MISMATCH REPAIR PROTEINS AND SURVIVIN IN ADENOMATOUS COLON POLYPS WITH LOW GRADE AND HIGH GRADE DYSPLASIA: AN IMMUNOHISTOCHEMICAL STUDY. Las proteínas para la reparación de desajustes y survivin en pólipos adenomatosos de colon con displasias de bajo y a

Autores/as

  • Marian Adamkov Comenius University, Jessenius Faculty of Medicine
  • Desanka Výbohová Comenius University, Jessenius Faculty of Medicine
  • Slávka Drahošová Hermes LabSystems
  • Štefan Galbavý Comenius University, Faculty of Medicine

DOI:

https://doi.org/10.31051/1852.8023.v10.n3.20923

Palabras clave:

mismatch repair proteins, survivin, colon adenoma, reparación de desajuste, pólipo del colon, displasia

Resumen

Objective: The aim of our study was to observe the immunohistochemical expression pattern of mismatch repair proteins (MMRP) MLH1, MSH2, MSH6 and PMS2, as well as survivin, in colon polyps. Methods: We assessed above mentioned proteins in a unified group of 124 tubular adenomatous colon polyps with regard to the presence of dysplastic abnormalities in order to explore their relationship. Furthermore, we studied their relation to such clinicomorphological parameters as the age of patients, size of adenoma, degree of dysplastic changes and localization of the lesion. Results: Survivin was expressed in 97 cases (78.2%), MLH1 was found in 111 cases (89.5%), MSH2 in 115 cases (92.7%), MSH6 in 118 cases (95.2%) and PMS2 in 105 cases (84.7%). The majority of absent MMRP cases was detected where the adenoma size was less than 10 mm with LGD (low-grade dysplasia). Survivin expression significantly correlated with the adenoma size and dysplasia grade. Subcellular survivin compartmentalization was statistically associated with the adenoma size, dysplasia grade and adenoma localization. Furthermore, we confirmed a significant relation between survivin expression and MMRP. In general, the intensity of immunoreaction was stronger in the MMRP than in survivin. Conclusions: Our recent results suggest that MMRP may suppress the antiapoptotic activity of survivin in LGD and HGD (high grade dysplasia) colon adenomas.

 

Antecedentes: Las proteínas de reparación de desajustes (MMRP) y survivin representan señales diametralmente opuestas que pueden controlar las vías apoptóticas. Además, se sabe que tanto MMRP como survivin son poderosos parámetros pronósticos. Material y métodos: El objetivo de nuestro estudio fue observar el patrón de expresión inmunohistoquímica de MMRP MLH1, MSH2, MSH6 y PMS2, y survivin en un grupo unificado de 124 adenomatosos pólipos tubulares de colon con respecto a la presencia de anomalías displásicas para explorar sus relaciones. Además, estudiamos su relación con los parámetros clinicomorfológicos, como la edad de los pacientes, el tamaño del adenoma, el grado de cambios displásicos y la localización de la lesión. Resultados: Survivin se expresó en 97 casos (78.2%), MLH1 se encontró en 111 casos (89.5%), MSH2 en 115 casos (92.7%), MSH6 en 118 casos (95.2%) y PMS2 en 105 casos (84.7%). La mayoría de los casos ausentes de MMRP se detectaron en un tamaño de adenoma inferior a 10 mm, estos casos se asociaron principalmente con displasia de bajo grado y fueron más frecuentes en el colon distal. La expresión de survivin se correlacionó significativamente con el tamaño del adenoma y el grado de displasia. La compartimentalización de survivin subcelular se asoció estadísticamente con el tamaño del adenoma, el grado de displasia y localización del adenoma. Además, confirmamos una relación significativa entre la expresión de survivin y el MMRP. En general, la intensidad de la inmunorreacción fue más fuerte en MMRP en comparación con la intensidad del survivin. Conclusiones: Con base en nuestros resultados recientes, sugerimos que el MMRP puede suprimir la actividad antiapoptótica del survivin en los adenomas de colon con displasias de bajo y alto grado.

Biografía del autor/a

Marian Adamkov, Comenius University, Jessenius Faculty of Medicine

Department of Histology and Embryology, Malá Hora 4, Martin

Desanka Výbohová, Comenius University, Jessenius Faculty of Medicine

Department of Anatomy, Malá Hora 4, Martin

Slávka Drahošová, Hermes LabSystems

Púchovská 2, Bratislava

Štefan Galbavý, Comenius University, Faculty of Medicine

Institute of Forensic Medicine, Sasinkova 4, Bratislava

Citas

Adamkov M, Kajo K, Vybohova D, Krajcovic J, Stuller F, Rajcani J. 2012. Correlations of survivin expression with clinicomorphological parameters and hormonal receptor status in breast ductal carcinoma. Neoplasma 59: 30-37.

