Prognostic and predictive molecular biomarkers of colorectal cancer

лукиан самосаткийThe search and application of genetic prognostic and predictive biomarkers in colorectal cancer (CRC) are aimed at identifying the characteristics of colorectal tumors for choosing a therapy strategy. The review is devoted to summarizing the achievements in scientific and clinical research on this topic.

Aim. Based on genetic and epigenetic changes in CRC to analyze and summarize the world practice of using them as prognostic and predictive biomarkers of CRC to assess the patient’s prognosis and response to therapy.

The analysis of modern literature data published in leading peer-reviewed journals in the Russian and international databases of scientific citation RSCI (Russian Science Citation Index), Medline and PubMed is carried out. The main phenotypes of the CRC pathogenesis are considered, as well as their possible functional intersections during the development of the disease. Both biomarkers already used in global clinical practice and potential promising biomarkers, including gene expression, are analyzed to identify subgroups of patients with high cancer risk at early stages of CRC. As a new approach from the perspective of personalized medicine, a set of tumor derivatives in biological media detected by liquid biopsy: circulating tumor cells, circulating DNA, microRNAs, and long non-coding RNAs is considered as biomarkers. It is noted that the joint use of biomarkers makes it possible to improve the prognosis and selection of therapeutic effects. A review of the literature confirms that modern methods of genetic analysis make a significant contribution to understanding the molecular mechanisms of CRC progression and resistance to antitumor therapy, thereby facilitating the selection of the most appropriate treatment strategy. To assess the potential of individual CRC biomarkers or biomarker panels, large-scale standardized studies and verification of these biomarkers in prospective international programs are necessary.

1. TNM classification of malignant tumours, 8th edn. Ed. by J.D. Brierley, M.K. Gospodarowicz, C. Wittekind. John Wiley & Sons, 2016. 272 p.

2. Fedyanin M.Yu., Gladkov O.A., Gordeev S.S. et al. Cancer of the colon, rectosigmoid junction and rectum. Practical recommendations for the drug treatment of rectal cancer. Zlokachestvennye opuholi = The Journal of Malignant Tumours 2024;14(3s2): 263–322. (In Russ.). DOI: 10.18027/2224-5057-2024-14-3s2-1.1-14

3. Kit O.I., Vodolashsky D.I. Molecular biology of colorectal cancer in clinical practice. Molekulyarnaya biologiya = Molecular Biology 2015;49(4):531–40. (In Russ.). DOI: 10.7868/S0026898415040084

4. Imyanitov E.N. Basic science in oncology: year 2016 overview. Prakticheskaya onkologiya = Рractical Oncology 2017;18(1):85–92. (In Russ.). DOI: 10.31917/1801085

5. Burt R. Inheritance of colorectal cancer. Drug Discov Today Dis Mech 2007;4(4):293–300. DOI: 10.1016/j.ddmec.2008.05.004

6. Lengauer C., Kinzler K., Vogelstein B. Genetic instabilities in human cancers. Nature 1998;396(6712):643–9. DOI: 10.1038/25292

7. Mármol I., Sánchez-de-Diego C., Pradilla Dieste A. et al. Colorectal carcinoma: a general overview and future perspectives in colorectal cancer. Int J Mol Sci 2017;18(1):197. DOI: 10.3390/ijms18010197

8. Tijhuis A.E., Johnson S.C., McClelland S.E. The emerging links between chromosomal instability (CIN), metastasis, inflammation and tumour immunity. Mol Cytogenet 2019;12:17. DOI: 10.1186/s13039-019-0429-1

9. Sarli L., Bottarelli L., Bader G. et al. Association between recurrence of sporadic colorectal cancer, high level of microsatellite instability, and loss of heterozygosity at chromosome 18q. Dis Colon Rectum 2004;47(9):1467–82. DOI: 10.1007/s10350-004-0628-6

10. Popat S., Houlston R.S. A systematic review and meta-analysis of the relationship between chromosome 18q genotype, DCC status and colorectal cancer prognosis. Eur J Cancer 2005;41(14):2060–70. DOI: 10.1016/j.ejca.2005.04.039

