Jump to ContentJump to Main Navigation

Open Medicine

formerly Central European Journal of Medicine

1 Issue per year

IMPACT FACTOR 2014: 0.153
5-year IMPACT FACTOR: 0.183

SCImago Journal Rank (SJR) 2014: 0.135
Source Normalized Impact per Paper (SNIP) 2014: 0.124
Impact per Publication (IPP) 2014: 0.193

Open Access


Molecular screening for hereditary nonpolyposis colorectal cancer in Bulgaria

1Laboratory of Molecular Pathology, University Hospital of Obstetrics and Gynaecology “Maichin Dom”, Sofia, 1431, Bulgaria

2Clinic of Abdominal Surgery, Queen Giovanna Hospital, Sofia, 1526, Bulgaria

3Department of Chemistry and Biochemistry, Medical University, Sofia, 1431, Bulgaria

© 2006 Versita Warsaw. This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License. (CC BY-NC-ND 3.0)

Citation Information: Open Medicine. Volume 1, Issue 2, Pages 128–135, ISSN (Online) 2391-5463, DOI: 10.2478/s11536-006-0013-z, June 2006

Publication History

Published Online:


Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant disease, caused by germline mutations in DNA mismatch-repair genes (MMR). These mutations lead to microsatellite instability (MSI). It has been found that the MSI is not confined to the setting of hereditary disease and may be seen in approximately 12-17% of the sporadic CRCs. In 1998 a National Registry for CRC was instituted in Queen Giovanna Hospital, Sofia. A total of 150 patients have been selected for MSI analysis and 25 tumors showed to be unstable, 14 with loss of heterozygosity (LOH). These tumors were further analyzed for MLH1 promoter hypermethylation and a significant association between this epigenetic change and MSI/LOH sporadic cases. We proposed this method as a step that follows the analysis for MSI and prior to the screening for MMR mutations. The mutation screening detected four known and two novel mutations, one unpublished and four known intronic polymorphisms in both hMLH1 and hMSH2 genes. The use of IHC analysis has been found effective in the investigation of some unclear molecular variations.

We developed an efficient diagnostic strategy for HNPCC testing and the mutation status of 80% MSI HNPCC cases could be detected.

Keywords: HNPCC; immunohistochemistry; hMLH1; hMSH2; MSI

  • [1] A. Jemal, T. Murray, E. Ward, A. Samuels, R.C. Tiwari, A. Ghafoor, E.J. Feuer and M.J. Thun: “Cancer statistics, 2005”, CA Cancer J. Clin., Vol. 55(1), (2005), pp. 10–30. http://dx.doi.org/10.3322/canjclin.55.1.10 [CrossRef]

  • [2] H.T. Lynch and A. de la Chapelle: “Genetic susceptibility to non-polyposis colorectal cancer”, J. Med. Genet., Vol. 36, (1999), pp. 801–818.

  • [3] P. Peltomaki and H.F. Vasen: “Mutations predisposing to hereditary nonpolyposis colorectal cancer, database and results of a collaborative study. The International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer”, Gastroenterology, Vol. 113, (1997), pp. 146–158. http://dx.doi.org/10.1053/gast.1997.v113.pm9322509 [CrossRef]

  • [4] Y. Ionov, M.A. Peinado, S. Malkhosyan, D. Shibata and M. Perucho: “Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis”, Nature, Vol. 363, (1993), pp. 558–561. http://dx.doi.org/10.1038/363558a0 [CrossRef]

  • [5] P.A. Jones and P.W. Laird: “Cancer epigenetics comes of age”, Nat. Genet., Vol. 21(2), (1999), pp. 163–167. http://dx.doi.org/10.1038/5947 [CrossRef]

  • [6] T. Kadiyska, M. Tzancheva, D. Nedin, A. Alexandrova, M. Marinov, R. Kaneva, D. Damyanov, V. Mitev and I. Kremensky: “MLH1 promoter hypermethylation in bulgarian patients with colorectal cancer”, BJMG, Vol. 6, (2003), pp. 3–8.

  • [7] C.R. Boland, S.N. Thibodeau, S.R. Hamilton, D. Sidransky, J.R. Eshleman, R.W. Burt, 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., Vol. 58, (1998), pp. 5248–5257.

