Advancements and Challenges in Biomarkers for Colorectal Cancer Detection: A Comprehensive Review
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Keywords

Colorectal cancer
Biomarker
Diagnosis
Detection

DOI

10.26689/par.v8i5.7177

Submitted : 2024-08-26
Accepted : 2024-09-10
Published : 2024-09-25

Abstract

This study provides an overview of the current landscape of biomarkers for colorectal cancer (CRC) detection, focusing on genetic, proteomic, circulating microRNA (miRNA), and metabolomic biomarkers. CRC remains a significant global health challenge, ranking among the most prevalent cancers worldwide and being a leading cause of cancer-related deaths. Despite advancements in screening methods such as colonoscopy, sigmoidoscopy, and fecal occult blood tests (FOBT), the asymptomatic nature of early-stage CRC often results in late diagnoses, negatively impacting patient outcomes. Genetic biomarkers like APC, KRAS, TP53, and microsatellite instability (MSI) play critical roles in CRC pathogenesis and progression. These biomarkers, detectable through polymerase chain reaction, next-generation sequencing, and other advanced techniques, guide early detection and personalized treatment decisions. Proteomic biomarkers such as CEA, CA 19-9, and novel signatures offer insights into CRC’s physiological changes and disease status, aiding prognosis and treatment response assessments through enzyme-linked immunosorbent assay and mass spectrometry. Circulating miRNAs, including miR-21 and miR-92a, present promising non-invasive biomarkers that can be detected in blood and stool samples, reflecting CRC presence, progression, and therapeutic response. Metabolomic biomarkers, encompassing amino acids, lipids, and TCA cycle intermediates, provide further insights into CRC-associated metabolic alterations, which are crucial for early detection and treatment monitoring using mass spectrometry and nuclear magnetic resonance. Despite these advancements, challenges such as biomarker validation, standardization, and clinical utility remain. Future research directions include integrating multi-omics approaches and leveraging technologies like liquid biopsies and AI for enhanced biomarker discovery and clinical application. By addressing these challenges and advancing research in biomarker development, CRC screening and management could potentially be revolutionized, improving patient outcomes and reducing the global burden of this disease.

References

Sung H, Ferlay J, Siegel RL, et al., 2021, Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin, 71(3): 209–249. https://doi.org/10.3322/caac.21660

Siegel RL, Miller KD, Jemal A, 2019, Cancer Statistics, 2019. CA Cancer J Clin, 69(1): 7–34. https://doi.org/10.3322/caac.21551

Nguyen HT, Duong HQ, 2018, The Molecular Characteristics of Colorectal Cancer: Implications for Diagnosis and Therapy. Oncol Lett, 16(1): 9–18. https://doi.org/10.3892/ol.2018.8679

Guinney J, Dienstmann R, Wang X, et al., 2015, The Consensus Molecular Subtypes of Colorectal Cancer. Nat Med, 21(11): 1350–1356. https://doi.org/10.1038/nm.3967

Sveen A, Kopetz S, Lothe RA, 2020, Biomarker-Guided Therapy for Colorectal Cancer: Strength in Complexity. Nat Rev Clin Oncol, 17(1): 11–32. https://doi.org/10.1038/s41571-019-0241-1

Imperiale TF, 2012, Noninvasive Screening Tests for Colorectal Cancer. Dig Dis, 30(2): 16–26. https://doi.org/10.1159/000341884

Hanash SM, Pitteri SJ, Faca VM, 2008, Mining the Plasma Proteome for Cancer Biomarkers. Nature, 452(7187): 571–579. https://doi.org/10.1038/nature06916

Pizzini S, Bisognin A, Mandruzzato S, et al., 2013, Impact of MicroRNAs on Regulatory Networks and Pathways in Human Colorectal Carcinogenesis and Development of Metastasis. BMC Genomics, 14: 589. https://doi.org/10.1186/1471-2164-14-589

Mabert K, Cojoc M, Peitzsch C, et al., 2014, Cancer Biomarker Discovery: Current Status and Future Perspectives. Int J Radiat Biol, 90(8): 659–677. https://doi.org/10.3109/09553002.2014.892229

Das V, Kalita J, Pal M, 2017, Predictive and Prognostic Biomarkers in Colorectal Cancer: A Systematic Review of Recent Advances and Challenges. Biomed Pharmacother, 87: 8–19. https://doi.org/10.1016/j.biopha.2016.12.064

