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Perne, Claudia; Peters, Sophia; Cartolano, Maria; Horpaopan, Sukanya; Grimm, Christina; Altmüller, Janine; Sommer, Anna K.; Hillmer, Axel M.; Thiele, Holger; Odenthal, Margarete; Möslein, Gabriela; Adam, Ronja; Sivalingam, Sugirthan; Kirfel, Jutta; Schweiger, Michal R.; Peifer, Martin; Spier, Isabel; Aretz, Stefan

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

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  • Media type: E-Article
  • Title: Variant profiling of colorectal adenomas from three patients of two families with MSH3-related adenomatous polyposis
  • Contributor: Perne, Claudia; Peters, Sophia; Cartolano, Maria; Horpaopan, Sukanya; Grimm, Christina; Altmüller, Janine; Sommer, Anna K.; Hillmer, Axel M.; Thiele, Holger; Odenthal, Margarete; Möslein, Gabriela; Adam, Ronja; Sivalingam, Sugirthan; Kirfel, Jutta; Schweiger, Michal R.; Peifer, Martin; Spier, Isabel; Aretz, Stefan
  • imprint: Public Library of Science (PLoS), 2021
  • Published in: PLOS ONE
  • Language: English
  • DOI: 10.1371/journal.pone.0259185
  • ISSN: 1932-6203
  • Keywords: Multidisciplinary
  • Origination:
  • Footnote:
  • Description: <jats:p>The spectrum of somatic genetic variation in colorectal adenomas caused by biallelic pathogenic germline variants in the <jats:italic>MSH3</jats:italic> gene, was comprehensively analysed to characterise mutational signatures and identify potential driver genes and pathways of <jats:italic>MSH3</jats:italic>-related tumourigenesis. Three patients from two families with <jats:italic>MSH3</jats:italic>-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 <jats:italic>APC</jats:italic> 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 <jats:italic>APC</jats:italic> indels was significantly higher than that reported in patients with familial adenomatous polyposis (FAP) (p &lt; 0.01) or in sporadic adenomas (p &lt; 0.0001). In MSH3-deficient adenomas, the occurrence of <jats:italic>APC</jats:italic> indels in a repetitive sequence context was significantly higher than in FAP patients (p &lt; 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 <jats:italic>ACVR2A</jats:italic> and <jats:italic>ARID</jats:italic> genes. Our data suggest that <jats:italic>MSH3</jats:italic>-related colorectal carcinogenesis seems to follow the classical <jats:italic>APC</jats:italic>-driven pathway. In line with the specific function of MSH3 in the mismatch repair (MMR) system, we identified a characteristic <jats:italic>APC</jats:italic> mutational pattern in MSH3-deficient adenomas, and confirmed further driver genes for colorectal tumourigenesis.</jats:p>
  • Access State: Open Access