A1 Journal article (refereed)
Mitotic abnormalities precede microsatellite instability in lynch syndrome-associated colorectal tumourigenesis (2024)
Pussila, M., Laiho, A., Törönen, P., Björkbacka, P., Nykänen, S., Pylvänäinen, K., Holm, L., Mecklin, J.-P., Renkonen-Sinisalo, L., Lehtonen, T., Lepistö, A., Linden, J., Mäki-Nevala, S., Peltomäki, P., & Nyström, M. (2024). Mitotic abnormalities precede microsatellite instability in lynch syndrome-associated colorectal tumourigenesis. EBioMedicine, 103, Article 105111. https://doi.org/10.1016/j.ebiom.2024.105111
JYU authors or editors
Publication details
All authors or editors: Pussila, Marjaana; Laiho, Aleksi; Törönen, Petri; Björkbacka, Pauliina; Nykänen, Sonja; Pylvänäinen, Kirsi; Holm, Liisa; Mecklin, Jukka-Pekka; Renkonen-Sinisalo, Laura; Lehtonen, Taru; et al.
Journal or series: EBioMedicine
ISSN: 2352-3964
eISSN: 2352-3964
Publication year: 2024
Volume: 103
Article number: 105111
Publisher: Elsevier
Publication country: United Kingdom
Publication language: English
DOI: https://doi.org/10.1016/j.ebiom.2024.105111
Publication open access: Openly available
Publication channel open access: Open Access channel
Publication is parallel published (JYX): https://jyx.jyu.fi/handle/123456789/94258
Abstract
Lynch syndrome (LS) is one of the most common hereditary cancer syndromes worldwide. Dominantly inherited mutation in one of four DNA mismatch repair genes combined with somatic events leads to mismatch repair deficiency and microsatellite instability (MSI) in tumours. Due to a high lifetime risk of cancer, regular surveillance plays a key role in cancer prevention; yet the observation of frequent interval cancers points to insufficient cancer prevention by colonoscopy-based methods alone. This study aimed to identify precancerous functional changes in colonic mucosa that could facilitate the monitoring and prevention of cancer development in LS.
Methods
The study material comprised colon biopsy specimens (n = 71) collected during colonoscopy examinations from LS carriers (tumour-free, or diagnosed with adenoma, or diagnosed with carcinoma) and a control group, which included sporadic cases without LS or neoplasia. The majority (80%) of LS carriers had an inherited genetic MLH1 mutation. The remaining 20% included MSH2 mutation carriers (13%) and MSH6 mutation carriers (7%). The transcriptomes were first analysed with RNA-sequencing and followed up with Gorilla Ontology analysis and Reactome Knowledgebase and Ingenuity Pathway Analyses to detect functional changes that might be associated with the initiation of the neoplastic process in LS individuals.
Findings
With pathway and gene ontology analyses combined with measurement of mitotic perimeters from colonic mucosa and tumours, we found an increased tendency to chromosomal instability (CIN), already present in macroscopically normal LS mucosa. Our results suggest that CIN is an earlier aberration than MSI and may be the initial cancer driving aberration, whereas MSI accelerates tumour formation. Furthermore, our results suggest that MLH1 deficiency plays a significant role in the development of CIN.
Interpretation
The results validate our previous findings from mice and highlight early mitotic abnormalities as an important contributor and precancerous marker of colorectal tumourigenesis in LS.
Keywords: Lynch syndrome; cancerous diseases; genes; tumours
Free keywords: Lynch syndrome; chromosomal instability; colon cancer; field defect; mismatch repair
Contributing organizations
Ministry reporting: Yes
VIRTA submission year: 2024
Preliminary JUFO rating: 1
