Evaluation de l’instabilité microsatellitaire, de l’expression de MLH1 et du status de méthylation du promoteur de hMLH1 dans une série tunisienne de cancers colorectaux
Mots-clés :
MSI; MLH1; hyperméthylation ; carcinome colorectal.Résumé
Prérequis : 10 à 15% des cancers colorectaux sporadiques montrent une instabilité microsatellitaire. Cette dernière est généralement associée à une hyperméthylation du promoteur du gène de hMLH1.But : Etudier la relation entre le phénotype MSI, l’expression de la protéine MLH1 et le statut de méthylation du promoteur du gène de hMLH1 dans notre série tunisienne de cancers colorectaux sporadiques.
Méthodes: Nous avons étudié l’expression de MLH1 et MSH2 par immunohistochimie, le phénotype MSI par électrophorèse automatisée et le statut de méthylation du promoteur du gène de hMLH1 par méthylation-specific PCR.
Résultats: 57% des cas sont MSS, 28% sont MSI-L et 15% sont MSI-H. Ces derniers montrent fréquemment une localisation droite, un stade III TNM, et sont majoritairement mucineux. La majorité des cas MSS/MSI-L (79%) sont non-méthylés contrairement aux cas MSI-H (26%). 84% des cas MSS/MSI-L expriment positivement MLH1et 52% des cas MSI-H. Pour les cas MSI-H méthylés, 35% expriment la protéine MLH1 alors que 100% des cas non-méthylés sont positif immunohistochimiquement pour MLH1. Concernant les 11 cas MSI-H qui sont negatifs pour MLH1, ils présentent une méthylation du promoteur du gène de hMLH1. Cepandant 50% des cas MSI-H, positifs pour MLH1, sont méthylés.
Conclusion: Nos resultants montrent que la phenotype MSI-H présente majoritairement une localisation droite, un Stade III TNM et est de type mucineux. La relation entre l’expression de MLH1 et le statut de méthylation du promoteur de hMLH1 dans notre série Tunisienne est en corrélation avec les résultats d’autres séries de la littérature.
Téléchargements
Références
Sablin MP, Italiano A, Spano JP. Colorectal cancers: prognostic and predictive factors of response to treatment. Bull Cancer 2009; 96: 417-23.
Irimura T, Matsushita Y, Sutton RC, et al. Increased content of an endogenous lactose binding lectin in human colorectal carcinoma progressed to metastatic stages. Cancer Res 1991; 51: 387-93.
Goh KL, Quek KF, Yeo GT, et al. Colorectal cancer in Asians: a demographic and anatomic survey in Malaysian patients undergoing colonoscopy. Aliment Pharmacol Ther 2005; 22:859- 64.
Bresalier RS, Mazurek N, Sternberg LR, et al. Metastasis of human colon cancer is altered by modifying expression of the beta-galactoside-binding protein galectin 3. Gastroenterology 1998;115:287-96.
Kinzler KW, Vogelstein B. Lessons from hereditary colorectal cancer. Cell 1996; 87:159-70.
Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 1990; 61: 759-67.
Aaltonen LA, Peltomaki P, Leach FS, et al. Clues to the pathogenesis of familial colorectal cancer. Science 1993; 260:812-6.
Ionov Y, Peinado MA, Malkhosyan S, Shibata D, Perucho M. Ubiquitous somatic mutations in simple repeated sequences reveals a new mechanism for colonic carcinogenesis. Nature 1993; 363:558-61.
Thibodeau SN, Bren G, Schaid D. Microsatellite instability in cancer of the proximal colon. Science 1993; 260:816-9.
Peltomaki P. The genetics of hereditary non-polyposis colorectal cancer and non-polypotic colon cancer. Adv Exp Med Biol 1999;470:95-8.
Boland CR, Thibodeau SN, Hamilton SR, et al. 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 1998;58:5248 -57.
Kane MF, Loda M, Gaida GM, et al. Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. Cancer Res 1997;57:808 -11.
Dietmaier W, Wallinger S, Bocker T, Kullmann F, Fishel R, Ruschoff J. Diagnostic microsatellite instability: definition and correlation with mismatch repair protein expression. Cancer Res 1997;57:4749 - 56.
Kim H, Jen J, Vogelstein B, Hamilton SR. Clinical and pathological characteristics of sporadic colorectal carcinomas with DNA replication errors in microsatellite sequences. Am J Pathol 1994;145: 148-56.