Adamkov M, Furjelová M, Horáček J, Benčat M, Kružliak P. 2014. Relationship of mismatch repair proteins and survivin in colon polyps and carcinomas. Acta Histochemica 116: 1007-14.

Amiri KI, Richmond A. 2005. Role of nuclear factor-k B in melanoma. Cancer Metastasis Rev 24: 301-13.

Brennan DJ, Rexhepaj E, O´Brien SL, Mcsherry E, O´Connor DP, Fagan A, Culhane AC, Higgins DG, Jirstrom K, Millikan RC, Landberg G, Duffy MJ, Hewitt SM, Gallagher WM. 2008. Altered cytoplasmic-to-nuclear ratio of survivin is a prognostic indicator in breast cancer. Clin Cancer Res 14: 2681-89.

Cejka P, Stojic L, Mojas N, Russell AM, Heinimann K, Cannavo E, di Pietro M, Marra G, Jiricny J. 2003. Methylation-induced G2/M arrest requires a full complement of the mismatch repair protein hMLH1. EMBO J 22: 2245-54.

Charames GS, Bapat B. 2003. Genomic instability and cancer. Curr Mol Med 3: 589-96.

Chaves P, Cruz C, Lage P. 2000. Immuno-histochemical detection of mismatch repair gene proteins as a useful tool for the identification of colorectal carcinoma with the mutator phenotype. J Pathol 191: 355-60.

Chipuk JE, Kuwana T, Bouchier-Hayes L. 2004. Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science 303: 1010-14.

De Jong AE, van Puijenbroek M, Hendriks Y, Tops C, Wijnen J, Ausems MG, Meijers-Heijboer H, Wagner A, van Os TA, Bröcker-Vriends AH, Vasen HF, Morreau H. 2004. Microsatellite instability, immunohistochemistry, and additional PMS2 staining in suspected hereditary nonpolyposis colorectal cancer. Clin Cancer Res 10: 972-80.

Duffy MJ, O´Donovan N, Brennan DJ, Gallagher WM, Ryan BM. 2007. Survivin: A promising tumor biomarker. Cancer Lett 249: 49-60.

Ge Q-X, Li Y-Y, Nie Y-Q, Zuo W-G, Du Y-L. 2013. Expression of survivin and its four splice variants in colorectal cancer and its clinical significances. Med Oncol 30: 535.

Halvarsson B, Lindblom A, Johansson L, Lagerstedt K, Nilbert M. 2005. Loss of mismatch repair protein immunostaining in colorectal adenomas from patients with hereditary nonpolyposis colorectal cancer. Modern Pathology 18: 1095-101.

Hassen S, Ali N, Chowdhury P. 2012. Molecular signaling mechanisms of apoptosis in hereditary non-polyposis colorectal cancer. World J Gastrointest Pathophysiol 3: 71-9.

Hawkins NJ, Ward RL. 2001. Sporadic colorectal cancers with microsatellite instability and their possible origin in hyperplastic polyps and serrated adenomas. J Natl Cancer Inst 93: 1307-13.

Hoffman WH, Biade S, Zilfou JT, Chen J, Murphy M. 2002. Transcriptional repression of the anti-apoptotic survivin gene by wild type p53. J Biol Chem 277: 3247-57.

Iinoa H, Simmsc L, Youngc J, Arnoldd J, Winshipd IM, Webbb SI, Furlongb KL, Leggettc B, Jassb JR. 2000. DNA microsatellite instability and mismatch repair protein loss in adenomas presenting in hereditary non-polyposis colorectal cancer. Gut 47: 37-42.

Ioana M, Angelescu C, Burada F, Mixich F, Riza A, Dumitrescu T, Alexandru D, Ciurea T, Cruce M, Saftoiu A. 2010. MMR gene expression pattern in sporadic colorectal cancer. J Gastrointestin Liver Dis 19: 155-59.

Jover R, Payá A, Alenda C, Poveda MJ, Peiró G, Aranda FI, Pérez-Mateo M. 2004. Defective mismatch-repair colorectal cancer clinic-pathologic characteristics and usefulness of immuno-histochemical analysis for diagnosis. Am J Clin Pathol 122: 389-94.

Khoo J-J, Gunn A, Peh S-Ch. 2013. Pattern of hMLH1, hMSH2 and hMSH6 expression and clinical characteristics in a sample of Malaysian colorectal carcinoma cases. Malaysian J Pathol 35: 45-57.

