Distinct Mutational Profile of Lynch Syndrome Colorectal Cancers Diagnosed under Regular Colonoscopy Surveillance
Ahadova, A., Pfuderer, P. L., Ahtiainen, M., Ballhausen, A., Bohaumilitzky, L., Kösegi, S., Müller, N., Tang, Y. L., Kosmalla, K., Witt, J., Endris, V., Stenzinger, A., von Knebel Doeberitz, M., Bläker, H., Renkonen-Sinisalo, L., Lepistö, A., Böhm, J., Mecklin, J.-P., Seppälä, T. T., & Kloor, M. (2021). Distinct Mutational Profile of Lynch Syndrome Colorectal Cancers Diagnosed under Regular Colonoscopy Surveillance. Journal of Clinical Medicine, 10(11), Article 2458. https://doi.org/10.3390/jcm10112458
Published inJournal of Clinical Medicine
© 2021 the Authors
Regular colonoscopy even with short intervals does not prevent all colorectal cancers (CRC) in Lynch syndrome (LS). In the present study, we asked whether cancers detected under regular colonoscopy surveillance (incident cancers) are phenotypically different from cancers detected at first colonoscopy (prevalent cancers). We analyzed clinical, histological, immunological and mutational characteristics, including panel sequencing and high-throughput coding microsatellite (cMS) analysis, in 28 incident and 67 prevalent LS CRCs (n total = 95). Incident cancers presented with lower UICC and T stage compared to prevalent cancers (p < 0.0005). The majority of incident cancers (21/28) were detected after previous colonoscopy without any pathological findings. On the molecular level, incident cancers presented with a significantly lower KRAS codon 12/13 (1/23, 4.3% vs. 11/21, 52%; p = 0.0005) and pathogenic TP53 mutation frequency (0/17, 0% vs. 7/21, 33.3%; p = 0.0108,) compared to prevalent cancers; 10/17 (58.8%) incident cancers harbored one or more truncating APC mutations, all showing mutational signatures of mismatch repair (MMR) deficiency. The proportion of MMR deficiency-related mutational events was significantly higher in incident compared to prevalent CRC (p = 0.018). In conclusion, our study identifies a set of features indicative of biological differences between incident and prevalent cancers in LS, which should further be monitored in prospective LS screening studies to guide towards optimized prevention protocols. ...
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Additional information about fundingThis research was funded by the Wilhelm Sander Foundation (grant number 2016.056.1), Emil Aaltonen Foundation, Finnish Medical Foundation, Sigrid Juselius Foundation, Finnish State Research Funds (VTR), the Finnish Cancer Foundation and Jane and Aatos Erkko Foundation. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
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