Ruschoff J, Dietmaier W, Luttges J, et al. Poorly differentiated colonic adenocarcinoma, medullary type: clinical, phenotypic, and molecular characteristics. Am J Pathol 1997;150:1815-25.
Thibodeau SN, Bren G, Schaid D. Microsatellite instability in cancer of the proximal colon. Science 1993;260:816-9.
Thibodeau SN, French AJ, Cunningham JM, et al. Microsatellite instability in colorectal cancer: different mutator phenotypes and the principal involvement of hMLH1. Cancer Res 1998;58:1713- 8.
Grady WM. Genomic instability and colon cancer. Cancer Metastasis Rev 2004; 23:11-27.
Sankila R, Aaltonen LA, Jarvinen HJ, Mecklin JP. Better survival rates in patients with MLH1-associated hereditary colorectal cancer. Gastroenterology 1996;110:682-7.
Carethers JM, Chauhan DP, Fink D, et al. Mismatch repair proficiency and in vitro response to 5-fluorouracil. Gastroenterology 1999; 117:123-31.
Meginatti M, di Gregorio C, Borghi F, et al. Methylation pattern of different regions of the MLH1 promoter and silincing of gene expression in hereditary and sporadic colorectal cancer. Genes Chromosomes Cancer 2001; 31:357-61.
Jass JR, Do KA, Simms LA, et al. Morphology of sporadic colorectal cancer with DNA replication errors. Gut 1998, 42:673-79.
Liang JT, Huang KC, Cheng AL, Jeng YM, Wu MS, Wang SM. Clinicopathological and molecular biological features of colorectal cancer in patients less than 40 years of age. Br J Surg 2003; 90: 205-14.
Losi L, Di Gregorio C, Pedroni M, et al. Molecular genetic alterations and clinical features in early-onset colorectal carcinomas and their role for the recognition of hereditary cancer syndromes. Am J Gastroenterol 2005;100:2280-87.
Gryfe R, Kim H, Hsieh ET, et al. Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med 2000;342:69-77.
Gonzalez-Garcia I, Moreno V, Navarro M, et al. Standardized approach for microsatellite instability detection in colorectal carcinomas. J Natl Cancer Inst 2000; 92:544-49.
Leung SY, Yuen ST, Chung LP, Chu KM, Chan AS, Ho JC. hMLH1 promoter methylation and lack of hMLH1 expression in sporadic gastric carcinomas with high-frequency microsatellite instability. Cancer Res 1999; 59:159-64.
Wright CM, Dent OF, Barker M et al. Prognostic significance of extensive microsatellite instability in sporadic clinicopathological stage C colorectal cancer. Br J Surg 2000; 87:1197-1202.
Ward R, Meagher A, Tomlinson I, et al. Microsatellite instability and the clinicopathological features of sporadic colorectal cancer. Gut 2001; 48:821-29.
Chaves P, Cruz C, Lage P, et al. Immunohistochemical detection of mismatch repair gene proteins as a useful tool for the identification of colorectal carcinoma with the mutator phenotype. J Pathol 2000;191:355-60.
Lindor NM, Burgart LJ, Leontovich O, et al. immunohistochemistry versus microsatellite instability testing in phenotyping colorectal tumors. J Clin Oncol 2002; 20:1043-8.
Cawkwell L, Gray S, Murgatroyd H, et al. Choice of management strategy for colorectal cancer based on a diagnostic immunohistochemical test for defective mismatch repair. Gut 1999; 45:409-15.
Terdiman JP, Gum Jr JR, Conrad PG, et al. Efficient detection of hereditary nonpolyposis colorectal cancer gene carriers by screening for tumor microsatellite instability before germline genetic testing. Gastroenterology 2001;120:21-30.
Marcus VA, Madlensky L, Gryfe R, et al. Immunohistochemistry for hMLH1 and hMSH2: Practical tests for DNA mismatch repair-deficient tumors. Am J Surg Pathol 1999; 59:1248-55.
Herman JG, Umar A, Polyak K, et al. Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci USA. 1998;95:6870-75.
Veigl ML, Kasturi L, Olechnowicz J, et al. Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers. Proc Natl Acad Sci USA. 1998;95:8698-702.
Elsaleh H, Powell B, Soontrapornchai P, et al. p53 gene mutation, microsatellite instability and adjuvant chemotherapy: impact on survival of 388 patients with Dukes' C colon carcinoma. Oncology. 2000; 58:52-9.
Ribic CM, Sargent DJ, Moore MJ, et al. Tumor microsatelliteinstability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med. 2003; 349:247-57.
