MGMT Immunohistochemical Expression in Colorectal Carcinoma and its Correlation with Tumor Progression

MGMT & Histopathology in CRC progression

Authors

  • Mohamed Ahmed Department of Pathology, Children Cancer Hospital Egypt (57357), Cairo, Egypt https://orcid.org/0000-0002-0637-6143
  • Badawia Bayoumi Department of Pathology, Faculty of Medicine, Cairo University, Giza, Egypt
  • Samira Abdallah Department of Pathology, Faculty of Medicine, Cairo University, Giza, Egypt
  • Maya Elserafy Department of Pathology, Faculty of Medicine, Cairo University, Giza, Egypt

DOI:

https://doi.org/10.3889/oamjms.2021.5879

Keywords:

Colorectal carcinoma, O6-methylguanine DNA methyltransferase, Tumor progression

Abstract

Introduction: There is an urgent need to identify predictive features and markers for colorectal carcinoma (CRC) progression and treatment. This study aimed to assess O6-methylguanine DNA methyltransferase (MGMT) expression in CRC and correlate with the clinico-pathological aspects of the tumor, also to evaluate the relationship between different histopathologic parameters and tumor progression.

Material and Methods: The study was carried on 70 colectomy using formalin fixed paraffin embedded tumor tissue. Immunohistochemistry was used to detect MGMT expression, and clinico-pathologic aspects as well as Tumor budding, type of desmoplastic reaction, inflammatory lymphocytic milieu, pattern of invasive front and necrosis were assessed Then correlated with MGMT expression and tumor progression, using parametric and nonparametric statistical methods.

Results: MGMT Loss of expression was detected in 42.9% of CRC cases. MGMT expression status was significantly correlated with tumor stage and metastatic status (p<0.05), while it was not correlated with other clinic-pathologic features, (p>0.05).  Desmoplastic reaction (DR), tumor budding, stromal tumor infiltrating lymphocytes (TIL-S) and necrosis were correlated with tumor stage (p<0.05). DR correlated with tumor budding (p<0.05). Both types of TIL and Crohn’s-like lymphoid reaction (CLR) showed a mutual correlation (p<0.05).

Conclusion: MGMT high expression and histopathologic parameters as DR, tumor budding, inflammatory lymphocytic milieu and necrosis could be correlated with CRC progression.

 

Downloads

Download data is not yet available.

Metrics

Metrics Loading ...

Plum Analytics Artifact Widget Block

References

Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;1:1-41. https://doi.org/10.3322/caac.21660 PMid:33538338 DOI: https://doi.org/10.3322/caac.21660

Ioannou M, Paraskeva E, Baxevanidou K, Simos G, Papamichali R, Papacharalambous C, et al. HIF-1α _in colorectal carcinoma: Review of the literature. J BUON. 2015;20(3):680-9. PMid:26214618

Jeggo PA, Pearl LH, Carr AM. DNA repair, genome stability and cancer: A historical perspective. Nat Rev Cancer. 2016;16(1):35- 42. https://doi.org/10.1038/nrc.2015.4 PMid:26667849 DOI: https://doi.org/10.1038/nrc.2015.4

Mojarad EN, Kuppen PJ, Aghdaei HA, Zali MR. The CpG island methylator phenotype (CIMP) in colorectal cancer. Gastroenterol Hepatol Bed Bench. 2013;6(3):120-8. PMid:24834258

Sharma S, Salehi F, Scheithauer BW, Rotondo F, Syro LV, Kovacs K. Role of MGMT in tumor development, progression, diagnosis, treatment and prognosis. Anticancer Res. 2009;29(10):3759-68. PMid:19846906

Cordeiro AT, Da Silva CM, Bartchewsky B Jr., Ribeiro ML, Martinez CA. Evaluation of the expression of the MGMT gene in normal and neoplastic tissue of patients with colorectal cancer. Rev Col Bras Cir. 2012;39(1):48-53. https://doi.org/10.1590/s0100-69912012000100010 PMid:22481706 DOI: https://doi.org/10.1590/S0100-69912012000100010

