Correlation of Minichromosome Maintenance Protein 6 Expression Rate and Clinical Outcome in Patients With Hodgkin's Lymphoma
Abstract
Minichromosome maintenance complex component 6 (MCM-6) is one of the six proteins of the MCM family, which are involved in the initiation of DNA replication, represents a marker of proliferating cells. The goal of this study was to evaluate the prognostic relevance of the neoplastic cell proliferation rate in patients with Hodgkin's lymphoma (HL). We evaluated the formalin-fixed paraffin-embedded lymph node biopsy specimens from 55 patients by using monoclonal antibody against MCM-6 and compared these findings with clinical data and treatment outcome. Median of MCM-6 expression was 85% (range: 35%-99%). In multivariate analysis, MCM-6 expression, B symptoms, and age were not statistically significant predictor for relapse in contrary to response (P=.001) and stage of disease (P=.048). Patients with lower MCM-6 expression rates showed higher relapse rate and lower disease-free survival (DFS). Meanwhile, patients with MCM-6 expression less than 85% showed shorter DFS (P=.031). We hypothesize that in group of patients with lower MCM-6 expression rate, a larger proportion of proliferating malignant cells are arrested in the very early phase of mitosis, in comparison to the group of patients with higher MCM-6 expression, and this could imply a shorter and probably higher relapse rate in the former group.
Saarinen S, Pukkala E, Vahteristo P, Mäkinen MJ, Franssila K, Aaltonen LA. High Familial Risk in Nodular LymphocytePredominant Hodgkin Lymphoma. JCO 2013 ;31:938-43 .
de la Cruz-Merino L, Lejeune M, Nogales Fernández E, Henao Carrasco F, Grueso López A, Illescas Vacas A, et al. Role of Immune Escape Mechanisms in Hodgkin’s Lymphoma Development and Progression: A Whole New World with Therapeutic Implications. Clin Dev Immunol 2012;2012:756353 .
Sánchez-Aguilera A, Delgado J, Camacho FI, Sánchez-Beato M, Sánchez L, Montalbán C, et al. Silencing of the p18INK4c gene by promoter hypermethylation in Reed–Sternberg cells in Hodgkin lymphomas. Blood 2004;103:2351-7.
García JF, Camacho FI, Morente M, Fraga M, Montalbán C, Alvaro T, et al. Hodgkin and Reed–Sternberg cells harbor alterations in the major suppressor pathways and cell-cycle checkpoints: analyses using tissue microarrays. Blood 2003;101:681-9.
Glaser SL, Clarke CA, Chang ET, Yang J, Gomez SL, Keegan TH. Hodgkin lymphoma incidence in California Hispanics: Influence of nativity and tumor Epstein–Barr virus. Cancer Causes Control 2014;25:709-25.
Juríkováa M, Danihelb L, PolákaŠ, Vargaa I. Ki67, PCNA, and MCM proteins: Markers of proliferation in the diagnosis of breast cancer. Acta Histochemica 2016;118:544–52.
Räty R, Franssila K, Joensuu H, Teerenhovi L, Elonen E. Ki-67 expression level, histological subtype, and the international prognostic index as outcome predictors in mantle cell lymphoma. Eur J Haematol 2002;69:11-20.
Gerdes J, Lemke H, Baisch H, Wacker H, Schwab U, Stein H. Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunol 1984;133:1710–5.
Verheijen R, Kuijpers HJ, Van Driel R, Beck JL, van Dierendonck JH, et al. Ki-67 detects a nuclear matrix-associated proliferationrelated antigen. II. Localization in mitotic cells and association with chromosomes. J Cell Sci 1989;92:531-40.
Cuccaro, A, Bartolomei, F, Cupelli E, Galli E, Giachelia M, Hohaus S. Prognostic Factors in Hodgkin Lymphoma Mediterr J Hematol Infect Dis 2014;6:e2014053.
Kearsey SE, Labib K. MCM proteins: evolution, properties, and role in DNA replication. Biochim Biophys Acta 1998;1398:113-36.
Madine MA, Swietlik M, Pelizon C, Romanowski P, Mills AD, Laskey RA. The roles of the MCM, ORC, and Cdc6 proteins in determining the replication competence of chromatin in quiescent cells. J Struct Biol 2000; 129:198–210.
Fujita M, Kiyono T, Hayashi Y, Ishibashi M. In vivo interaction of human MCM heterohexameric complexes with chromatin. Possible involvement of ATP. J Biol Chem 1997;272:10928-35.
Gakipoulou H, Korkopoulou P, Levidou G, Thymara I, Saetta A, Piperi C, et al. Minichromosome maintenance proteins 2 and 5 in non-benign epithelial ovarian tumuors: relationship with cell cycle regulators and prognostic implications. Br J Cancer 2007;97:1124-34.
