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

Claudia Perne1,2, Sophia Peters1, Isabel Spier1,2, Sukanya Hurpaopan3, Christina Grimm4, Janine Altmüller5,6, Axel Hillmer7, Holger Thiele5, Gabriela Möslein8, Margarete Odenthal7, Ronja Adam9, Jutta Kirfel10, Maria Cartolano11, Martin Peifer11, Michal-Ruth Schweiger4,5, Stefan Aretz1,2

1Institute of Human Genetics, University of Bonn, Germany. 2Center for Hereditary Tumor Syndromes, University Hospital Bonn, Germany. 3Naresuan University, Phitsanulok, Thailand. 4Translational Epigenetics and Tumor Genetics, University of Cologne, Germany. 5Cologne Center for Genomics, University of Cologne, Germany. 6Institute of Human Genetics, University of Cologne, Germany. 7Institute of Pathology, University of Cologne, Germany. 8HELIOS Klinikum Wuppertal, University of Witten/Herdecke, Germany. 9Center for Experimental and Molecular Medicine, Academic Medical Center, Netherlands. 10Institute of Pathology, University of Luebeck, Germany. 11Department of Translational Genomics, University of Cologne, Germany

Abstract

Objective: Biallelic MSH3 germline mutations cause a rare subtype of adenomatous polyposis. In the present study we comprehensively analyzed the variant spectrum of colorectal adenomas from patients with biallelic MSH3 germline mutations to identify potential driver genes and pathways of MSH3 related tumorigenesis.

Methods: We performed whole exome sequencing (WES) and array-based copy number variant (CNV) analysis of 2-3 adenomas and matched normal tissue in three patients with biallelic MSH3 mutations.

Results: The amount of all somatic variants in the MSH3 adenomas (36-120) and the pattern of single nucleotide variants (SNVs) seem to be similar to sporadic adenomas, whereas the fraction (16-40%) of small insertions/deletions (Indels) is higher. Interestingly, pathogenic somatic APC mutations were found in all adenomas, and the vast majority (6 of 7) are Indels, which seem to occur more often (4 of 6) in short nucleotide tandem repeats compared to published somatic and germline APC Indels. On average, 26 large deletions were found in each of three fresh-frozen adenomas per patient. Besides APC, five more genes harbor truncating mutations, missense variants, or deletions in more than one polyp, including the suggested tumor suppressor gene ELF3. A second hit was only found in APC.

Conclusions: Our preliminary data demonstrate that MSH3-related carcinogenesis seem to follow mainly the classical APC-driven pathway. We found similar mutation patterns of SNVs in MSH3-deficient polyps compared to sporadic adenomas, however, in line with the specific function of MSH3 in the mismatch repair system, we observed a high proportion of Indels.

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