Mitotic abnormalities precede microsatellite instability in lynch syndrome-associated colorectal tumourigenesisResearch in context
Marjaana Pussila,
Aleksi Laiho,
Petri Törönen,
Pauliina Björkbacka,
Sonja Nykänen,
Kirsi Pylvänäinen,
Liisa Holm,
Jukka-Pekka Mecklin,
Laura Renkonen-Sinisalo,
Taru Lehtonen,
Anna Lepistö,
Jere Linden,
Satu Mäki-Nevala,
Päivi Peltomäki,
Minna Nyström
Affiliations
Marjaana Pussila
Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland; Corresponding author. Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, PO Box 56, FI-00014 University of Helsinki, Finland.
Aleksi Laiho
Organismal and Evolutionary Biology Research Program, Faculty of Biosciences, and Institute of Biotechnology, Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland
Petri Törönen
Organismal and Evolutionary Biology Research Program, Faculty of Biosciences, and Institute of Biotechnology, Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland
Pauliina Björkbacka
Department of Veterinary Biosciences, and Finnish Centre for Laboratory Animal Pathology (FCLAP), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland
Sonja Nykänen
Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland
Kirsi Pylvänäinen
Faculty of Sports and Health Sciences, University of Jyväskylä, Jyväskylä, Finland
Liisa Holm
Organismal and Evolutionary Biology Research Program, Faculty of Biosciences, and Institute of Biotechnology, Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland
Jukka-Pekka Mecklin
Well Being Services County of Central Finland, Department of Science, Jyväskylä, Finland; Faculty of Sports and Health Sciences, University of Jyväskylä, Jyväskylä, Finland
Laura Renkonen-Sinisalo
Department of Surgery, Helsinki University Hospital, Helsinki, Finland; Applied Tumour Genomics, Research Programs Unit, University of Helsinki, Helsinki, Finland
Taru Lehtonen
Department of Surgery, Helsinki University Hospital, Helsinki, Finland
Anna Lepistö
Department of Surgery, Helsinki University Hospital, Helsinki, Finland; Applied Tumour Genomics, Research Programs Unit, University of Helsinki, Helsinki, Finland
Jere Linden
Department of Veterinary Biosciences, and Finnish Centre for Laboratory Animal Pathology (FCLAP), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland
Satu Mäki-Nevala
Department of Medical and Clinical Genetics, University of Helsinki, Finland
Päivi Peltomäki
Department of Medical and Clinical Genetics, University of Helsinki, Finland; HUSLAB Laboratory of Genetics, HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland
Minna Nyström
Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland
Summary: Background: 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. Funding: This work was supported by grants from the Jane and Aatos Erkko Foundation, the Academy of Finland (330606 and 331284), Cancer Foundation Finland sr, and the Sigrid Jusélius Foundation. Open access is funded by Helsinki University Library.
