INTRODUCTION: The development of colorectal cancer (CRC) is a multistep process accompanied by the accumulation of mutations that start from specific precancerous lesion - colorectal adenomas (CA). CRC incidence and mortality can be reduced by the early identification of these neoplasm. Colonoscopy is the most widely used screening method for CRC identification. Nowadays, clinical research interest is shifting to the use of liquid biopsy that may help with the early diagnosis of CA and CRC. In our previous study, we identified long non-coding RNA MALAT1 gene amplification associated with the development of CA. METHODS: This study aimed to describe the potential of MALAT1 expression levels in the adenoma tissue of patients used in the previous study by real-time qPCR. Furthermore, we analysed the plasma samples of an independent group of patients with CA (n=97), CRC (n=101), and cancer-free individuals (CFI, n=48). RESULTS: There was no difference in the MALAT1 expression level between CA patients with or without MALAT1 amplification. However, the plasma MALAT1 expression levels were significantly upregulated in patients with CRC and CA compared to CFI (for both p<0.001). Moreover, a correlation between MALAT1 expression and histological types of adenomas was identified- high-CRC-risk adenomas also displayed the highest MALAT1 expression levels. Furthermore, in CRC patients, MALAT1 levels were associated with a response to therapy. CONCLUSION: MALAT1 expression levels could serve as a promising circulating biomarker for early CA and CRC diagnosis, and even as a predictor of therapy response in CRC patients.

• Klíčová slova
• MALAT1, colorectal adenomas, colorectal cancer, liquid biopsy, plasma,
• Publikační typ
• časopisecké články MeSH

A colorectal adenoma, an aberrantly growing tissue, arises from the intestinal epithelium and is considered as precursor of colorectal cancer (CRC). In this study, we investigated structural and numerical chromosomal aberrations in adenomas, hypothesizing that chromosomal instability (CIN) occurs early in adenomas. We applied array comparative genomic hybridization (aCGH) to fresh frozen colorectal adenomas and their adjacent mucosa from 16 patients who underwent colonoscopy examination. In our study, histologically similar colorectal adenomas showed wide variability in chromosomal instability. Based on the obtained results, we further stratified patients into four distinct groups. The first group showed the gain of MALAT1 and TALAM1, long non-coding RNAs (lncRNAs). The second group involved patients with numerous microdeletions. The third group consisted of patients with a disrupted karyotype. The fourth group of patients did not show any CIN in adenomas. Overall, we identified frequent losses in genes, such as TSC2, COL1A1, NOTCH1, MIR4673, and GNAS, and gene gain containing MALAT1 and TALAM1. Since long non-coding RNA MALAT1 is associated with cancer cell metastasis and migration, its gene amplification represents an important event for adenoma development.

• Klíčová slova
• MALAT1, adenomas, array comparative genomic hybridization, colorectal cancer, long non-coding RNA,
• MeSH
• adenom * genetika   patologie   MeSH
• chromozomální nestabilita MeSH
• kolorektální nádory * genetika   patologie   MeSH
• lidé MeSH
• prekancerózy * genetika   patologie   MeSH
• RNA dlouhá nekódující * genetika   MeSH
• srovnávací genomová hybridizace MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• MALAT1 long non-coding RNA, human MeSH Prohlížeč
• RNA dlouhá nekódující * MeSH

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.

• MeSH
• adenom genetika   patologie   MeSH
• karcinom in situ genetika   patologie   MeSH
• kolorektální nádory genetika   patologie   MeSH
• lidé MeSH
• metylace DNA MeSH
• mikrosatelitní nestabilita * MeSH
• mutace * MeSH
• nádorové biomarkery genetika   MeSH
• následné studie MeSH
• prognóza MeSH
• senioři MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• nádorové biomarkery MeSH