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Variant profiling of colorectal adenomas from three patients of two families with MSH3-related adenomatous polyposis

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Title:Variant profiling of colorectal adenomas from three patients of two families with MSH3-related adenomatous polyposis
Creators Name:Perne, C. and Peters, S. and Cartolano, M. and Horpaopan, S. and Grimm, C. and Altmüller, J. and Sommer, A.K. and Hillmer, A.M. and Thiele, H. and Odenthal, M. and Möslein, G. and Adam, R. and Sivalingam, S. and Kirfel, J. and Schweiger, M.R. and Peifer, M. and Spier, I. and Aretz, S.
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.
Keywords:Type II Activin Receptors, Adenomatous Polyposis Coli, Adenomatous Polyposis Coli Protein, Colorectal Neoplasms, INDEL Mutation, MutS Homolog 3 Protein, Single Nucleotide Polymorphism
Source:PLoS ONE
Publisher:Public Library of Science
Page Range:e0259185
Date:29 November 2021
Official Publication:https://doi.org/10.1371/journal.pone.0259185
PubMed:View item in PubMed

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