A1 Journal article (refereed)
Somatic mutation profiles as molecular classifiers of ulcerative colitis‐associated colorectal cancer (2021)

Mäki‐Nevala, S., Ukwattage, S., Olkinuora, A., Almusa, H., Ahtiainen, M., Ristimäki, A., Seppälä, T., Lepistö, A., Mecklin, J., & Peltomäki, P. (2021). Somatic mutation profiles as molecular classifiers of ulcerative colitis‐associated colorectal cancer. International Journal of Cancer, 148(12), 2997-3007. https://doi.org/10.1002/ijc.33492

JYU authors or editors

Publication details

All authors or editors: Mäki‐Nevala, Satu; Ukwattage, Sanjeevi; Olkinuora, Alisa; Almusa, Henrikki; Ahtiainen, Maarit; Ristimäki, Ari; Seppälä, Toni; Lepistö, Anna; Mecklin, Jukka‐Pekka; Peltomäki, Päivi

Journal or series: International Journal of Cancer

ISSN: 0020-7136

eISSN: 1097-0215

Publication year: 2021

Publication date: 31/01/2021

Volume: 148

Issue number: 12

Pages range: 2997-3007

Publisher: John Wiley & Sons

Publication country: United States

Publication language: English

DOI: https://doi.org/10.1002/ijc.33492

Publication open access: Openly available

Publication channel open access: Partially open access channel

Publication is parallel published (JYX): https://jyx.jyu.fi/handle/123456789/75179


Ulcerative colitis increases colorectal cancer risk by mechanisms that remain incompletely understood. We approached this question by determining the genetic and epigenetic profiles of colitis‐associated colorectal carcinomas (CA‐CRC). The findings were compared to Lynch syndrome (LS), a different form of cancer predisposition that shares the importance of immunological factors in tumorigenesis. CA‐CRCs (n=27) were investigated for microsatellite instability, CpG island methylator phenotype, and somatic mutations of 999 cancer‐relevant genes (“Pan‐cancer” panel). A subpanel of “Pan‐cancer” design (578 genes) was used for LS colorectal tumors (n=28). Mutational loads and signatures stratified CA‐CRCs into three subgroups: hypermutated microsatellite‐unstable (group 1, n=1), hypermutated microsatellite‐stable (group 2, n=9), and non‐hypermutated microsatellite‐stable (group 3, n=17). The group 1 tumor was the only one with MLH1 promoter hypermethylation and exhibited the mismatch repair deficiency‐associated signatures 21 and 15. Signatures 30 and 32 characterized group 2, whereas no prominent single signature existed in group 3. TP53, the most common mutational target in CA‐CRC (16/27, 59%), was similarly affected in groups 2 and 3, but DNA repair genes and Wnt signaling genes were mutated significantly more often in group 2. In LS tumors, the degree of hypermutability exceeded that of the hypermutated CA‐CRC groups 1 and 2, and somatic mutational profiles and signatures were different. In conclusion, groups 1 (4%) and 3 (63%) comply with published studies, whereas group 2 (33%) is novel. The existence of molecularly distinct subgroups within CA‐CRC may guide clinical management, such as therapy options.

Keywords: cancerous diseases; bowel cancer; inflammatory bowel diseases; Lynch syndrome; DNA analysis; microsatellites; mutations

Free keywords: ulcerative colitis; Lynch syndrome; colorectal cancer; microsatellite instability; somatic mutation

Contributing organizations

Ministry reporting: Yes

Reporting Year: 2021

JUFO rating: 2

Last updated on 2022-20-09 at 15:40