Bresalier RS, Senore C, Young GP, et al., 2023, An Efficient Strategy for Evaluating New Non-Invasive Screening Tests for Colorectal Cancer: The Guiding Principles. Gut, 72(10): 1904–1918. https://doi.org/10.1136/gutjnl-2023-329701

Pellino G, Gallo G, Pallante P, et al., 2018, Noninvasive Biomarkers of Colorectal Cancer: Role in Diagnosis and Personalised Treatment Perspectives. Gastroenterol Res Pract, 2018: 2397863. https://doi.org/10.1155/2018/2397863

Vargas AC, McCart Reed AE, Waddell N, et al., 2012, Gene Expression Profiling of Tumour Epithelial and Stromal Compartments During Breast Cancer Progression. Breast Cancer Res Treat, 135(1): 153–165. https://doi.org/10.1007/s10549-012-2123-4

Zheng E, Wlodarczyk M, Wegiel A, et al., 2024, Navigating Through Novelties Concerning mCRC Treatment – The Role of Immunotherapy, Chemotherapy, and Targeted Therapy in mCRC. Front Surg, 11: 1398289. https://doi.org/10.3389/fsurg.2024.1398289

Saadh MJ, Allela OQB, Sattay ZJ, et al., 2024, Deciphering the Functional Landscape and Therapeutic Implications of Noncoding RNAs in the TGF-Beta Signaling Pathway in Colorectal Cancer: A Comprehensive Review. Pathol Res Pract, 255: 155158.

Lee SY, Haq F, Kim D, et al., 2014, Comparative Genomic Analysis of Primary and Synchronous Metastatic Colorectal Cancers. PLoS One, 9(3): e90459. https://doi.org/10.1371/journal.pone.0090459. Erratum in PLoS One, 10(1): e0117753. https://doi.org/10.1371/journal.pone.0117753

Smith G, Carey FA, Beattie J, et al., 2002, Mutations in APC, Kirsten-ras, and p53–Alternative Genetic Pathways to Colorectal Cancer. Proc Natl Acad Sci U S A, 99(14): 9433–9438. https://doi.org/10.1073/pnas.122612899

Jones S, Chen WD, Parmigiani G, et al., 2008, Comparative Lesion Sequencing Provides Insights into Tumor Evolution. Proc Natl Acad Sci U S A, 105(11): 4283–4288. https://doi.org/10.1073/pnas.0712345105

Thewjitcharoen Y, Shuangshoti S, Lerdlum S, et al., 2014, Colorectal Cancer Manifesting with Metastasis to Prolactinoma: Report of A Case Involving Symptoms Mimicking Pituitary Apoplexy. Intern Med, 53(17): 1965–1969. https://doi.org/10.2169/internalmedicine.53.2353

Guan C, Zhang X, Yu L, 2024, A Review of Recent Advances in the Molecular Mechanisms Underlying Brain Metastasis in Lung Cancer. Mol Cancer Ther, 23(5): 627–637. https://doi.org/10.1158/1535-7163.MCT-23-0416

Martinelli E, Troiani T, Sforza V, et al., 2018, Sequential HER2 Blockade as Effective Therapy in Chemorefractory, HER2 Gene-Amplified, RAS Wild-Type, Metastatic Colorectal Cancer: Learning From A Clinical Case. ESMO Open, 3(1): e000299. https://doi.org/10.1136/esmoopen-2017-000299. Erratum in ESMO Open, 4(2): e000299corr1. https://doi.org/10.1136/esmoopen-2017-000299corr1

Cancer Genome Atlas Network, 2012, Comprehensive Molecular Characterization of Human Colon and Rectal Cancer. Nature, 487(7407): 330–337. https://doi.org/10.1038/nature11252

Kandoth C, McLellan MD, Vandin F, et al., 2013, Mutational Landscape and Significance Across 12 Major Cancer Types. Nature, 502(7471): 333–339. https://doi.org/10.1038/nature12634

Boland CR, Goel A, 2010, Microsatellite Instability in Colorectal Cancer. Gastroenterology, 138(6): 2073–2087.e3. https://doi.org/10.1053/j.gastro.2009.12.064

Le DT, Uram JN, Wang H, et al., 2015, PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med, 372(26): 2509–2520. https://doi.org/10.1056/NEJMoa1500596

