journal article Open Access May 15, 2024

Evaluation of the Immunohistochemical Scoring System of CDX2 Expression as a Prognostic Biomarker in Colon Cancer

Diagnostics Vol. 14 No. 10 pp. 1023 · MDPI AG
View at Publisher Save 10.3390/diagnostics14101023
Abstract
Encoded by the CDX2 homeobox gene, the CDX2 protein assumes the role of a pivotal transcription factor localized within the nucleus of intestinal epithelial cells, orchestrating the delicate equilibrium of intestinal physiology while intricately guiding the precise development and differentiation of epithelial tissue. Emerging research has unveiled that positive immunohistochemical expression of this protein shows that the CDX2 gene exerts a potent suppressive impact on tumor advancement in colorectal cancer, impeding the proliferation and distant dissemination of tumor cells, while the inhibition or suppression of CDX2 frequently correlates with aggressive behavior in colorectal cancer. In this study, we conducted an immunohistochemical assessment of CDX2 expression on a cohort of 43 intraoperatively obtained tumor specimens from patients diagnosed with colon cancer at Colțea Clinical Hospital in Bucharest, between April 2019 and December 2023. Additionally, we shed light on the morphological diversity within colon tumors, uncovering varying differentiation grades within the same tumor, reflecting the variations in CDX2 expression as well as the genetic complexity underlying these tumors. Based on the findings, we developed an innovative immunohistochemical scoring system that addresses the heterogeneous nature of colon tumors. Comprehensive statistical analysis of CDX2 immunohistochemical expression unveiled significant correlations with known histopathological parameters such as tumor differentiation grades (p-value = 0.011) and tumor budding score (p-value = 0.002), providing intriguing insights into the complex involvement of the CDX2 gene in orchestrating tumor progression through modulation of differentiation processes, and highlighting its role in metastatic predisposition. The compelling correlation identified between CDX2 expression and conventional histopathological parameters emphasizes the prognostic significance of the CDX2 biomarker in colon cancer. Moreover, our novel immunohistochemical scoring system reveals a distinct subset of colon tumors exhibiting reserved prognostic outcomes, distinguished by their “mosaic” CDX2 expression pattern.
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References
54
[1]
Ferlay, J., Ervik, M., Lam, F., Laversanne, M., Colombet, M., Mery, L., Piñeros, M., Znaor, A., Soerjomataram, I., and Bray, F. (2024). Global Cancer Observatory: Cancer Today, International Agency for Research on Cancer. Available online: https://gco.iarc.who.int/today.
[2]
Global Cancer Incidence and Mortality Rates and Trends—An Update

Lindsey A. Torre, Rebecca L. Siegel, Elizabeth M. Ward et al.

Cancer Epidemiology, Biomarkers & Prevention 2016 10.1158/1055-9965.epi-15-0578
[3]
Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up

A. Cervantes, R. Adam, S. Roselló et al.

Annals of Oncology 2023 10.1016/j.annonc.2022.10.003
[4]
Xu "Combination of CDX2 expression and T stage improves prognostic prediction of colorectal cancer" J. Int. Med. Res. (2019) 10.1177/0300060518819620
[5]
Testa, U., Castelli, G., and Pelosi, E. (2020). Genetic Alterations of Metastatic Colorectal Cancer. Biomedicines, 8. 10.3390/biomedicines8100414
[6]
Slikker "Biomarkers and Their Impact on Precision Medicine" Exp. Biol. Med. (2018) 10.1177/1535370217733426
[7]
Chen "Pathological Features and Prognostication in Colorectal Cancer" Curr. Oncol. (2021) 10.3390/curroncol28060447
[8]
Ogunwobi, O.O., Mahmood, F., and Akingboye, A. (2020). Biomarkers in Colorectal Cancer: Current Research and Future Prospects. Int. J. Mol. Sci., 21. 10.3390/ijms21155311
[9]
Linares "The Prognostic Potential of CDX2 in Colorectal Cancer: Harmonizing Biology and Clinical Practice" Cancer Treat. Rev. (2023) 10.1016/j.ctrv.2023.102643
[10]
(2024). Referenced with Permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Colon Cancer V.1.2024, The National Comprehensive Cancer Network® (NCCN®). Available online: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428.
[11]
Localised colon cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

