Journal of Molecular Histology

, Volume 43, Issue 2, pp 137–143 | Cite as

High-frequency microsatellite instability and BRAF mutation (V600E) in unselected Serbian patients with colorectal cancer

  • Srdjan MarkovicEmail author
  • Jadranka Antic
  • Neda Dragicevic
  • Richard Hamelin
  • Zoran Krivokapic


Microsatellite instability (MSI) is a genetic consequence of a MisMatch Repair defect in colorectal cancer (CRC). We compared clinicopathohistological features with MSI status of CRC and evaluated prognostic significance of MSI status and BRAF mutation in the group of MSI-H tumors. 155 primary CRCs were excised surgically, 2006–2008. MSI analysis was carried out using a fluorescence-based pentaplex polymerase chain reaction technique. BRAF mutation (V600E) was analyzed by direct sequencing in MSI-H tumors. For all patients were evaluated: age, gender, localization, tumor cell type, tumor differentiation, mucin production, lymphocytic infiltration (TILs) and TNM stage. Patients’ disease-free survival (DFS) was compared according to MSI and BRAF status using Kaplan–Meier test. Of the 155 CRCs, 19 (12.3%) were MSI-H, and 136 (87.7%) were MSS/L. BRAF mutations were found in 4 of the MSI-H tumors. Patients with MSI-H CRC had lower recurrence rate (log rank test; P = 0.04) than MSS/L group. Patients with MSI-H tumor and BRAF mutation had worse DFS than MSI-H tumors without this mutation (log rank test; P = 0.01). Most of the clinicopathologic characteristics of MSI-H CRC in Serbian patients are similar to those reported in previous studies. Patients with MSI tumor phenotype had favourable prognosis, but in those with BRAF mutation higher recurrence rate was observed.


Microsatellite instability Colon cancer Clinicopathohistological features BRAF mutation 



This work was supported by Ministry of Science; Republic of Serbia: Grant No 41033.

Conflict of interest

The authors declare that they have no conflict of interest.


