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Abstract
Introduction. When selecting tactics for rectal cancer (RC) treatment, healthcare professionals consider the prognosis and early recurrence diagnosis. It is recognised that malignant cell transformation is accompanied by a change in the DNA methylation profile of the genome. In malignant neoplasms, fragments of tumor-associated DNA accumulate in the content of circulating blood plasma DNA (cirDNA) and cirDNA associated with the surface of blood cells (csb-cirDNA), which are potential cancer markers. Previous research has demonstrated alterations in the methylation levels of specific genes, including LINE-1 retroelements and SEPTIN9, IKZF1, in plasma circulating DNA (cirDNA) from the blood of colorectal cancer patients when compared to healthy donors.
Aim. To study the changes in the methylation level changes of the SEPTIN9, IKZF1 genes and LINE-1 retrotransposons in cirDNA from blood of RC patients at the stages of combined treatment and dynamic follow-up with an assessment of their prognostic significance.
Materials and Methods. Venous blood samples were obtained from 24 RC patients before treatment, after preoperative chemotherapy, 10-15 days after surgery and then every three months as part of the dynamic follow-up. The methylation levels of the selected markers were determined by real-time methyl-specific PCR.
Results. The methylation level of the SEPTIN9 gene in csb-cirDNA decreased by 1.7-fold following chemotherapy and by 2.3-fold following tumor resection, in comparison to the levels observed prior to treatment. In turn, methylation level of the IKZF1 gene in csb-cirDNA decreased by 2-folds after the combined treatment. The study revealed a notable increase in the methylation level of the LINE-1 elements in csb-cirDNA, with a 1.6-fold rise after chemotherapy and a 3-fold rise after tumor resection, in comparison to the initial data. During the follow-up period, a stabilization of the methylation levels for all markers was observed in patients who did not experience a recurrence of RC. In patients with signs of progression, these markers showed repeated changes compared to the levels at 10–15 days after surgery.
Conclusion. The results demonstrate the potential for using the studied aberrantly methylated DNA markers to assess the efficacy of therapy and detect early signs of recurrence in RC cases.
References
Злокачественные новообразования в России в 2021 году (заболеваемость и смертность). Под ред. А.Д. Каприна, В.В. Старинского, А.О. Шахзадовой. М. 2022; 252.-DOI: 10.21294/1814-4861-2023-22-5-5-13. [Malignant tumors in Russia in 2021 (morbidity and mortality). Ed. by A.D. Kaprin, V.V. Starinsky, A.O. Shakhzadova. Moscow. 2022; 252.-DOI: https://doi.org/10.21294/1814-4861-2023-22-5-5-13. (In Rus)].
Sung H., Ferlay J., Siegel R.L., et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021; 71(3): 209-249.-DOI: https://doi.org/10.3322/caac.21660.
Oronsky B., Reid T., Larson C., et al. Locally advanced rectal cancer: The past, present, and future. Semin Oncol. 2020; 47(1): 85-92.-DOI: https://doi.org/10.1053/j.seminoncol.2020.02.001.
Bahadoer R., Djkstra A., Ettent B., et al. Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): a randomised, open-label, phase3 trial. Lancet Oncol. 2021; 22: 29-42.-DOI: https://doi.org/10.1016/S1470-2045(20)30555-6.
Deng Y., Chi P., Lan P., et al. Neoadjuvant modified FOLFOX6 with or without radiation versus fluorouracil plus radiation for locally advanced rectal cancer: final results of the Chinese FOWARC trial. J Clin Oncol. 2019; 37(34): 3223-3233.-DOI: https://doi.org/10.1200/JCO.18.02309 37:3223-3233.
