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

PLoS One. 2021 Nov 29;16(11):e0259185. doi: 10.1371/journal.pone.0259185. eCollection 2021.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activin Receptors, Type II / genetics
  • Adenomatous Polyposis Coli / genetics
  • Adenomatous Polyposis Coli / pathology*
  • Adenomatous Polyposis Coli Protein / genetics
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / pathology*
  • Humans
  • INDEL Mutation
  • MutS Homolog 3 Protein / genetics*
  • Polymorphism, Single Nucleotide


  • APC protein, human
  • Adenomatous Polyposis Coli Protein
  • MSH3 protein, human
  • MutS Homolog 3 Protein
  • Activin Receptors, Type II
  • activin receptor type II-A

Grants and funding

This work was supported by the German Cancer Aid (Deutsche Krebshilfe e.V. Bonn, Grant number 108421) to SA, the Volkswagenstiftung, the Center for Molecular Medicine Cologne (CMMC), and the German Research Foundation (Deutsche Forschungsgemeinschaft, SFB1399) to MRS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.