  • [8] H. Hampel, W.L. Frankel, E. Martin, M. Arnold, K. Khanduja, P. Kuebler, H. Nakagawa, K. Sotamaa, T.W. Prior, J. Westman, J. Panescu, D. Fix, J. Lockman, I. Comeras and A. de la Chapelle: “Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer)”, N. Engl. J. Med., Vol. 352(18), (2005), pp. 1851–1860. http://dx.doi.org/10.1056/NEJMoa043146 [CrossRef]

  • [9] A. Percesepe, F. Borghi, M. Menigatti, L. Losi, M. Foroni, C. Di Gregorio, G. Rossi, M. Pedroni, E. Sala, F. Vaccina, L. Roncucci, P. Benatti, A. Viel, M. Genuardi, G. Marra, P. Kristo, P. Peltomaki and M. Ponz de Leon: “Molecular screening for hereditary nonpolyposis colorectal cancer: a prospective, population-based study”, J. Clin. Oncol., Vol. 19(19), (2001), pp. 3944–3950.

  • [10] R.A. Lothe, P. Peltomaki, G.I. Meling, L.A. Aaltonen, M. Nystrom-Lahti, L. Pylkkanen, K. Heimdal, T.I. Andersen, P. Moller and T.O. Rognum: “Genomic instability in colorectal cancer: relationship to clinicopathological variables and family history”, Cancer Res., Vol. 53(24), (1993), pp. 5849–5852.

  • [11] S.N. Thibodeau, A.J. French, J.M. Cunningham, D. Tester, L.J. Burgart, P.C. Roche, S.K. McDonnell, D.J. Schaid, C.W. Vockley, V.V. Michels, G.H. Farr and M.J. O’Connell: “Microsatellite instability in colorectal cancer: different mutator phenotypes and the principal involvement of hMLH1”, Cancer Res., Vol. 58, (1998), pp. 1713–1718.

  • [12] Y.M. Song and S. Zheng: “Analysis for phenotype of HNPCC in China”, World J. Gastroenterol., Vol. 8(5), (2002), pp. 837–840.

  • [13] J.G. Herman, A. Umar, K. Polyak, J.R. Graff, N. Ahuja, J.P. Issa, S. Markowitz, J.K. Willson, S.R. Hamilton, K.W. Kinzler, M.F. Kane, R.D. Kolodner, B. Vogelstein, T.A. Kunkel and S.B. Baylin: “Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma”, Proc. Natl. Acad. Sci. USA, Vol. 95(12), (1998), pp. 6870–6875. http://dx.doi.org/10.1073/pnas.95.12.6870 [CrossRef]

  • [14] J.M. Cunningham, E.R. Christensen, D.J. Tester, C.Y. Kim, P.C. Roche, L.J. Burgart and S.N. Thibodeau: “Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability”, Cancer Res., Vol. 58(15), (1998), pp. 3455–3460.

  • [15] M.L. Veigl, L. Kasturi, J. Olechnowicz, A.H. Ma, J.D. Lutterbaugh, S. Periyasamy, G.M. Li, J. Drummond, P.L. Modrich, W.D. Sedwick and S.D. Markowitz: “Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers”, Proc. Natl. Acad. Sci. USA, Vol. 95(15), (1998), pp. 8698–8702. http://dx.doi.org/10.1073/pnas.95.15.8698 [CrossRef]

  • [16] S. Ramchandani, A.R. MacLeod, M. Pinard, E. von Hofe, M. Szyf: “Inhibition of tumorigenesis by a cytosine-DNA, methyltransferase, antisense oligodeoxynucleotide”, Proc. Natl. Acad. Sci. USA, Vol. 94(2), (1997), pp. 684–689. http://dx.doi.org/10.1073/pnas.94.2.684 [CrossRef]

  • [17] K. Drotschmann, A.B. Clark, H.T. Tran, M.A. Resnick, D.A. Gordenin and T.A. Kunkel: “Mutator phenotypes of yeast strains heterozygous for mutations in the MSH2 gene”, Proc. Natl. Acad. Sci. USA, Vol. 96(6), (1999), pp. 2970–2975. http://dx.doi.org/10.1073/pnas.96.6.2970 [CrossRef]

Citing Articles

Here you can find all Crossref-listed publications in which this article is cited. If you would like to receive automatic email messages as soon as this article is cited in other publications, simply activate the “Citation Alert” on the top of this page.

Tanya K. Kadiyska, Darina V. Konstantinova, Venceslav R. Atanasov, Ivo M. Kremensky, and Vanio I. Mitev
Cancer Detection and Prevention, 2007, Volume 31, Number 3, Page 254

Comments (0)

Please log in or register to comment.