G. Argilés, J. Tabernero, R. Labianca et al.

Annals of Oncology 2020 10.1016/j.annonc.2020.06.022
[12]
Molina-Cerrillo, J., San Román, M., Pozas, J., Alonso-Gordoa, T., Pozas, M., Conde, E., Rosas, M., Grande, E., García-Bermejo, M.L., and Carrato, A. (2020). BRAF Mutated Colorectal Cancer: New Treatment Approaches. Cancers, 12. 10.3390/cancers12061571
[13]
De Palma, F.D.E., D’Argenio, V., Pol, J., Kroemer, G., Maiuri, M.C., and Salvatore, F. (2019). The Molecular Hallmarks of the Serrated Pathway in Colorectal Cancer. Cancers, 11. 10.3390/cancers11071017
[14]
Harada "Molecular Pathology of Colorectal Cancer" Adv. Anat. Pathol. (2020) 10.1097/pap.0000000000000247
[15]
Noack "Molecular Pathology of Colorectal Cancer" Memo—Magazine of European Medical Oncology (2023) 10.1007/s12254-023-00893-2
[16]
Nojadeh "Microsatellite Instability in Colorectal Cancer" EXCLI J. (2018)
[17]
Baraibar "Incorporating Traditional and Emerging Biomarkers in the Clinical Management of Metastatic Colorectal Cancer: An Update" Expert Rev. Mol. Diagn. (2020) 10.1080/14737159.2020.1782194
[18]
Koulis, C., Yap, R., Engel, R., Jardé, T., Wilkins, S., Solon, G., Shapiro, J.D., Abud, H., and McMurrick, P. (2020). Personalized Medicine-Current and Emerging Predictive and Prognostic Biomarkers in Colorectal Cancer. Cancers, 12. 10.3390/cancers12040812
[19]
Chung "Predictive and Prognostic Biomarkers with Therapeutic Targets in Colorectal Cancer: A 2021 Update on Current Development, Evidence, and Recommendation" J. Oncol. Pharm. Pract. Off. Publ. Int. Soc. Oncol. Pharm. Pract. (2022) 10.1177/10781552211005525
[20]
Singh "Molecular Subtypes of Colorectal Cancer: An Emerging Therapeutic Opportunity for Personalized Medicine" Genes Dis. (2019) 10.1016/j.gendis.2019.10.013
[21]
Wang "Methylation of CDX2 Gene Promoter in the Prediction of Treatment Efficacy in Colorectal Cancer" Oncol. Lett. (2018)
[22]
Luo "Relationship between CpG Island Methylation Phenotype, Microsatellite Instability Phenotype and Mutation of KRAS, NRAS, and BRAF Genes in Colorectal Cancer" Int. J. Clin. Exp. Pathol. (2019)
[23]
Chen "Current Perspectives on the Importance of Pathological Features in Prognostication and Guidance of Adjuvant Chemotherapy in Colon Cancer" Curr. Oncol. (2022) 10.3390/curroncol29030116
[24]
George "Predictive and Prognostic Markers in Colorectal Cancer" Curr. Oncol. Rep. (2011) 10.1007/s11912-011-0162-3
[25]
Prognostic and Predictive Molecular Biomarkers for Colorectal Cancer: Updates and Challenges

Eric Koncina, Serge Haan, Stefan Rauh et al.

Cancers 10.3390/cancers12020319
[26]
Filip, S., Vymetalkova, V., Petera, J., Vodickova, L., Kubecek, O., John, S., Cecka, F., Krupova, M., Manethova, M., and Cervena, K. (2020). Distant Metastasis in Colorectal Cancer Patients-Do We Have New Predicting Clinicopathological and Molecular Biomarkers? A Comprehensive Review. Int. J. Mol. Sci., 21. 10.3390/ijms21155255
[27]
Incorporating Novel Technologies in Precision Oncology for Colorectal Cancer: Advancing Personalized Medicine

Pankaj Ahluwalia, Kalyani Ballur, Tiffanie Leeman et al.