Davies H, Bignell GR, Cox C, et al., 2002, Mutations of the BRAF Gene in Human Cancer. Nature, 417(6892): 949–954. https://doi.org/10.1038/nature00766

Kopetz S, Grothey A, Yaeger R, et al., 2019, Encorafenib, Binimetinib, and Cetuximab in BRAF V600E-Mutated Colorectal Cancer. N Engl J Med, 381(17): 1632–1643. https://doi.org/10.1056/NEJMoa1908075

Samuels Y, Diaz LA Jr, Schmidt-Kittler O, et al., 2005, Mutant PIK3CA Promotes Cell Growth and Invasion of Human Cancer Cells. Cancer Cell, 7(6): 561–573. https://doi.org/10.1016/j.ccr.2005.05.014

Liao X, Morikawa T, Lochhead P, et al., 2012, Prognostic Role of PIK3CA Mutation in Colorectal Cancer: Cohort Study and Literature Review. Clin Cancer Res, 18(8): 2257–2268. https://doi.org/10.1158/1078-0432.CCR-11-2410

Saridaki Z, Tzardi M, Sfakianaki M, et al., 2013, BRAFV600E Mutation Analysis in Patients with Metastatic Colorectal Cancer (mCRC) in Daily Clinical Practice: Correlations with Clinical Characteristics, and Its Impact on Patients’ Outcome. PLoS One, 8(12): e84604. https://doi.org/10.1371/journal.pone.0084604

Tran B, Kopetz S, Tie J, et al., 2011, Impact of BRAF Mutation and Microsatellite Instability on the Pattern of Metastatic Spread and Prognosis in Metastatic Colorectal Cancer. Cancer, 117(20): 4623–4632. https://doi.org/10.1002/cncr.26086

Imperiale TF, Ransohoff DF, Itzkowitz SH, et al., 2004, Fecal DNA Versus Fecal Occult Blood for Colorectal-Cancer Screening in An Average-Risk Population. N Engl J Med, 351(26): 2704–2714. https://doi.org/10.1056/NEJMoa033403

NCCN Clinical Practice Guidelines in Oncology, 2020, Colorectal Cancer Screening, https://www.nccn.org/professionals/physician_gls/pdf/colorectal_screening.pdf

Amado RG, Wolf M, Peeters M, et al., 2008, Wild-Type KRAS is Required for Panitumumab Efficacy in Patients with Metastatic Colorectal Cancer. J Clin Oncol, 26(10): 1626–1634. https://doi.org/10.1200/JCO.2007.14.7116

Diaz A, Park K, Lim DA, et al., 2012, Normalization, Bias Correction, and Peak Calling for ChIP-seq. Stat Appl Genet Mol Biol, 11(3): Article 9. https://doi.org/10.1515/1544-6115.1750

Donehower LA, Soussi T, Korkut A, et al., 2019, Integrated Analysis of TP53 Gene and Pathway Alterations in The Cancer Genome Atlas. Cell Rep, 28(5): 1370–1384.e5. https://doi.org/10.1016/j.celrep.2019.07.001. Erratum in Cell Rep, 28(11): 3010. https://doi.org/10.1016/j.celrep.2019.08.061

Boland CR, Thibodeau SN, Hamilton SR, et al., 1998, A National Cancer Institute Workshop on Microsatellite Instability for Cancer Detection and Familial Predisposition: Development of International Criteria for the Determination of Microsatellite Instability in Colorectal Cancer. Cancer Res, 58(22): 5248–5257.

Sargent DJ, Marsoni S, Monges G, et al., 2010, Defective Mismatch Repair as A Predictive Marker for Lack of Efficacy of Fluorouracil-Based Adjuvant Therapy in Colon Cancer. J Clin Oncol, 28(20): 3219–3226. https://doi.org/10.1200/JCO.2009.27.1825. Erratum in J Clin Oncol, 28(30): 4664.

Anderson NL, Anderson NG, 2002, The Human Plasma Proteome: History, Character, and Diagnostic Prospects. Mol Cell Proteomics, 1(11): 845–867. https://doi.org/10.1074/mcp.r200007-mcp200. Erratum in Mol Cell Proteomics, 2(1): 50.