11. Watanabe T., Kobunai T., Yamamoto Y. et al. Chromosomal instability (CIN) phenotype, CIN high or CIN low, predicts survival for colorectal cancer. J Clin Oncol 2012;30(18):2256–64. DOI: 10.1200/jco.2011.38.6490

12. Watanabe T., Wu T.T., Catalano P.J. et al. Molecular predictors of survival after adjuvant chemotherapy for colon cancer. N Engl J Med 2001;344(16):1196–206. DOI: 10.1056/NEJM200104193441603

13. Schell M.J., Mingli Y., Jamie K. et al. A multigene mutation classification of 468 colorectal cancers reveals a prognostic role for APC. Nat Commun 2015;7:11743. DOI: 10.1038/ncomms11743

14. Bogomolova I.A., Antoneeva I.I., Dolgova D.R. Clinical characteristics of colorectal cancer in patients with EGFR-signaling pathway gene mutations. Ul'yanovskiy mediko-biologicheskiy zhurnal = Ulyanovsk Medico-Biological Journal 2019;1:60–6. (In Russ.). DOI: 10.34014/2227-1848-2019-1-60-67

15. Liu J., Zeng W., Huang C. et al. Predictive and prognostic implications of mutation profiling and microsatellite instability status in patients with metastatic colorectal carcinoma. Gastroenterol Res Pract 2018;2018:4585802. DOI: 10.1155/2018/4585802

16. Irahara N., Baba Y., Nosho K. et al. NRAS mutations are rare in colorectal cancer. Diagn Mol Pathol 2010;19:157–63. DOI: 10.1097/PDM.0b013e3181c93fd1

17. Schirripa M., Cremolini C., Loupakis F. et al. Role of NRAS mutations as prognostic and predictive markers in metastatic colorectal cancer. Int J Cancer 2015;136(1):83–90. DOI: 10.1002/ijc.28955

18. De Roock W., Claes B., Bernasconi D. et al. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapyrefractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol 2010;11(8):753–62. DOI: 10.1016/S1470-2045(10)70130-3

19. Cervantes A., Adam R., Roselló S. et al. Metastatic colorectal cancer: ESMO clinical practice guideline for diagnosis, treatment and follow-up. Ann Oncol 2023;34(1):10–32. DOI: 10.1016/j.annonc.2022.10.003

20. Russo A., Bazan V., Iacopetta B. et al. The TP53 colorectal cancer international collaborative study on the prognostic and predictive significance of p53 mutation: influence of tumor site, type of mutation, and adjuvant treatment. J Clin Oncol 2005;23(30):7518–28. DOI: 10.1200/JCO.2005.00.471

21. Chang K., Jiang L., Sun·Y. et al. Effect of E-cadherin on prognosis of colorectal cancer: a meta-analysis update. Mol Diagn Ther 2022;26(4):397–409. DOI: 10.1007/s40291-022-00593-3

22. Liao X., Morikawa T., Lochhead P. et al. Prognostic role of PIK3CA mutation in colorectal cancer: cohort study and literature review. Clin Cancer Res 2012;18(8):2257–68. DOI: 10.1158/1078-0432. CCR-11-2410

23. Ogino S., Nosho K., Kirkner G.J. et al. PIK3CA mutation is associated with poor prognosis among patients with curatively resected colon cancer. J Clin Oncol 2009;27(9):1477–84. DOI: 10.1200/JCO.2008.18.6544

24. Alhopuro P., Alazzouzi H., Sammalkorpi H. et al. SMAD4 levels and response to 5-fluorouracil in colorectal cancer. Clin Cancer Res 2005;11(17):6311–6. DOI: 10.1158/1078-0432.CCR-05-0244

25. Wang C., Sandhu J., Tsao A. et al. Presence of concurrent TP53 mutations is necessary to predict poor outcomes within the SMAD4 mutated subgroup of metastatic colorectal cancer. Cancers (Basel) 2022;14(15):3644. DOI: 10.3390/cancers14153644

