpaopan, SukanyaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grimm, ChristinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmuller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sommer, Anna K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hillmer, Axel M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thiele, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Odenthal, MargareteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moeslein, GabrielaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Adam, RonjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sivalingam, SugirthanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kirfel, JuttaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schweiger, Michal R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peifer, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Spier, IsabelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aretz, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
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:
KeywordsLanguage
GERMLINE MUTATIONS; GENETIC INSTABILITY; TUMOR LOCATION; APC MUTATIONS; REPAIR; MSH3; DNA; IDENTIFICATION; SIGNATURE; CANCERMultiple languages
Multidisciplinary SciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/59953

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