Comparative segmental molecular genetic assessment of colorectal cancer in the community of endoscopy and surgery of a multidisciplinary hospital

The aim of the study was to compare the frequency of segmental detection of colon cancer during routine endoscopy with the results of surgical treatment of tumor intestinal obstruction together with paired molecular genetic analysis of CRC and the mucous membrane of the index segment of the colon from the standpoint of studying precancerous changes. Material and methods. In a continuous cross-sectional retrospective study, the results of 3086 colonoscopies and 63 surgical protocols of patients with tumor intestinal obstruction were studied. In a prospective study, 401 cell samples were studied: colon cancer - 118, index segment mucosa - 114, normal mucosa - 169. The relative expression levels of 9 miRNA markers associated with the development of CRC were determined: miR-135b-5p, -141-3p, -143-3p, -200a-3p, -20a-5p, -21-5p, -31-5p, -34a-5p, -92a-3p, small nuclear RNA U6, as well as miRNA-16-5p and -191-5p. The mRNA of the following genes was also assessed: MUC2, CDX2, NOX1, LGR5, SMAD4, MS4A12, TIMP1, Ki-67, TERT with normalization to the housekeeping genes PGK1 and PUM1. Results. The overall frequency of CRC detection during colonoscopy was 4.93% (152 cases). During colonoscopy and surgical interventions, cancers of the left half of the colon prevailed. The expression levels of miRNA and mRNA in tumors between colon segments vary significantly, which may hide some patterns, but allows us to talk about the uniqueness of each segment of the colon. The same expression levels in the index mucosa and in cancers were found for miRNA-200a in the ascending colon, for miRNA-21 in the rectum, for miRNA-34a and LGR5 in the left half. Tumors of different segments of the colon turned out to be heterogeneous in the studied mutations, however, there is no such diversity in the mucosa of different segments of the colon. Conclusion. The obtained results allow us to speak about the necessity of searching for precancerous changes during colonoscopy.

colorectal cancer, colon segments, molecular genetic changes in the mucous membrane, miRNA expression, gene expression, gene mutations, precancerous changes

1. Tang X.J., Wang W., Hann S.S.Interactions among lncRNAs, miRNAs and mRNA in colorectal cancer. Biochimie. 2019;163:58-72. doi: 10.1016/j.biochi.2019.05.010.

2. Brito-Rocha T., Constâncio V., Henrique R., Jerónimo C. Shifting the Cancer Screening Paradigm: The Rising Potential of Blood-Based Multi-Cancer Early Detection Tests. Cells. 2023;12(6):935. doi: 10.3390/cells12060935.

3. Chung D.C., Gray D.M. 2nd, Singh H. et al. A Cell-free DNA Blood-Based Test for Colorectal Cancer Screening. N Engl J Med. 2024;390(11):973-983. doi: 10.1056/NEJMoa2304714.

4. Ivashkin V.T., Maev I.V., Kaprin A.D. et al. Early detection of oncological diseases of the digestive organs (methodological guidelines of the Russian Gastroenterological Association and the Association of Oncologists of Russia for primary care physicians).Russian Journal of Gastroenterology, Hepatology, coloproctology. 2019; 29(5): 53-74. (in Russ.)@@ Ивашкин В.Т., Маев И.В., Каприн А.Д., и др. Раннее выявление онкологических заболеваний органов пищеварения (методическое руководство Российской гастроэнтерологической ассоциации и ассоциации онкологов России для врачей первичного звена здравоохранения). Российский журнал гастроэнтерологии, гепатологии, колопроктологии. 2019; 29(5): 53-74.

5. Kanth P., Inadomi J.M. Screening and prevention of colorectal cancer. BMJ. 2021;374: n1855. doi: 10.1136/bmj.n1855.

6. Kaltenbach T., Anderson J.C., Burke C.A. et al. Endoscopic Removal of Colorectal Lesions-Recommendations by the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology. 2020;158(4):1095-1129. doi: 10.1053/j.gastro.2019.12.018

7. Petersen M.M., Kleif J., Liggett J. et al. Development of an algorithm combining blood-based biomarkers, fecal immunochemical test, and age for population-based colorectal cancer screening. Gastrointest Endosc. 2024;100(6):1061-1069.e3. doi: 10.1016/j.gie.2024.06.015.

8. Li Y., Li B., Jiang R. et al. A novel screening method of DNA methylation biomarkers helps to improve the detection of colorectal cancer and precancerous lesions. Cancer Med. 2023;12(21):20626-20638. doi: 10.1002/cam4.6511.

9. Wu S., Yun J., Tang W. et al. Therapeutic m(6) A Eraser ALKBH5 mRNA-Loaded Exosome-Liposome Hybrid Nanoparticles Inhibit Progression of Colorectal Cancer in Preclinical Tumor Models. ACS Nano. 2023;17(12):11838-11854. doi: 10.1021/acsnano.3c03050.

10. Jiang C., Zhou Q., Yi K., Yuan Y., Xie X. Colorectal cancer initiation: Understanding early-stage disease for intervention. Cancer Lett. 2024;589:216831. doi: 10.1016/j.canlet.2024.216831.