26. Pan W., Wang W., Huang J. et al. The prognostic role of c-MYC amplification in schistosomiasis-associated colorectal cancer. Jpn J Clin Oncol 2020;50(4):446–55. DOI: 10.1093/jjco/hyz210

27. Merok M.A., Ahlquist T., Røyrvik E.C. et al. Microsatellite instability has a positive prognostic impact on stage II colorectal cancer after complete resection: results from a large, consecutive Norwegian series. Ann Oncol 2013;24(5):1274–82. DOI: 10.1093/annonc/mds614

28. Van Rijnsoever M., Elsaleh H., Joseph D. et al. CpG island methylator phenotype is an independent predictor of survival benefit from 5-fluorouracil in stage III colorectal cancer. Clin Cancer Res 2003;9(8):2898–903.

29. Kit O.I., Vodolazhskiy D.I., Dvadnenko K.V. et al. Aberrant methylation of the promoter of APC, CDH13 and MGMT genes in colorectal cancer patients. Sibirskiy onkologicheskiy zhurnal = Siberian Journal of Oncology 2016;15(2):48–55. (In Russ.). DOI: 10.21294/1814-4861-2016-15-2-48-55

30. Ogino S., Nosho K., Kirkner G.J. et al. A cohort study of tumoral LINE-1 hypomethylation and prognosis in colon cancer. J Natl Cancer Inst 2008;100(23):1734–8. DOI: 10.1093/jnci/djn359

31. Guinney J., Dienstmann R., Wang X. et al. The consensus molecular subtypes of colorectal cancer. Nat Med 2015;21(11):1350–6. DOI: 10.1038/nm.3967

32. Lenz H.-J., Ou F.-S., Venook A. et al. Impact of consensus molecular subtyping (CMS) on overall survival (OS) and progression free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): analysis of CALGB/SWOG 80405 (Alliance). J Clin Oncol 2017;35:3511. DOI: 10.1200/JCO.2017.35.15_suppl.3511

33. O’Connell M.J., Lavery I., Yothers G. et al. Relationship between tumor gene expression and recurrence in four independent studies of patients with stage II/III colon cancer treated with surgery alone or surgery plus adjuvant fluorouracil plus leucovorin. J Clin Oncol 2010;28(25):3937–44. DOI: 10.1200/JCO.2010.28.9538

34. El Messaoudi S., Mouliere F., Du Manoir S. et al. Circulating DNA as a strong multimarker prognostic tool for metastatic colorectal cancer patient management care. Clin Cancer Res 2016;22(12):3067–77. DOI: 10.1158/1078-0432

35. Bidard F.C., Kiavue N., Ychou M. et al. Circulating tumor cells and circulating tumor DNA detection in potentially resectable metastatic colorectal cancer: a prospective ancillary study to the unicancer prodige-14 trial. Cells 2019;8(6):516. DOI: 10.3390/cells8060516

36. Tie J., Wang Y., Cohen J. et al. Circulating tumor DNA dynamics and recurrence risk in patients undergoing curative intent resection of colorectal cancer liver metastases: a prospective cohort study. PLoS Med 2021;18(5):e1003620. DOI: 10.1371/journal.pmed.1003620

37. Liu H.N., Liu T.T., Wu H. et al. Serum microRNA signatures and metabolomics have high diagnostic value in colorectal cancer using two novel methods. Cancer Sci 2018;109(4):1185–94. DOI: 10.1111/cas.13514

38. Shengnan J., Dafei X., Hua J. et al. Long non-coding RNA HOTAIR as a competitive endogenous RNA to sponge miR-206 to promote colorectal cancer progression by activating CCL2. J Cancer 2020;11(15):4431–41. DOI: 10.7150/jca.42308

39. Van Cutsem E., Köhne C.H., Láng I. et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol 2011;29(15):2011–9. DOI: 10.1200/JCO.2010.33.5091