Lee KE. Immunohistochemical assessment of O(6)- methylguanine-DNA methyltransferase (MGMT) and Its relationship with p53 expression in endometrial cancers. J Cancer Prev. 2013;18(4):351-4. https://doi.org/10.15430/jcp.2013.18.4.351 PMid:25337565 DOI: https://doi.org/10.15430/JCP.2013.18.4.351

Cankovic M, Nikiforova MN, Snuderl M, Adesina AM, Lindeman N, Wen PY, et al. The role of MGMT testing in clinical practice: A report of the association for molecular pathology. J Mol Diagn. 2013;15)5(:539-55. https://doi.org/10.1016/j.jmoldx.2013.05.011 PMid:23871769 DOI: https://doi.org/10.1016/j.jmoldx.2013.05.011

Jacinto FV, Esteller M. MGMT hypermethylation: A prognostic foe, a predictive friend. DNA Repair (Amst). 2007;6(8):1155-60. https://doi.org/10.1016/j.dnarep.2007.03.013 PMid:17482895 DOI: https://doi.org/10.1016/j.dnarep.2007.03.013

Zhang J, Stevens MF, Bradshaw TD. Temozolomide: Mechanisms of action, repair and resistance. Curr Mol Pharmacol. 2012;5(1):102-14. PMid:22122467 DOI: https://doi.org/10.2174/1874467211205010102

Reifenberger G, Hentschel B, Felsberg J, Schackert G, Simon M, Schnell O, et al. Predictive impact of MGMT promoter methylation in glioblastoma of the elderly. Int J Cancer. 2012;131(6):1342-50. https://doi.org/10.1002/ijc.27385 PMid:22139906 DOI: https://doi.org/10.1002/ijc.27385

Nagtegaal ID, Arends MJ, Telle S. Colorectal adenocarcinoma. In: Nagtegaal ID, Arends MJ, Odze RD, Lam AK, editors. Tumors of the Colon and Rectum WHO Classification of Tumors Editorial Board. WHO Classification of Tumors: Digestive System Tumors. 5th ed. Geneva: World Health Organization Press; 2019. p. 177-87. https://doi.org/10.1007/978-3-7091-6821-9_2 DOI: https://doi.org/10.1007/978-3-7091-6821-9_2

Jessup JM, Goldberg RM, Asare EA, Benson AB, Brierley JD, Chang GJ, et al. Colon and rectum. In: Amin MB, editor. AJCC Cancer Staging Manual. 8th ed. New York: Springer Nature; 2017. p. 251-74.

Lugli A, Kirsch R, Ajioka Y, Bosman F, Cathomas G, Dawson H, et al. Recommendations for reporting tumor budding in colorectal cancer based on the international tumor budding consensus conference (ITBCC) 2016. Mod Pathol. 2017;30(9):1299-311. https://doi.org/10.1038/modpathol.2017.46 PMid:28548122 DOI: https://doi.org/10.1038/modpathol.2017.46

Ueno H, Kanemitsu Y, Sekine S, Ishiguro M, Ito E, Hashiguchi Y, et al. Desmoplastic pattern at the tumor front defines poor-prognosis subtypes of colorectal cancer. Am J Surg Pathol. 2017;41(11):1506-12. https://doi.org/10.1097/pas.0000000000000946 PMid:28877064 DOI: https://doi.org/10.1097/PAS.0000000000000946

Jakubowska K, Kisielewski W, Kanczuga-Koda L, Koda M, Famulski W. Stromal and intraepithelial tumor-infiltrating lymphocytes in colorectal carcinoma. Oncol Lett. 2017;14(6):6421-32. https://doi.org/10.3892/ol.2017.7013 PMid:29151905 DOI: https://doi.org/10.3892/ol.2017.7013

Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G, et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: Recommendations by an International TILs working group 2014. Ann Oncol. 2015;26(2):259-71. https://doi.org/10.1093/annonc/mdu450 PMid:25214542 DOI: https://doi.org/10.1093/annonc/mdu450

Väyrynen JP, Sajanti SA, Klintrup K, Mäkelä J, Herzig KH, Karttunen TJ, et al. Characteristics and significance of colorectal cancer associated lymphoid reaction. Int J Cancer. 2014;134(9):2126-35. https://doi.org/10.1002/ijc.28533 PMid:24154855 DOI: https://doi.org/10.1002/ijc.28533

Richards CH, Flegg KM, Roxburgh CS, Going JJ, Mohammed Z, Horgan PG, et al. The relationships between cellular components of the peritumoural inflammatory response, clinicopathological characteristics and survival in patients with primary operable colorectal cancer. Br J Cancer. 2012;106(12):2010-5. https://doi.org/10.1038/bjc.2012.211 PMid:22596238 DOI: https://doi.org/10.1038/bjc.2012.211

Sartore-Bianchi A, Pietrantonio F, Amatu A, Milione M, Cassingena A, Ghezzi S, et al. Digital PCR assessment of MGMT promoter methylation coupled with reduced protein expression optimises prediction of response to alkylating agents in metastatic colorectal cancer patients. Eur J Cancer. 2017;71:43-50. https://doi.org/10.1016/j.ejca.2016.10.032 PMid:27997874 DOI: https://doi.org/10.1016/j.ejca.2016.10.032

Michailidi C, Theocharis S, Tsourouflis G, Pletsa V, Kouraklis G, Patsouris E, et al. Expression and promoter methylation status of hMLH1, MGMT, APC, and CDH1 genes in patients with colon adenocarcinoma. Exp Biol Med (Maywood). 2015;240(12):1599- 605. https://doi.org/10.1177/1535370215583800 PMid:25908636 DOI: https://doi.org/10.1177/1535370215583800

Pietrantonio F, De Braud F, Milione M, Maggi C, Iacovelli R, Dotti KF, et al. Dose-dense temozolomide in patients with MGMT-silenced chemorefractory colorectal cancer. Target Oncol. 2016;11(3):337-43. https://doi.org/10.1007/s11523-015-0397-2 PMid:26538496 DOI: https://doi.org/10.1007/s11523-015-0397-2

Oliver JA, Oritz R, Melguizo C, Alvarez PJ, Millan JG, Prados J. Prognostic impact of MGMT promoter methylation and MGMT and CD133 expression in colorectal adenocarcinoma. BMC Cancer. 2014;14:511. https://doi.org/10.1186/1471-2407-14-511 PMid:25015560 DOI: https://doi.org/10.1186/1471-2407-14-511

Zhang L, Zeng J, Zeng Z, Wang F, Wang D, Chen C, et al. MGMT in colorectal cancer: A promising component of personalized treatment. Tumor Biol. 2016;37(8):11443-56. https://doi.org/10.1007/s13277-016-5014-1 PMid:27006309 DOI: https://doi.org/10.1007/s13277-016-5014-1

Liddell C, Droy-Dupré L, Métairie S, Airaud F, Volteau C, Bezieau S, et al. Mapping clinicopathological entities within colorectal mucinous adenocarcinomas: A hierarchical clustering approach. Mod Pathol. 2017;30(8):1177-89. https://doi.org/10.1038/modpathol.2017.18 PMid:28429715 DOI: https://doi.org/10.1038/modpathol.2017.18

Lugli A, Karamitopoulou E, Zlobec I. Tumour budding: A promising parameter in colorectal cancer. Br J Cancer. 2012;106(11):1713-7. https://doi.org/10.1038/bjc.2012.127 PMid:22531633 DOI: https://doi.org/10.1038/bjc.2012.127

Ueno H, Shinto E, Shimazaki H, Kajiwara Y, Sueyama T, Yamamoto J, et al. Histologic categorization of desmoplastic reaction: Its relevance to the colorectal cancer microenvironment and prognosis. Ann Surg Oncol. 2015;22(5):1504-12. https://doi.org/10.1245/s10434-014-4149-9 PMid:25395146 DOI: https://doi.org/10.1245/s10434-014-4149-9