Невольских А.А., Авдеенко В.А., Белохвостова А.С., et al. Неоадъювантная химиотерапия как альтернатива лучевой терапии в лечении больных прогностически неблагоприятным раком прямой кишки. Колопроктология. 2022; 21(2): 91-104.-DOI: https://doi.org/10.33878/2073-7556-2022-21-2-91-104. [Nevolskikh A.A., Avdeenko V.A., Belohvostova A.S., et al. Neoadjuvant chemotherapy without radiation therapy for rectal cancer with negative prognosis. Koloproktologia. 2022; 21(2): 91-104.-DOI: https://doi.org/10.33878/2073-7556-2022-21-2-91-104. (In Rus)].
Добродеев А.Ю., Тарасова А.С., Афанасьев С.Г., et al. Результаты комбинированного лечения с предоперационной химиотерапией больных раком верхнеампулярного отдела прямой кишки. Колопроктология. 2023; 22(4): 45-52.-DOI: https://doi.org/10.33878/2073-7556-2023-22-4-45-52. [Dobrodeev A.Yu., Tarasova A.S., Afanasiev S.G., et al. Outcomes of multimodal treatment including preoperative chemotherapy for upper rectal cancer. Koloproktologia. 2023; 22(4): 45-52.-DOI: https://doi.org/10.33878/2073-7556-2023-22-4-45-52. (In Rus)].
Wang Y., Wang X., Chen J., et al. Comparative analysis of preoperative chemoradiotherapy and upfront surgery in the treatment of upper-half rectal cancer: oncological benefits, surgical outcomes, and cost implications. Updates Surg. 2024; 76(3): 949–62.-DOI: https://doi.org/10.1007/s13304-023-01744-9.
Knebel F.H., Bettoni F., da Fonseca L.G., et al. Circulating tumor DNA detection in the management of anti-EGFR therapy for advanced colorectal cancer. Front Oncol. 2019; 22(9): 170.-DOI: https://doi.org/10.3389/fonc.2019.00170.
Dai X., Ren T., Zhang Y., Nan N. Methylation multiplicity and its clinical values in cancer. ERMM. 2021; 23(e2): 1-10.-DOI: https://doi.org/10.1017/ erm.2021.4.
Guo M., Peng Y., Gao A., et al. Epigenetic heterogeneity in cancer. Biomark Res. 2019; 7: 23.-DOI: https://doi.org/10.1186/s40364-019-0174-y.
Tulsyan S., Aftab M., Sisodiya S., et al. Molecular basis of epigenetic regulation in cancer diagnosis and treatment. Front Genet. 2022; 13: 885635.-DOI: https://doi.org/10.3389/fgene.2022.885635.
Kong C., Fu T. Value of methylation markers in colorectal cancer (Review). Oncol Rep. 2021; 46(2): 177.-DOI: https://doi.org/10.3892/or.2021.8128.
Sun X., Guo Y., Zhang Y., et al. Colon cancer-related genes identification and function study based on single-cell multi-omics integration. Front Cell Dev Biol. 2021; 9: 789587.-DOI: https://doi.org/10.3389/fcell.2021.789587.
Lamb Y.N., Dhillon S. Epi proColon 2.0 CE: a blood-based screening test for colorectal cancer. Mol Diagn Ther. 2017; 21(2): 225-232.-DOI: https://doi.org/10.1007/s40291-017-0259-y.
Zhao G., Liu, X., Liu Y., et al. Methylated SFRP2and SDC2 in stool specimens for colorectal cancer early detection: a cost-effective strategy for chinese population. J Cancer. 2021; 12: 2665-2672.-DOI: https://doi.org/10.7150/jca.52478.
Ponomaryova A.A., Rykova E.Y., Gervas P.A., et al. Aberrant methylation of LINE-1 transposable elements: a search for cancer biomarkers. Cells. 2020; 9(9): 2017.-DOI: https://doi.org/10.3390/cells9092017.
Rykova E.Y., Ponomaryova A.A., Zaporozhchenko I.A., et al. Circulating DNA-based lung cancer diagnostics and follow-up: looking for epigenetic markers. Transl Cancer Res. 2018; 7(S2): S153-S170.-DOI: https://doi.org/10.21037/tcr.2018.02.08.