Cancers 10.3390/cancers16030480
[28]
Andrei "Integrated Approaches for Precision Oncology in Colorectal Cancer: The More You Know, the Better" Semin. Cancer Biol. (2022) 10.1016/j.semcancer.2021.04.007
[29]
Chewchuk "Cdx2 Regulates Immune Cell Infiltration in the Intestine" Sci. Rep. (2021) 10.1038/s41598-021-95412-w
[30]
Saad "CDX2 as a Marker for Intestinal Differentiation: Its Utility and Limitations" World J. Gastrointest. Surg. (2011) 10.4240/wjgs.v3.i11.159
[31]
Slik "CDX2 Loss with Microsatellite Stable Phenotype Predicts Poor Clinical Outcome in Stage II Colorectal Carcinoma" Am. J. Surg. Pathol. (2019) 10.1097/pas.0000000000001356
[32]
Olsen "The Clinical Perspectives of CDX2 Expression in Colorectal Cancer: A Qualitative Systematic Review" Surg. Oncol. (2014) 10.1016/j.suronc.2014.07.003
[34]
Karimian "CDX2 Protein Expression in Colorectal Cancer and Its Correlation with Clinical and Pathological Characteristics, Prognosis, and Survival Rate of Patients" J. Gastrointest. Cancer (2020) 10.1007/s12029-019-00314-w
[35]
Tomasello "Association of CDX2 Expression with Survival in Early Colorectal Cancer: A Systematic Review and Meta-analysis" Clin. Color. Cancer (2018) 10.1016/j.clcc.2018.02.001
[36]
Bae "Loss of CDX2 Expression Is Associated with Poor Prognosis in Colorectal Cancer Patients" World J. Gastroenterol. (2015) 10.3748/wjg.v21.i5.1457
[37]
Calik "Decreased CDX2 Expression Adversely Affects the Prognosis of Patients with Colorectal Cancer" Dicle Tıp Derg. Dicle Med. J. (2020) 10.5798/dicletip.706005
[38]
CDX2 as a Prognostic Biomarker in Stage II and Stage III Colon Cancer

Piero Dalerba, Debashis Sahoo, Soonmyung Paik et al.

New England Journal of Medicine 2016 10.1056/nejmoa1506597
[39]
Baba "Relationship of CDX2 Loss with Molecular Features and Prognosis in Colorectal Cancer" Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. (2009) 10.1158/1078-0432.ccr-09-0401
[40]
Isaac, R., Masih, D., Ranjan, M., and Pulimood, A.B. (Indian J. Cancer, 2023). Primary Adenocarcinoma of Colon: A Clinicopathological Study with the Prevalence and Correlation of CDX2 Biomarker Expression—A Tertiary Care Center Experience, Indian J. Cancer, advance online publication. 10.4103/ijc.ijc_760_21
[41]
Lugli "Differential Diagnostic and Functional Role of the Multi-marker Phenotype CDX2/CK20/CK7 in Colorectal Cancer Stratified by Mismatch Repair Status" Mod. Pathol. (2008) 10.1038/modpathol.2008.117
[42]
Nayak "Histopathological and Immunohistochemical Study of the Prognostic Significance of Cox2 and CDX2 Expression in the Available Cases of Colorectal Carcinoma" Med. J. Cairo Univ. (2019) 10.21608/mjcu.2019.52323
[43]
Dawson "Loss of Cdx2 Expression in Primary Tumors and Lymph Node Metastases is Specific for Mismatch Repair-Deficiency in Colorectal Cancer" Front. Oncol. (2013) 10.3389/fonc.2013.00265
[44]
Dawson "Molecular and Pathogenetic Aspects of Tumor Budding in Colorectal Cancer" Front. Med. (2015) 10.3389/fmed.2015.00011
[45]
Hestetun "Mismatch Repair Phenotype Determines the Implications of Tumor Grade and CDX2 Expression in Stage II–III Colon Cancer" Mod. Pathol. (2021) 10.1038/s41379-020-0634-9
[46]
Hansen "Prognostic Impact of CDX2 in Stage II Colon Cancer: Results from Two Nationwide Cohorts" Br. J. Cancer (2018) 10.1038/s41416-018-0285-5
[47]
Dragomir "CDX2: A Prognostic Marker in Metastatic Colorectal Cancer Defining a Better BRAF Mutated and a Worse KRAS Mutated Subgroup" Front. Oncol. (2020) 10.3389/fonc.2020.00008
[48]
Zlobec "Clinicopathological and Protein Characterization of BRAF- and K-RAS-Mutated Colorectal Cancer and Implications for Prognosis" Int. J. Cancer (2010) 10.1002/ijc.25042
[49]
Konukiewitz "Loss of CDX2 in Colorectal Cancer Is Associated with Histopathologic Subtypes and Microsatellite Instability but Is Prognostically Inferior to Hematoxylin-Eosin-Based Morphologic Parameters from the WHO Classification" Br. J. Cancer (2021) 10.1038/s41416-021-01553-0
[50]
Zlobec "Selecting Immunohistochemical Cut-Off Scores for Novel Biomarkers of Progression and Survival in Colorectal Cancer" J. Clin. Pathol. (2007) 10.1136/jcp.2006.044537

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Published
May 15, 2024
Vol/Issue
14(10)
Pages
1023
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Cite This Article
Andreea-Corina Ilie-Petrov, Daniel-Alin Cristian, Florin Andrei Grama, et al. (2024). Evaluation of the Immunohistochemical Scoring System of CDX2 Expression as a Prognostic Biomarker in Colon Cancer. Diagnostics, 14(10), 1023. https://doi.org/10.3390/diagnostics14101023