A large proportion of colorectal carcinomas (CRC) evolve from colorectal adenomas. However, not all individuals with colonic adenomas have a risk of CRC substantially higher than those of the general population. The aim of the study was to determine the differences or similarities of mutation profile among low- and high-grade adenomas and in situ carcinoma with detailed follow up. We have investigated the mutation spectrum of well-known genes involved in CRC (such as APC, BRAF, EGFR, NRAS, KRAS, PIK3CA, POLE, POLD1, SMAD4, PTEN, and TP53) in a large, well-defined series of 96 adenomas and in situ carcinomas using a high-throughput genotyping technique. Besides, the microsatellite instability and APC and MLH1 promoter methylation were studied as well. We observed a high frequency of pathogenic variants in the studied genes. The APC, KRAS and TP53 mutation frequencies were slightly lower in adenoma samples than in in situ carcinoma samples. Further, when we stratified mutation frequency based on the grade, the frequency distribution was as follows: low-grade adenoma-high-grade adenomas-in situ carcinoma: APC gene 42.9-56.0-54.5%; KRAS gene 32.7-32.0-45.5%; TP53 gene 8.2-20.0-18.2%. The occurrence of KRAS mutation was associated with the presence of villous histology and methylation of the APC promoter was significantly associated with the presence of POLE genetic variations. However, no association was noticed with the presence of any singular mutation and occurrence of subsequent adenoma or CRC. Our data supports the multistep model of gradual accumulation of mutations, especially in the driver genes, such as APC, TP53 and KRAS.

2nd Department of Internal Medicine 3rd Faculty of Medicine Charles University Srobarova 50 100 34 Prague 10 Czech Republic

Biomedical Center Faculty of Medicine in Pilsen Charles University Alej Svobody 76 323 00 Pilsen Czech Republic

Department of Hepatogastroenterology Institute for Clinical and Experimental Medicine Videnska 1958 9 140 21 Prague Czech Republic

Department of Internal Medicine 3rd Faculty of Medicine Charles University and Thomayer University Hospital Ruska 87 100 00 Prague Czech Republic

Department of Molecular Biology of Cancer Institute of Experimental Medicine of the Czech Academy of Sciences Videnska 1083 142 00 Prague Czech Republic

Department of Oncology 1st Faculty of Medicine Charles University and Thomayer University Hospital Videnska 800 140 59 Prague Czech Republic

Department of Pathology 3rd Faculty of Medicine Charles University and University Hospital Kralovske Vinohrady Srobarova 50 100 34 Prague 10 Czech Republic

Department of Pathology and Molecular Medicine 3rd Faculty of Medicine Charles University and Thomayer University Hospital Videnska 800 140 59 Prague Czech Republic

Department of Pathology Leiden University Medical Center Leiden The Netherlands

Department of Radiotherapy and Oncology 3rd Faculty of Medicine Charles University Srobarova 50 100 34 Prague 10 Czech Republic

Department of Surgery Weiden Clinic Söllnerstraße 16 92637 Weiden in der Oberpfalz Germany

DT Gastroenterology Roskotova 1 1225 Prague 4 Czech Republic

Institute of Biology and Medical Genetics Institute of Physiology 1st Faculty of Medicine Charles University Albertov 4 128 00 Prague Czech Republic

Institute of Molecular Genetics of the Czech Academy of Sciences Videnska 1083 142 20 Prague Czech Republic

Sci Rep. 2022 Apr 4;12(1):5595. doi: 10.1038/s41598-022-09561-7. PubMed

Sci Rep. 2022 Oct 21;12(1):17701. doi: 10.1038/s41598-022-21956-0. PubMed

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Differences in genome, transcriptome, miRNAome, and methylome in synchronous and metachronous liver metastasis of colorectal cancer

Discovery of Long Non-Coding RNA MALAT1 Amplification in Precancerous Colorectal Lesions