Köster F, Schröer A, Fischer D, Greweldinger T, Diedrich K, Friedrich M. 2007. Correlation of DNA mismatch repair protein hMSH2 immunohistochemistry with p53 and apoptosis in cervical carcinoma. Anticancer Research 27: 63-68.

Kuniyasu H, Sasaki T, Sasahira T, Chihara Y, Ohmori H. 2004. Repression of MLH1 and MGMT genes in colon mucosa adjacent to implanted cancer in athymic mouse. J Exp Clin Cancer Res 23: 317-23.

Lanza G, Messerini L, Gafa R, Risio M. 2011. Colorectal tumors: The histology report. Digestive and Liver Disease 43S: 344-55.

Lee EJ, Choi Ch, Park ChK, Maeng L, Lee J, Lee A, Kim K-M. 2005. Tracing origin of serrated adenomas with BRAF and KRAS mutations. Virchows Arch 447: 597-602.

Li F. 2005. Role of Survivin and its Splice Variants in Tumorigenesis. Br J Cancer 92: 212-16.

Li F, Brattain MG. 2006. Role of the survivin gene in pathobiology. Am J Pathol 169: 1-11.

Li G-M. 2008. Mechanisms and functions of DNA mismatch repair. Cell Research 18: 85-98.

Luo Y, Lin F-T, Lin W-Ch. 2004. ATM-mediated stabilization of hMutL DNA mismatch repair proteins augments p53 activation during DNA damage. Mol Cell Biol 24: 6430-44.

Mesri M, Wall NR, Li J, Kim RW, Altieri DC. 2001. Cancer gene therapy using a survivin mutant adenovirus. J Clin Invest 108: 981-90.

Mirza A, McGuirk M, Hockenberry TN, Wu Q, Ashar H, Black S, Wen SF, Wang L, Kirschmeier P, Bishop WR, Nielsen LL, Pickett CB, Liu S. 2002. Human survivin is negatively regulated by wild-type p53 and participates in p53-dependent apoptotic pathway. Oncogene 21: 2613-22.

Molaei M, Yadollahzadeh M, Almasi S, Shivarani S, Fatemi SR, Zali MR. 2011. Sporadic colorectal polyps and mismatch repair proteins. Indian J Pathol Microbiol 54: 725-29.

Muto T, Bussey HJR, Morson, BC. 1975. The evolution of cancer of the colon and rectum. Cancer 36: 2251-70.

Nakagawa H, Nuovo GJ, Zervos EE, Martin EW Jr, Salovaara R, Aaltonen LA, de la Chapelle A. 2001. Age-related hypermethylation of the 5´region of MLH1 in normal colonic mucosa is associated with microsatellite-unstable colo-rectal cancer development. Cancer Res 61: 6991-95.

Nusko G, Mansmann U, Altendorf H. 1997. Risk of invasive carcinoma in colorectal adenomas assessed by size and site. Int J Colorectal Dis 12: 267-71.

Oh K, Redston M, Odze RD. 2005. Support for hMLH1 and MGMT silencing as a mechanism of tumorigenesis in the hyperplastic-adenoma-carcinoma (serrated) carcinogenic pathway in the colon. Hum Pathol 36: 101-11.

Oh JW, Yang WI, Lee MJ, Park S, Park BW, Lee KS. 2009. The prognostic significance of survivin expression in breast cancer. J Breast Cancer 12: 285-94.

Peltomäki P. 2003. Role of DNA mismatch repair defects in the pathogenesis of human cancer. J Clin Oncol 21: 1174-79.

Pino MS, Mino-Kenudson M, Wildemore BM, Ganguly A, Batten J, Sperduti I, Iafrate AJ, Chung DC. 2009. Deficient DNA mismatch repair is common in Lynch syndrome-associated colorectal adenomas. J Mol Diagn 11: 238-47.

Piras F, Murtas D, Minerba L, Ugalde J, Floris C, Maxia C, Colombari R, Perra MT, Sirigu P. 2007. Nuclear survivin is associated with disease recurrence and poor survival in patients with cutaneous malignant melanoma. Histopathology 50: 835-42.

Rijcken FE, Hollema H, Kleibeuker JH. 2002. Proximal adenomas in hereditary non-polyposis colorectal cancer are prone to rapid malignant transformation. Gut 50: 382-6.

Samowitz WS, Curtin K, Ma KN, Schaffer D, Coleman LW, Leppert M, Slattery ML. 2001. Microsatellite instability in sporadic colon cancer is associated with an improved prognosis at the population level. Cancer Epidemiol Biomarkers Prev 10: 917-23.