Cho SJ, Kakar S. Tumor budding in colorectal carcinoma: Translating a morphologic score into clinically meaningful results. Arch Pathol Lab Med. 2018;142(8):952-7. https://doi.org/10.5858/arpa.2018-0082-ra PMid:30040461 DOI: https://doi.org/10.5858/arpa.2018-0082-RA

Klintrup K, Mäkinen JM, Kauppila S, Väre PO, Melkko J, Tuominen H, et al. Inflammation and prognosis in colorectal cancer. Eur J Cancer. 2005;41(17):2645-54. https://doi.org/10.1016/j.ejca.2005.07.017 PMid:16239109 DOI: https://doi.org/10.1016/j.ejca.2005.07.017

Rozek LS, Schmit SL, Greenson JK, Tomsho LP, Rennert HS, Rennert G, et al. Tumor-infiltrating lymphocytes, Crohn’s-like lymphoid reaction and survival from colorectal cancer. J Natl Cancer Inst. 2016;108(8):djw027. https://doi.org/10.1093/jnci/djw027 PMid:27172903 DOI: https://doi.org/10.1093/jnci/djw027

Fuchs TL, Sioson L, Sheen A, Jafari-Nejad K, Renaud CJ, Andrici J, et al. Assessment of tumor-infiltrating lymphocytes using international TILs working group (ITWG) system is a strong predictor of overall survival in colorectal carcinoma. Am J Surg Pathol. 2020;44(4):536-44. https://doi.org/10.1097/pas.0000000000001409 PMid:31743129 DOI: https://doi.org/10.1097/PAS.0000000000001409

Pollheimer MJ, Kornprat P, Lindtner RA, Harbaum L, Schlemmer A, Rehak P, et al. Tumor necrosis is a new promising prognostic factor in colorectal cancer. Hum Pathol. 2010;41(12):1749-57. https://doi.org/10.1016/j.humpath.2010.04.018 PMid:20869096 DOI: https://doi.org/10.1016/j.humpath.2010.04.018

Morano F, Corallo S, Niger M, Barault L, Milione M, Berenato R, et al. Temozolomide and irinotecan (TEMIRI regimen) as salvage treatment of irinotecan-sensitive advanced colorectal cancer patients bearing MGMT methylation. Ann Oncol. 2018;29(8):1800-6. https://doi.org/10.1093/annonc/mdy197 PMid:29860358 DOI: https://doi.org/10.1093/annonc/mdy197

Mori Y. Nagasaka T, Tazawa H, Umeda Y, Morikawa T, Kubota N, et al. MGMT methylation as a novel biomarker for the identification of stage III colorectal cancers at high-risk of disease recurrence following curative surgery. Gastroenterology. 2013;144(5):S-85. https://doi.org/10.1016/s0016-5085(13)60315-7 DOI: https://doi.org/10.1016/S0016-5085(13)60315-7

Shah N, Lin B, Sibenaller Z, Ryken T, Lee H, Yoon JG, et al. Comprehensive analysis of MGMT promoter methylation: Correlation with MGMT expression and clinical response in GBM. PLoS One. 2011;6(1):e16146. https://doi.org/10.1371/journal.pone.0016146 PMid:21249131 DOI: https://doi.org/10.1371/journal.pone.0016146

Downloads

Published

2021-05-14

How to Cite

1.
Ahmed M, Bayoumi B, Abdallah S, Elserafy M. MGMT Immunohistochemical Expression in Colorectal Carcinoma and its Correlation with Tumor Progression: MGMT &amp; Histopathology in CRC progression. Open Access Maced J Med Sci [Internet]. 2021 May 14 [cited 2024 Dec. 3];9(A):244-51. Available from: https://oamjms.eu/index.php/mjms/article/view/5879