11. Zhang Y., Wang Y., Zhang B., Li P., Zhao Y. Methods and biomarkers for early detection, prediction, and diagnosis of colorectal cancer. Biomed Pharmacother. 2023;163:114786. doi: 10.1016/j.biopha.2023.114786.

12. Patel S.G., Karlitz J.J., Yen T., Lieu C.H., Boland C.R. The rising tide of early-onset colorectal cancer: a comprehensive review of epidemiology, clinical features, biology, risk factors, prevention, and early detection. Lancet Gastroenterol Hepatol. 2022;7(3):262-274. doi: 10.1016/S2468-1253(21)00426-X.

13. Medawar E., Djinbachian R., Rex D.K. et al. Clinical management of patients with colorectal intramucosal carcinoma compared to high-grade dysplasia and T1 colorectal cancer. Gastrointest Endosc. 2024. (Epub ahead of print) doi: 10.1016/j.gie.2024.11.021.

14. Anishchenko V.V., Arkhipova A.A., Titov S.E. et al. Analysis of the expression of miRNA and mRNA in the cellular material of the gastric mucosa obtained during esophagogastroduodenoscopy to detect dysplasia and gastric cancer. Surgical practice. 2021;(4):53-60. (in Russ.)@@ Анищенко В.В., Архипова А.А., Титов С.Е., Полоз Т.Л., Бубнов И.В. Анализ экспрессии миРНК и мРНК в клеточном материале слизистой оболочки желудка, полученного при эзофагогастродуоденоскопии, для выявления дисплазии и рака желудка. Хирургическая практика. 2021;(4):53-60.

15. Livak K.J., Schmittgen T.D. Analysis of relative gene expression data using real-time quantitative PCR and the 2- ΔΔCt method. Methods. 2001;25:402-408. doi: 10.1006/meth.2001.1262.

16. Jiao L., Kourkoumpetis T., Hutchinson D. et al. Spatial Characteristics of Colonic Mucosa-Associated Gut Microbiota in Humans. Microb Ecol. 2022;83(3):811-821. doi: 10.1007/s00248-021-01789-6.

17. Zhu H., Zhang Y., Du S., Wang H., Zheng Y. Colonic mucosal biopsy location can not affect the results of mucosal metabolomics and mucosal microbiota analysis in IBS. Front Med (Lausanne). 2023;10:1183484. doi: 10.3389/fmed.2023.1183484.

18. Zhu Q., Zhu C., Zhang X., Zhu X., Chen Z., Gu D., He Y., Jin C.Comprehension of rectosigmoid junction cancer molecular features by comparison to the rectum or sigmoid colon cancer. J Gastrointest Oncol. 2023;14(3):1307-1319. doi: 10.21037/jgo-23-120.

19. Yao B., Zhang Q., Yang Z. et al. CircEZH2/miR-133b/IGF2BP2 aggravates colorectal cancer progression via enhancing the stability of m(6) A-modified CREB1 mRNA. Mol Cancer. 2022;21(1):140. doi: 10.1186/s12943-022-01608-7.

20. Min L., Bu F., Meng J., Liu X., Guo Q., Zhao L., Li Z., Li X., Zhu S., Zhang S. Circulating small extracellular vesicle RNA profiling for the detection of T1a stage colorectal cancer and precancerous advanced adenoma. Elife. 2024;12: RP88675. doi: 10.7554/eLife.88675.

21. Cardoso R., Guo F., Heisser T. et al. Proportion and stage distribution of screen-detected and non-screen-detected colorectal cancer in nine European countries: an international, population-based study. Lancet Gastroenterol Hepatol. 2022;7(8):711-723. doi: 10.1016/S2468-1253(22)00084-X.

22. Liu G., Li B. Role of miRNA in transformation from normal tissue to colorectal adenoma and cancer. J Cancer Res Ther. 2019;15(2):278-285. doi: 10.4103/jcrt.JCRT_135_18.

23. Gao W., Gao X., Zhu L., Gao S., Sun R., Feng Z., Wu D., Liu Z., Zhu R., Jiao N. Multimodal metagenomic analysis reveals microbial single nucleotide variants as superior biomarkers for early detection of colorectal cancer. Gut Microbes. 2023;15(2):2245562. doi: 10.1080/19490976.2023.2245562.

24. Gagrat Z.D., Krockenberger M., Bhattacharya A. et al. Next-generation Multi-target Stool DNA Panel Accurately Detects Colorectal Cancer and Advanced Precancerous Lesions. Cancer Prev Res (Phila). 2024;17(3):119-126. doi: 10.1158/1940-6207.CAPR-23-0285.

25. Mohammadpour S., Noukabadi F.N., Esfahani A.T. et al. Non-coding RNAs in Precursor Lesions of Colorectal Cancer: Their Role in Cancer Initiation and Formation. Curr Mol Med. 2024;24(5):565-575. doi: 10.2174/1566524023666230523155719.