Sheridan TB, Fenton H, Lewin MR, Burkart AL, Iacobuzio-Donahue ChA, Frankel WL, Montgomery E. 2006. Sessile serrated adenomas with low- and high-grade dysplasia and early carcinomas. Am J Clin Pathol 126: 564-71.

Shimodaira H, Yoshioka-Yamashita A, Kolodner RD, Wang JY. 2003. Interaction of mismatch repair protein PMS2 and the p53-related transcription factor p73 in apoptosis response to cisplatin. Proc Natl Acad Sci USA 100: 2420-25.

Scherer SJ, Seib T, Seitz G, Dooley S, Welter C. 1996a . Isolation and characterization of the human mismatch repair gene hMSH2 promoter region. Hum Genet 97: 114-16.

Scherer SJ, Welter C, Zang KD, Dooley S. 1996b . Specific in vitro binding of p53 to the promoter region of the human mismatch repair gene hMSH2. Biochem Biophys Res Commun 221: 722-28.

Scherer SJ, Avdievich E, Edelmann W. 2005. Functional consequences of DNA mismatch repair missense mutations in murine models and their impact on cancer disposition. Biochem Soc Trans 33: 689-93.

Stojic L, Brun R, Jiricny J. 2004. Mismatch repair and DNA damage signaling. DNA Repair 3: 1091-101.

Sun Z, Yu X, Wang H, Zhang S, Zhao Z, Xu R. 2014. Clinical significance of mismatch repair gene expression in sporadic colorectal cancer. Exp Ther Med 8: 1416-22.

Talbot I, Price A, Salto-Tellez M. 2006. Biopsy pathology in colorecatal dissease, 2nd ed. Chapter 15-POLYPS: 400p.

Toll AD, Fabius D, Hyslop T, Pequignot E, DiMarino AJ, Infantolino A, Palazzo JP. 2011. Prognostic significance of high-grade dysplasia in colorectal adenomas. Colorectal Dis 13: 370-73.

Vilar E, Gruber SB. 2010. Microsatellite instability in colorectal cancer-the stable evidence. Nat Rev Clin Oncol 7: 153-62.

Walsh MD, Buchanan DD, Pearson S-A, Clendenning M, Jenkins MA, Ko Win A, Walters RJ, Spring K, Nagler B, Pavluk E, Arnold ST, Goldblatt J, George J, Suthers G, Phillips K, Hopper JL, Jass JR, Baron JA, Ahnen D, Thibodeau S, Lindor N, Parry S, Walker N, Rosty Ch, Young JP. 2012. Immuno-histochemical testing of conventional adenomas for loss of expression of mismatch repair proteins in lynch syndrome mutation carriers: a case series from the Australasian site of the colon cancer family registry. Mod Parhol 25: 722-30.

Young J, Barker M, Fraser L, Walsh M, Spring K, Biden K, Hopper JL, Leggett BA, Jass JR. 2002. Mutation searching in colorectal cancer studies: experience with a denaturing high-pressure liquid chromatography system for exon-by-exon scanning of tumour suppressor genes. Pathology 34: 529-33.

Yurgelun MB, Goel A, Hornick JL, Sen A, Turgeon DK, Ruffin IV MT, Marcon NE, Baron JA, Bresalier RS, Syngal S, Brenner DE, Boland CR, Stoffel EM. 2012. Microsatellite instability and DNA mismatch repair protein deficiency in lynch syndrome colorectal polyps. Cancer Prev Res (Phila) 5: 574-82.

Zhang H, Richards B, Wilson T, Lloyd M, Cranston A, Thorburn A, Fishel R, Meuth M. 1999. Apoptosis induced by overexpression of hMSH2 or hMLH1. Cancer Res 59: 3021-27.

Descargas

Publicado

2018-11-22

Cómo citar

Adamkov, M., Výbohová, D., Drahošová, S., & Galbavý, Štefan. (2018). MISMATCH REPAIR PROTEINS AND SURVIVIN IN ADENOMATOUS COLON POLYPS WITH LOW GRADE AND HIGH GRADE DYSPLASIA: AN IMMUNOHISTOCHEMICAL STUDY. Las proteínas para la reparación de desajustes y survivin en pólipos adenomatosos de colon con displasias de bajo y a. Revista Argentina De Anatomía Clínica, 10(3), 98–111. https://doi.org/10.31051/1852.8023.v10.n3.20923

Número

Sección

Contribuciones Originales