40. De Roock W., Jonker D.J., Di Nicolantonio F. et al. Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. JAMA 2010;304(16):1812–20. DOI: 10.1001/jama.2010.1535

41. Price T.J., Hardingham J.E., Lee C.K. et al. Impact of KRAS and BRAF gene mutation status on outcomes from the phase III AGITG MAX trial of capecitabine alone or in combination with bevacizumab and mitomycin in advanced colorectal cancer. J Clin Oncol 2011;29(19):2675–82. DOI: 10.1200/JCO.2010.34.5520

42. Kandioler D., Mittlböck M., Kappel S. et al. TP53 mutational status and prediction of benefit from adjuvant 5-fluorouracil in stage III colon cancer patients. EBioMedicine 2015;2(8):825–30. DOI: 10.1016/j.ebiom.2015.06.0032352-3964

43. Liao X., Lochhead P., Nishihara R. et al. Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N Engl J Med 2012;367:1596–606. DOI: 10.1056/NEJMoa120775

44. Sood A., McClain D., Maitra R. et al. PTEN gene expression and mutations in the PIK3CA gene as predictors of clinical benefit to anti-epidermal growth factor receptor antibody therapy in patients with KRAS wild-type metastatic colorectal cancer. Clin Colorectal Cancer 2012;11(2):143–50. DOI: 10.1016/j.clcc.2011.12.001

45. Raghav K., Loree J.M., Morris J.S. et al. Validation of HER2 amplification as a predictive biomarker for anti-epidermal growth factor receptor antibody therapy in metastatic colorectal cancer. JCO Precis Oncol 2019;3:1–13. DOI: 10.1200/PO.18.00226

46. Stintzing S., Wirapati P., Lenz H.-J. et al. Consensus molecular subgroups (CMS) of colorectal cancer (CRC) and first-line efficacy of FOLFIRI plus cetuximab or bevacizumab in the FIRE3 (AIO KRK-0306) trial. Ann Oncol 2019;30(11):1796–803. DOI: 10.1093/annonc/mdz387

47. Azad N.S., El-Khoueiry A., Yin J. et al. Combination epigenetic therapy in metastatic colorectal cancer (mCRC) with subcutaneous 5-azacitidine and entinostat: a phase 2 consortium/stand up 2 cancer study. Oncotarget 2017;8(21):35326–38. DOI: 10.18632/oncotarget.15108

48. Kaneko M., Kotake M., Bando H. et al. Prognostic and predictive significance of long interspersed nucleotide element-1 methylation in advanced-stage colorectal cancer. BMC Cancer 2016;16(1):945. DOI: 10.1186/s12885-016-2984-8

49. Tie J., Cohen K., Lahouel K. et al. Adjuvant chemotherapy guided by circulating tumor DNA analysis in stage II colon cancer: the randomized DYNAMIC trial. J Clin Oncol 2022;40(17_suppl.): LBA100. DOI: 10.1200/JCO.2022.40.17_suppl.LBA100

50. Caramés C., Cristóbal I., Moreno V. et al. MicroRNA-21 predicts response to preoperative chemoradiotherapy in locally advanced rectal cancer. Int J Colorectal Dis 2015;30(7):899–906. DOI: 10.1007/s00384-015-2231-9

51. Han J., Sun W., Liu R. et al. Plasma exosomal miRNA expression profile as oxaliplatin-based chemoresistant biomarkers in colorectal adenocarcinoma. Front Oncol 2020;10:1495. DOI: 10.3389/fonc.2020.01495

52. Mlcochova J., Faltejskova-Vychytilova P., Ferracin M. et al. MicroRNA expression profiling identifies miR-31-5p/3p as associated with time to progression in wild-type RAS metastatic colorectal cancer treated with cetuximab. Oncotarget 2015;6(36):38695–704. DOI: 10.18632/oncotarget.5735

53. Malki A., ElRuz R.A., Gupta I. et al. Molecular mechanisms of colon cancer progression and metastasis: recent insights and advancements. Int J Mol Sci 2020;22(1):130. DOI: 10.3390/ijms22010130

