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

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

doi:10.1371/journal.pone.0259185

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.

Authors

Claudia Perne^{1

2}, Sophia Peters¹, Maria Cartolano^{3

4}, Sukanya Horpaopan⁵, Christina Grimm⁶, Janine Altmüller^{4

7

8

9}, Anna K Sommer¹, Axel M Hillmer¹⁰, Holger Thiele⁷, Margarete Odenthal^{4

10}, Gabriela Möslein¹¹, Ronja Adam¹², Sugirthan Sivalingam^{13

14

15}, Jutta Kirfel¹⁶, Michal R Schweiger^{4

6}, Martin Peifer³, Isabel Spier^{1

2}, Stefan Aretz^{1

2}

Affiliations

¹ Institute of Human Genetics, Medical Faculty, University of Bonn, Bonn, Germany.
² Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany.
³ Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, Cologne, Germany.
⁴ Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
⁵ Department of Anatomy, Faculty of Medical Science, Naresuan University, Phitsanulok, Thailand.
⁶ Institute for Translational Epigenetics, Medical Faculty and University Clinic Cologne, University of Cologne, Cologne, Germany.
⁷ Cologne Center for Genomics (CCG), Faculty of Medicine, University of Cologne, University Hospital Cologne, Cologne, Germany.
⁸ Berlin Institute of Health at Charité, Core Facility Genomics, Berlin, Germany.
⁹ Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
¹⁰ Institute of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
¹¹ Zentrum für Hereditäre Tumore, BETHESDA Khs. Duisburg, Duisburg, Germany.
¹² Cancer Center Amsterdam, Amsterdam University Medical Centers, Amsterdam, The Netherlands.
¹³ Core Unit for Bioinformatics Data Analysis, Medical Faculty, University of Bonn, Bonn, Germany.
¹⁴ Institute for Genomic Statistics and Bioinformatics, Medical Faculty, University of Bonn, Bonn, Germany.
¹⁵ Institute for Medical Biometry, Informatics and Epidemiology, Medical Faculty, University of Bonn, Bonn, Germany.
¹⁶ Institute of Pathology, University of Lübeck, Lübeck, Germany.

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.

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

Substances

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.