Ponomaryova A.A., Rykova E.Y., Azhikina T.L., et al. Long interspersed nuclear element-1 methylation status in the circulating DNA from blood of patients with malignant and chronic inflammatory lung diseases. Eur J Cancer Prev. 2021; 30(2): 127-131.-DOI: https://doi.org/10.1097/CEJ.0000000000000601.
Warren J.D., Xiong W., Bunker A.M., et al. Septin 9 methylated DNA is a sensitive and specific blood test for colorectal cancer. BMC Med. 2011; 9: 133.-DOI: https://doi.org/10.1186/1741-7015-9-133.
Pedersen S.K., Symonds E.L., Baker R.T., et al. Evaluation of an assay for methylated BCAT1 and IKZF1 in plasma for detection of colorectal neoplasia. BMC Cancer. 2015; 15: 654.-DOI: https://doi.org/10.1186/s12885-015-1674-2.
Szigeti K.A., Kalmár A., Galamb O., et al. Global DNA hypomethylation of colorectal tumours detected in tissue and liquid biopsies may be related to decreased methyl-donor content. BMC Cancer. 2022; 22(1): 605.-DOI: https://doi.org/10.1186/s12885-022-09659-1.
Sun J., Fei F., Zhang M., et al. The role of mSEPT9 in screening, diagnosis, and recurrence monitoring of colorectal cancer. BMC Cancer. 2019; 19(1): 450.-DOI: https://doi.org/10.1186/s12885-019-5663-8.
Sun J., Xu J., Sun C., et al. Screening and prognostic value of methylated septin9 and its association with clinicopathological and molecular characteristics in colorectal cancer. Front Mol Biosci. 2021; 8: 568818.-DOI: https://doi.org/10.3389/fmolb.2021.568818.
Jin S., Zhu D., Shao F., et al. Efficient detection and post-surgical monitoring of colon cancer with a multi-marker DNA methylation liquid biopsy. Proc Natl Acad Sci U S A. 2021; 118(5): e2017421118.-DOI: https://doi.org/10.1073/pnas.2017421118.
Huang M., He J., Lai W., et al. Methylated septin 9 gene is an important prognostic marker in stage II and stage III colorectal cancer for evaluating local recurrence or distant metastasis after surgery. BMC Gastroenterol. 2022; 22(1): 87.-DOI: https://doi.org/10.1186/s12876-022-02172-6.
Lu P., Zhu X., Song Y., et al. Methylated septin 9 as a promising biomarker in the diagnosis and recurrence monitoring of colorectal cancer. Dis Markers. 2022; 2022: 7087885.-DOI: https://doi.org/10.1155/2022/7087885.
Yuan Z., Wang S., Ni K., et al. Circulating methylated SEPT9 DNA analyses to predict recurrence risk and adjuvant chemotherapy benefit in stage II to III colorectal cancer. Med Sci Monit. 2022; 28: e937757.-DOI: https://doi.org/10.12659/MSM.937757.
Nassar F.J., Msheik Z.S., Nasr R.R., Temraz S.N. Methylated circulating tumor DNA as a biomarker for colorectal cancer diagnosis, prognosis, and prediction. Clin Epigenetics. 2021; 13(1): 111.-DOI: https://doi.org/10.1186/s13148-021-01095-5.
Pedersen S.K., Symonds E.L., Roy A.C., et al. Detection of methylated BCAT1 and IKZF1 after curative-intent treatment as a prognostic indicator for colorectal cancer recurrence. Cancer Med. 2023; 12(2): 1319-1329.-DOI: https://doi.org/10.1002/cam4.5008.
Murray D.H., Symonds E.L., Young G.P., et al. Relationship between post-surgery detection of methylated circulating tumor DNA with risk of residual disease and recurrence-free survival. J Cancer Res Clin Oncol. 2018; 144(9): 1741-1750.-DOI: https://doi.org/10.1007/s00432-018-2701-x.
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