  1. Banerjea A, Hands RE, Powar MP, Bustin SA, Dorudi S (2009) Microsatellite and chromosomal stable colorectal cancers demonstrate poor immunogenicity and early disease recurrence. Colorectal Dis 11(6):601–608. doi: 10.1111/j.1463-1318.2008.01639 PubMedCrossRefGoogle Scholar
  2. Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW et al (1998) 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 58:5248–5257PubMedGoogle Scholar
  3. Buhard O, Suraweera N, Lectard A, Duval A, Hamelin R (2004) Quasimonomorphic mononucleotide repeats for high-level microsatellite instability analysis. Dis Markers 20(4–5):251–257. doi: 10.1200/JCO.2005.02.7227 PubMedGoogle Scholar
  4. Carethers JM, Smith EJ, Behling CA et al (2004) Use of 5-fluorouracil and survival in patients with microsatellite-unstable colorectal cancer mismatch repair proficiency and in vitro response to 5-fluorouracil. Gastroenterology 126:394–401. doi: 10.1053/j.gastro.2003.12.023 PubMedCrossRefGoogle Scholar
  5. Deng G, Bell I, Crawley S, Gum J, Terdiman J, Allen B et al (2004) BRAF mutation is frequently present in sporadic colorectal cancer with methylated hMLH1, but not hereditary nonpolyposis colorectal cancer. Clin Cancer Res 10:191–195. doi: 10.1158/1078-0432.CCR-1118-3 PubMedCrossRefGoogle Scholar
  6. Domingo E, Laiho P, Ollikainen M, Pinto M, Wang L, French AJ et al (2004) BRAF screening as a low-cost effective strategy for simplifying HNPCC genetic testing. J Med Genet 41:664–668. doi: 10.1136/jmg.2004.020651 PubMedCrossRefGoogle Scholar
  7. French AJ, Sargent DJ, Burgart LJ, Foster NR, Kabat BF, Goldberg R et al (2008) Prognostic significance of defective mismatch repair and BRAF V600E in patients with colon cancer. Clin Cancer Res 14(11):3408–3415. doi: 10.1158/1078-0432.CCR-07-1489 PubMedCrossRefGoogle Scholar
  8. Greenson JK, Huang S, Herron C, Moreno V, Bonner J, Tomsho LP (2009) Pathologic predictors of microsatellite instability in colorectal cancer. Am J Surg Pathol 33(1):126–133. doi: 10.1097/PAS.0b013e31817ec2b1 PubMedCrossRefGoogle Scholar
  9. Ishikubo T, Nishimura Y, Yamaguchi K, Khansuwan U, Arai Y, Kobayashi T et al (2004) The clinical features of rectal cancers with high-frequency microsatellite instability (MSI-H) in Japanese males. Cancer Lett 216:55–62. doi: 10.1016/j.canlet.2004.07.017 PubMedCrossRefGoogle Scholar
  10. Jass JR (2007) Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology 50:113–130. doi: 10.1111/j.1365-2559.2006.02549 PubMedCrossRefGoogle Scholar
  11. Jenkins MA, Hayashi S, O’Shea AM, Burgart LJ, Smyrk TC, Shimizu D et al (2007) Pathology features in Bethesda guidelines predict colorectal cancer microsatellite instability: a population-based study. Gastroenterology 133(1):48–56. doi: 10.1053/j.gastro.2007.04.044 PubMedCrossRefGoogle Scholar
  12. Kazama Y, Watanabe T, Kanazawa T, Tanaka J, Tanaka T, Nagawa H (2007) Microsatellite instability in poorly differentiated adenocarcinomas of the colon and rectum: relationship to clinicopathological features. J Clin Pathol 60(6):701–704. doi: 10.1136/jcp.2006.039081 PubMedCrossRefGoogle Scholar
  13. Kazama Y, Watanabe T, Kanazawa T, Tanaka J, Tanaka T, Nagawa H (2008) Poorly differentiated colorectal adenocarcinomas show higher rates of microsatellite instability and promoter methylation of p16 and hMLH1: a study matched for T classification and tumor location. J Surg Oncol 97(3):278–283. doi: 10.1002/jso.20960 PubMedCrossRefGoogle Scholar
  14. Lamberti C, Lundin S, Bogdanow M et al (2007) Microsatellite instability did not predict individual survival of unselected patients with colorectal cancer. Int J Colorectal Dis 22(2):145–152. doi: 10.1007/s00384-006-0131-8 PubMedCrossRefGoogle Scholar
  15. Malesci A, Laghi L, Bianchi P, Delconte G, Randolph A, Torri V et al (2007) Reduced likelihood of metastases in patients with microsatellite-unstable colorectal cancer. Clin Cancer Res 13(13):3831–3839. doi: 10.1158/1078-0432.CCR-07-0366 PubMedCrossRefGoogle Scholar
  16. McGivern A, Wynter CV, Whitehall VL, Kambara T, Spring KJ, Walsh MD et al (2004) Promoter hypermethylation frequency and BRAF mutations distinguish hereditary non-polyposis colon cancer from sporadic MSI-H colon cancer. Fam Cancer 3:101–107. doi: 10.1023/B:FAME.0000039861.30651.c8 PubMedCrossRefGoogle Scholar
  17. Ng K, Schrag D (2010) Microsatellite instability and adjuvant fluorouracil chemotherapy: a mismatch? J Clin Oncol 28(20):3207–3210. doi: 10.1200/JCO.2010.28.9314 PubMedCrossRefGoogle Scholar
  18. Pawlik TM, Raut CP, Rodriguez-Bigas MA (2004) Colorectal carcinogenesis: MSI-H versus MSI-L. Dis Markers 20:199–206PubMedGoogle Scholar
  19. Ribic CM, Sargent DJ, Moore MJ, Thibodeau SN, French AJ, Goldberg RM et al (2003) Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med 349:247–257. doi: 10.1056/NEJMoa022289 PubMedCrossRefGoogle Scholar
  20. Samowitz WS, Sweeney C, Herrick J, Albertsen H, Levin TR, Murtaugh MA et al (2005) Poor survival associated with the BRAF V600E mutation in microsatellite-stable colon cancers. Cancer Res 65:6063–6069. doi: 10.1158/0008-5472.CAN-05-0404 PubMedCrossRefGoogle Scholar
  21. Saridaki Z, Papadatos-Pastos D, Tzardi M, Mavroudis D, Bairaktari E et al (2010) BRAF mutations, microsatellite instability status and cyclin D1 expression predict metastatic colorectal patients’ outcome. Br J Cancer 102:1762–1768. doi: 10.1038/sj.bjc.6605694 PubMedCrossRefGoogle Scholar
  22. Shitoh K, Konishi F, Miyakura Y, Togashi K, Okamoto T, Nagai H (2002) Microsatellite instability as a marker in predicting metachronous multiple colorectal carcinomas after surgery. Dis Colon Rectum 45:329–333. doi: 10.1007/s10350-004-6177-1 PubMedCrossRefGoogle Scholar
  23. Suraweera N, Duval A, Reperant M, Vaury C, Furlan D, Leroy K et al (2002) Evaluation of tumor microsatellite instability using five quasimonomorphic mononucleotide repeats and pentaplex PCR. Gastroenterology 123(6):1804–1811. doi: 10.1053/gast.2002.37070 PubMedCrossRefGoogle Scholar
  24. Ward R, Meagher A, Tomlinson I, O’Connor T, Norrie M, Wu R et al (2001) Microsatellite instability and the clinicopathological features of sporadic colorectal cancer. Gut 48:821–829. doi: 10.1136/gut.48.6.821 PubMedCrossRefGoogle Scholar
  25. Westra J, Schaapveld M, Hollema H et al (2005) Determination of TP53 mutation is more relevant than microsatellite instability status for the prediction of disease-free survival in adjuvant-treated stage III colon cancer patients. J Clin Oncol 23:5635–5643. doi: 10.1200/JCO.2005.04.096 PubMedCrossRefGoogle Scholar
  26. Yearsley M, Hampel H, Lehman A, Nakagawa H, de la Chapelle A, Frankel WL (2006) Histologic features distinguish microsatellite high from microsatellite-low and microsatellite-stable colorectal carcinomas, but do not differentiate germline mutations from methylation of the MLH1 promoter. Hum Pathol 37:831–838. doi: 10.1016/j.humpath.2006.02.009 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  • Srdjan Markovic
    • 1
    Email author
  • Jadranka Antic
    • 2
  • Neda Dragicevic
    • 2
  • Richard Hamelin
    • 3
    • 4
  • Zoran Krivokapic
    • 5
  1. 1.Center for Gastroenterology and Hepatology, Zvezdara University Clinical CenterBelgradeSerbia
  2. 2.Institute of Endocrinology, Diabetes and Metabolic Diseases, Clinical Center of SerbiaBelgradeSerbia
  3. 3.Université Pierre et Marie Curie-Paris6ParisFrance
  4. 4.INSERM, UMRS 938, Centre de Recherche Saint Antoine, Equipe “Instablité des Microsatellites et Cancers”ParisFrance
  5. 5.Center for Colorectal Surgery, Clinical Center of SerbiaBelgradeSerbia

Personalised recommendations