Somatic mutation profiles as molecular classifiers of ulcerative colitis‐associated colorectal cancer
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
Published inInternational Journal of Cancer
© 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.
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. ...
PublisherJohn Wiley & Sons
ISSN Search the Publication Forum0020-7136
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- Liikuntatieteiden tiedekunta 
Additional information about fundingThis study was supported by Jane and Aatos Erkko Foundation (to PP and J-PM); the Academy of Finland (grant numbers 294643 and 330606 to PP and 331284 to SM-N); the Finnish Cancer Foundation (to PP, J-PM and AR); the Sigrid Juselius Foundation (to PP and AR) and the HiLIFE Fellows 2017 – 2020 (to PP).
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