Domon B, Aebersold R, 2006, Mass Spectrometry and Protein Analysis. Science, 312(5771): 212–217. https://doi.org/10.1126/science.1124619

Kumar VR, Kampan NC, Abd Aziz NH, et al., 2023, Recent Advances in Surface Plasmon Resonance (SPR) Technology for Detecting Ovarian Cancer Biomarkers. Cancers (Basel), 15(23): 5607. https://doi.org/10.3390/cancers15235607

Li C, Sun YD, Yu GY, et al., 2020, Integrated Omics of Metastatic Colorectal Cancer. Cancer Cell, 38(5): 734–747.e9. https://doi.org/10.1016/j.ccell.2020.08.002

Zhang W, Yang C, Wang S, et al., 2021, SDC2 and TFPI2 Methylation in Stool Samples as an Integrated Biomarker for Early Detection of Colorectal Cancer. Cancer Manag Res, 13: 3601–3617. https://doi.org/10.2147/CMAR.S300861. Erratum in Cancer Manag Res, 14: 1845–1846. https://doi.org/10.2147/CMAR.S375358

Grunnet M, Sorensen JB, 2012, Carcinoembryonic Antigen (CEA) as Tumor Marker in Lung Cancer. Lung Cancer, 76(2): 138–143. https://doi.org/10.1016/j.lungcan.2011.11.012

Locker GY, Hamilton S, Harris J, et al., 2006, ASCO 2006 Update of Recommendations for the Use of Tumor Markers in Gastrointestinal Cancer. J Clin Oncol, 24(33): 5313–5327. https://doi.org/10.1200/JCO.2006.08.2644

Cortez MA, Bueso-Ramos C, Ferdin J, et al., 2011, MicroRNAs in Body Fluids – The Mix of Hormones and Biomarkers. Nat Rev Clin Oncol, 8(8): 467–477. https://doi.org/10.1038/nrclinonc.2011.76

Arman K, Dalloul Z, Bozgeyik E, 2023, Emerging Role of microRNAs and Long Non-Coding RNAs in COVID-19 with Implications to Therapeutics. Gene, 861: 147232. https://doi.org/10.1016/j.gene.2023.147232

Liu Q, Yang W, Luo Y, et al., 2018, Correlation between miR-21 and miR-145 and the Incidence and Prognosis of Colorectal Cancer. J BUON, 23(1): 29–35.

Toiyama Y, Hur K, Tanaka K, et al., 2014, Serum miR-200c is A Novel Prognostic and Metastasis-Predictive Biomarker in Patients with Colorectal Cancer. Ann Surg, 259(4): 735–43. https://doi.org/10.1097/SLA.0b013e3182a6909d

Volinia S, Calin GA, Liu CG, et al., 2006, A MicroRNA Expression Signature of Human Solid Tumors Defines Cancer Gene Targets. Proc Natl Acad Sci U S A, 103(7): 2257–2261. https://doi.org/10.1073/pnas.0510565103

Bandres E, Cubedo E, Agirre X, et al., 2006, Identification by Real-time PCR of 13 Mature microRNAs Differentially Expressed in Colorectal Cancer and Non-Tumoral Tissues. Mol Cancer, 5: 29. https://doi.org/10.1186/1476-4598-5-29

Wang K, Yuan Y, Cho J-H, et al., 2012, Comparing the MicroRNA Spectrum between Serum and Plasma. PLoS ONE, 7(7): e41561. https://doi.org/10.1371/journal.pone.0041561

Wang J, Xu J, Fu J, et al., 2021, MiR-29a Regulates Radiosensitivity in Human Intestinal Cells by Targeting PTEN Gene. Radiat Res, 186(3): 292–301. https://doi.org/10.1667/RR14428.1

Pidikova P, Herichova I, 2021, miRNA Clusters with Up-Regulated Expression in Colorectal Cancer. Cancers (Basel), 13(12): 2979. https://doi.org/10.3390/cancers13122979

Fang L, Li H, Wang L, et al., 2014, MicroRNA-17-5p Promotes Chemotherapeutic Drug Resistance and Tumour Metastasis of Colorectal Cancer by Repressing PTEN Expression. Oncotarget, 5(10): 2974–2987. https://doi.org/10.18632/oncotarget.1614

Michael MZ, O'Connor SM, van Holst Pellekaan NG, et al., 2003, Reduced Accumulation of Specific MicroRNAs in Colorectal Neoplasia. Mol Cancer Res, 1(12): 882–891.