54. Disoma C., Zhou Y., Li S. et al. Wnt/β-catenin signaling in colorectal cancer: is therapeutic targeting even possible? Biochimie 2022;195:39–53. DOI: 10.1016/j.biochi.2022.01.009

55. Kopetz S., Murphy D.A., Pu J. et al. Molecular profiling of BRAF-V600E-mutant metastatic colorectal cancer in the phase 3 BEACON CRC trial. Nat Med 2024;30(11):3261–71. DOI: 10.1038/s41591-024-03235-9

56. Morkel M., Riemer P., Bläker H. et al. Similar but different: distinct roles for KRAS and BRAF oncogenes in colorectal cancer development and therapy resistance. Oncotarget 2015;6(25):20785–800. DOI: 10.18632/oncotarget.4750

57. Combined study. cBioPortal. Available at: https://www.cbioportal.org/study/summary?id=rectal_radiation_msk_2024%2Ccrc_ hta11_htan_2021%2Ccrc_msk_2017%2Ccrc_nigerian_2020%2Ccrc_dd_2022

58. Koncina E., Haan S., Rauh S. et al. Prognostic and predictive molecular biomarkers for colorectal cancer: updates and challenges. Cancers (Basel) 2020;12(2):319. DOI: 10.3390/cancers12020319

59. Lichtenstern C.R., Ngu R.K., Shalapour S. et al. Immunotherapy, inflammation and colorectal cancer. Cells 2020;9(3):618. DOI: 10.3390/cells9030618

60. Gallois C., Laurent-Puig P., Taieb J. Methylator phenotype in colorectal cancer: a prognostic factor or not? Crit Rev Oncol Hematol 2016;99:74–80. DOI: 10.1016/j.critrevonc.2015.11.001

61. Kondratova V.N., Botezatu I.V., Stroganova A.M. et al. Hypomethylation of LINE-1 and hypermethylation of HIST1H4F as cancer markers in liquid biopsy of colorectal cancer. Uspekhi molekulyarnoy onkologii = Advances in Molecular Oncology 2024;11(2):85–96. (In Russ.). DOI: 10.17650/2313-805X-2024-11-2-85-96

62. Mustafin R.N., Khusnutdinova E.K. Retro elements as targets of targeted therapy. Nauchnye resultaty biomedicinskih issledovaniy = Research Results in Biomedicine 2024;10(1):5–22. (In Russ.). DOI: 10.18413/2658-6533-2024-10-1-0-1

63. Zeng C., Matsuda K., Jia W.H. et al. Identification of susceptibility loci and genes for colorectal cancer risk. GWAS. Available at: https://www.ebi.ac.uk/gwas/publications/26965516

64. De Sousa E.M.F., Wang X., Jansen M. et al. Poor-prognosis colon cancer is defined by a molecularly distinct subtype and develops from serrated precursor lesions. Nat Med 2013;19(5):614–8. DOI: 10.1038/nm.3174

65. Rejali L., Seifollahi Asl R., Sanjabi F. et al. Principles of molecular utility for CMS classification in colorectal cancer management. Cancers (Basel) 2023;15(10):2746. DOI: 10.3390/cancers15102746

66. Kidess-Sigal E., Liu H.E., Triboulet M.M. et al. Enumeration and targeted analysis of KRAS, BRAF and PIK3CA mutations in CTCs captured by a label-free platform: comparison to ctDNA and tissue in metastatic colorectal cancer. Oncotarget 2016;7(51):85349–64. DOI: 10.18632/oncotarget.13350

67. Tarazona N., Gimeno-Valiente F., Gambardella V. et al. Targeted next-generation sequencing of circulating-tumor DNA for tracking minimal residual disease in localized colon cancer. Ann Oncol 2019;30(11):1804–12. DOI: 10.1093/annonc/mdz390

68. Strubberg A.M., Madison B.B. MicroRNAs in the etiology of colorectal cancer: pathways and clinical implications. Dis Model Mech 2017;10(3):197–214. DOI: 10.1242/dmm.027441