Ramanth N, Hernandez FJ, Tan DF, Huberman JA, Natarajan N, et al. MCM2 is an independent predictor of survival in patients with non-small-cell- lung cancer. J Clin Oncol 2001;19:4259-66.
Kodani I, Osaki M, Shomori K, Araki K, Goto E, Ryoke K, et al. Minichromosome Maintenance 2 expression is correlated with mode of invasion and prognosis in oral squamous cell carcinoma. J Oral Pathol Med 2003;32:468-74.
Li SS, Xue WC, Khoo US, Ngan HY, Chan KY, Tam IY, et al. Replicative MCM7 protein as a proliferative marker in endometrial carcinoma: a tissue microarray and clinicopathological analysis. Histopathology 2005;46:307-13.
Guida T, Salvatore G, Favian P, Giannini R, Garcia-Rostan G, Provitera L, et al. Mitogenic effects of the up-regulation of minichromosome maintenance (MCM) proteins in anaplastic thyroid carcinoma. J Clin Endocrinol Metab 2005;19:4703-9.
Tiemann M, Claviez A, Lüders H, Zimmermann M, Günther S, Dörffel W, et al. Proliferation characteristics in pediatric Hodgkin’s lymphoma point to a cell cycle arrest in the G1 phase. Mod Pathol 2005;18:1440-7.
Heidebrecht HJ, Buck F, Endl E, Kruse ML, Kruse ML, Adam-Klages S, Andersen K, et al. Ki-MCM6, a new monoclonal antibody specific to MCM6: Compression of the distribution profile of MCM6 and Ki-67 antigen. Lab Invest 2001;81:1163-5.
Helfenstein A, O'fraham S, Krams M Drescher W, Parwaresch R, Hassenpflug J. Minichromosome maintenance protein (MCM6) in low grade chondrosarcoma: Distinction from enchondroma an identification of progressive tumors. Clin Pathol 2004;122:912-8.
Schrader C, Janssen D, Klapper W, Siebmann JU, Meusers P, Brittinger G, et al. Minichromosome maintenance protein 6, a proliferation marker superior to Ki-67 and independent predictor of survival in patients with mantle cell lymphoma. Br J Cancer 2005 17;93:939-45.
Karimi S, Mohammadi F, Khodadad K, Emami H, Seyfollahi L. High expression of Minichromosome maintenance protein 6 in classic Hodgkin's Lymphoma points to a cell cycle arrest in G1 phase. Arch Iran Med 2008;11:532-8.
Jaffe ES. The 2008 WHO classification of lymphomas: implications for clinical practice and translational research. Hematology Am Soc Hematol Educ Program 2009:523-31.
Lister TA, Crowther D, Sutcliffe SB, Glatstein E, Canellos GP, Young RC, et al. Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin's disease: Cotswolds meeting. J Clin Oncol 1989;7:1630-6.
Bradley AJ, Carrington BM, Lawrance JA, Ryder WD, Radford JA. Assessment and significance of mediastinal bulk in Hodgkin’s disease: comparison between computed tomography and chest radiography. J Clin Oncol1999;17:2493-8.
Cheson B.D, Horning S.J, Coiffier B, Shipp MA, Fisher RI, Connors JM, et al. Report of an International Workshop to standardize response criteria for non-Hodgkin lymphomas. J Clin Oncol 1999;17:1244-53.
Hsu M, Raine L, Fanger H. use of avidin-biotinperoxidase complex (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabeled antibody (PAP) procedures. J Histochem Cytochem 1981;29:577-80.
Hasenclever D, Diehl V. A prognostic score for advanced Hodgkin's disease: International Prognostic Factors Project on Advanced Hodgkin's Disease. N Engl J Med 1998; 339:1506-14.
Freeman A, Morris L.S, Mills A.D, Stoeber K, Laskey R.A, Williams G.H, et al. Minichromosome maintenance proteins as biological markers of dysplasia and malignancy. Clin Cancer Res 1999;5:2121-32.
Ishimi Y, Okayasu L, Kato C, Kwon H.J, Kimura H, Yamada K, et al. Enhanced expression of Mcm proteins in cancer cells derived from uterine cervix. Eur J Biochem 2003;270:1089-101.
Nishihara K, Shomori K, Fujioka S, Tokuyasu N, Inaba A, Osaki M, et al. Minichromosome maintenance protein 7 in colorectal cancer: implication of prognostic significance. Int J Oncol 2008;33:245-51.
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Issue | Vol 55, No 9 (2017) | |
Section | Original Article(s) | |
Keywords | ||
Hodgkin’s disease Minichromosome maintenance complex component 6 (MCM-6) Lymphoma |
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