Slaby O, Svoboda M, Fabian P, et al., 2008, Altered Expression of miR-21, miR-31, miR-143 and miR-145 is Related to Clinicopathologic Features of Colorectal Cancer. Oncology, 72(5–6): 397–402.

Witwer KW, Buzas EI, Bemis LT, et al., 2013, Standardization of Sample Collection, Isolation and Analysis Methods in Extracellular Vesicle Research. J Extracell Vesicles, 2. https://doi.org/10.3402/jev.v2i0.20360

Schwarzenbach H, Nishida N, Calin GA, et al., 2014, Clinical Relevance of Circulating Cell-Free MicroRNAs in Cancer. Nat Rev Clin Oncol, 11(3): 145–156. https://doi.org/10.1038/nrclinonc.2014.5

Igder S, Zamani M, Fakher S, et al., 2024, Circulating Nucleic Acids in Colorectal Cancer: Diagnostic and Prognostic Value. Dis Markers, 2024: 9943412. https://doi.org/10.1155/2024/9943412

Ng EK, Chong WW, Jin H, et al., 2009, Differential Expression of MicroRNAs in Plasma of Patients with Colorectal Cancer: A Potential Marker for Colorectal Cancer Screening. Gut, 58(10): 1375–1381. https://doi.org/10.1136/gut.2008.167817

Johnson CH, Gonzalez FJ, 2012, Challenges and Opportunities of Metabolomics. J Cell Physiol, 227(8): 2975–2981. https://doi.org/10.1002/jcp.24002

Beger RD, Dunn W, Schmidt MA, et al., 2016, Metabolomics Enables Precision Medicine: “A White Paper, Community Perspective”. Metabolomics, 12(10): 149. https://doi.org/10.1007/s11306-016-1094-6

Mayers JR, Wu C, Clish CB, et al., 2014, Elevation of Circulating Branched-Chain Amino Acids is An Early Event in Human Pancreatic Adenocarcinoma Development. Nat Med, 20(10): 1193–1198. https://doi.org/10.1038/nm.3686

Ragni M, Fornelli C, Nisoli E, et al., 2022, Amino Acids in Cancer and Cachexia: An Integrated View. Cancers (Basel), 14(22): 5691. https://doi.org/10.3390/cancers14225691

Hilvo M, Denkert C, Lehtinen L, et al., 2011, Novel Theranostic Opportunities Offered by Characterization of Altered Membrane Lipid Metabolism in Breast Cancer Progression. Cancer Res, 71(9): 3236–3245. https://doi.org/10.1158/0008-5472.CAN-10-3894

Scheurlen KM, Billeter AT, O'Brien SJ, et al., 2020, Metabolic Dysfunction and Early-Onset Colorectal Cancer – How Macrophages Build The Bridge. Cancer Med, 9(18): 6679–6693. https://doi.org/10.1002/cam4.3315

Soreide K, Ismail W, Roalso M, et al., 2023, Early Diagnosis of Pancreatic Cancer: Clinical Premonitions, Timely Precursor Detection and Increased Curative-Intent Surgery. Cancer Control, 30: 10732748231154711. https://doi.org/10.1177/10732748231154711

Xu Y, Dong X, Qin C, et al., 2023, Metabolic Biomarkers in Lung Cancer Screening and Early Diagnosis (Review). Oncol Lett, 25(6): 265. https://doi.org/10.3892/ol.2023.13851

van Best N, Rolle-Kampczyk U, Schaap FG, et al., 2020, Bile Acids Drive the Newborn’s Gut Microbiota Maturation. Nat Commun, 11(1): 3692. https://doi.org/10.1038/s41467-020-17183-8

Kiriyama Y, Nochi H, 2021, Physiological Role of Bile Acids Modified by the Gut Microbiome. Microorganisms, 10(1): 68. https://doi.org/10.3390/microorganisms10010068

Heinken A, Ravcheev DA, Baldini F, et al., 2019, Systematic Assessment of Secondary Bile Acid Metabolism in Gut Microbes Reveals Distinct Metabolic Capabilities in Inflammatory Bowel Disease. Microbiome, 7(1): 75. https://doi.org/10.1186/s40168-019-0689-3

Mardinoglu A, Agren R, Kampf C, et al., 2013, Integration of Clinical Data with A Genome-Scale Metabolic Model of the Human Adipocyte. Mol Syst Biol, 9: 649. https://doi.org/10.1038/msb.2013.5