Familial Cancer

, 4:285 | Cite as

MLH1 and MSH2 Mutations in Colombian Families with Hereditary Nonpolyposis Colorectal Cancer (Lynch syndrome) – Description of Four Novel Mutations

  • Alejandro Giraldo
  • Andrea Gómez
  • Gustavo Salguero
  • Herbert García
  • Fabio Aristizábal
  • Óscar Gutiérrez
  • Luis Alberto Ángel
  • Jorge Padrón
  • Carlos Martínez
  • Humberto Martínez
  • Omar Malaver
  • Luis Flórez
  • Rosa Barvo


This study searched for mutations in the MLH1 and MSH2 genes in 23 unrelated Colombian families with suspected hereditary nonpolyposis colorectal cancer (HNPCC). The families were grouped according to the fulfillment of the Amsterdam II criteria or the Bethesda guidelines. We screened all probands by single-strand conformational polymorphism (SSCP) and direct DNA sequencing. Eleven families fulfilled the Amsterdam criteria II and 12 families the Bethesda guidelines. Germline mutations were detected in 11 families, which corresponds to a mutation detection rate of 48%. When only families fulfilling the Amsterdam II criteria were analyzed, the mutation detection rate rose to 82%. Only 8% of the mutation detection rate was found in families following the Bethesda guidelines. Three mutations were shared by two different families, which corresponds to a total of eight different mutations, seven of them found in the MLH1 gene and one in the MSH2 gene. We have identified four mutations that have not been previously reported to the International Collaborative Group of HNPCC. Three of these are pathogenic, a single base substitution (C > T) at codon 640, exon 17, a G deletion at codon 619, exon 16 and in the MLH1 gene and a two-nucleotide deletion (TG) at codon 184, exon 3 in the MSH2. Also, an unclassified variant, a substitution (C > G) at the codon 141, exon 5 of the MLH1, was detected.


Colombian families familial cancer HNPCC Lynch syndrome MLH1 MSH2 


  1. 1.
    Peto, J 2001Cancer epidemiology in the last century and the next decadeNature4113905CrossRefPubMedGoogle Scholar
  2. 2.
    Anderson, WF, Umar, A, Brawley, OW 2003Colorectal carcinoma in black and white raceCancer Metastasis Rev226782CrossRefPubMedGoogle Scholar
  3. 3.
    Jemal, A, Tiwari, RC, Murray, T 2004Cancer statistics, 2004CACancer J Clin54829CrossRefGoogle Scholar
  4. 4.
    Angel, LA, Giraldo, A, Pardo, CE 2004Mortalidad por cánceres del aparato digestivo en Colombia entre 1980 y 1998. Análisis de tendencias y comparación regionalRev Fac Medicina (Universidad Nacional de Colombia)521937Google Scholar
  5. 5.
    GLOBOCAN. Cancer Incidence, Mortality and Prevalence Worldwide. http://www-dep.iarc.fr/globocan/globocan.html 2000.
  6. 6.
    Lynch, HT, la Chapelle, A 1999Genetic susceptibility to non-polyposis colorectal cancerJ Med Genet3680118PubMedGoogle Scholar
  7. 7.
    Wijnen, JT, Vasen, HF, Khan, PM 1998Clinical findings with implications for genetic testing in families with clustering of colorectal cancerN Engl J Med3395118CrossRefPubMedGoogle Scholar
  8. 8.
    Aaltonen, LA, Salovaara, R, Kristo, P 1998Incidence of hereditary nonpolyposis colorectal cancer and the feasibility of molecular screening for the diseaseN Engl J Med33814817CrossRefPubMedGoogle Scholar
  9. 9.
    Vasen, HFA, Watson, P, Mecklin, JP 1999New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch Syndrome) proposed by the International Collaborative Group on HNPCCGastroenterology11614536CrossRefPubMedGoogle Scholar
  10. 10.
    Umar, A, Boland, CR, Terdiman, JP 2004Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instabilityJ Natl Cancer Inst962618PubMedGoogle Scholar
  11. 11.
    la Chapelle, A 2003Inherited human diseases: Victories, challenges, disappointmentsAm J Hum Genet7223640Google Scholar
  12. 12.
    Ramsey, SD, Burke, W, Clarke, L 2003An economic viewpoint on alternative strategies for identifying persons with hereditary nonpolyposis colorectal cancerGenet Med535363PubMedCrossRefGoogle Scholar
  13. 13.
    Miller, SA, Dykes, DD, Polesky, HF 1988A simple salting out procedure for extracting DNA from human nucleated cellsNucleic Acid Res161215PubMedGoogle Scholar
  14. 14.
    Weber, TK, Conlon, W, Petrelli, NJ 1997Genomic DNA-based hMSH2 and hMLH1 mutation screening in 32 Eastern United States hereditary nonpolyposis colorectal cancer pedigreesCancer Res5737983803PubMedGoogle Scholar
  15. 15.
    Beck, NE, Tomlinson, IP, Homfray, T 1997Use of SSCP analysis to identify germline mutations in HNPCC families fulfilling the Amsterdam criteriaHum Genet9921924CrossRefPubMedGoogle Scholar
  16. 16.
    Bateman, A, Coin, L, Durbin, R 2004The Pfam protein families databaseNucleic Acids Res32D13841CrossRefPubMedGoogle Scholar
  17. 17.
    Apweiler, R, Bairoch, A, Wu, CH 2004UniProt: The universal protein knowledgebaseNucleic Acids Res32D1159CrossRefPubMedGoogle Scholar
  18. 18.
    Yuan, J, Amend, A, Borkowski, J 1999MULTICLUSTAL: A systematic method for surveying Clustal W alignment parametersBioinformatics158623CrossRefPubMedGoogle Scholar
  19. 19.
    Thompson, JD, Gibson, TJ, Plewniak, F 1997The CLUSTAL_X windows interface: Flexible strategies for multiple sequence alignment aided by quality analysis toolsNucleic Acids Res25487682CrossRefPubMedGoogle Scholar
  20. 20.
    Rossi, BM, Lopes, A, Oliveira Ferreira, F 2002hMLH1 and hMSH2 gene mutation in Brazilian families with suspected hereditary nonpolyposis colorectal cancerAnn Surg Oncol955561CrossRefPubMedGoogle Scholar
  21. 21.
    Sarroca, C, Peltomäki, P, Alfano, N 2003Three new mutations in hereditary nonpolyposis colorectal cancer (Lynch syndrome II) in UruguayCancer Genet Cytogenet1421320CrossRefPubMedGoogle Scholar
  22. 22.
    Tannergard, P, Lipford, JR, Kolodner, R 1995Mutation screening in the hMLH1 gene in Swedish hereditary nonpolyposis colon cancer familiesCancer Res5560926PubMedGoogle Scholar
  23. 23.
    Nystrom-Lahti, M, Wu, Y, Moisio, AL 1996DNA mismatch repair gene mutations in 55 kindreds with verified or putative hereditary nonpolyposis colorectal cancerHum Mol Genet57639CrossRefPubMedGoogle Scholar
  24. 24.
    Viel, A, Genuardi, M, Capozzi, E 1997Characterization of MSH2 and MLH1 mutations in Italian families with hereditary nonpolyposis colorectal cancerGenes Chromosom Cancer18818CrossRefPubMedGoogle Scholar
  25. 25.
    Lynch, HT, Watson, P, Shaw, TG 1999Clinical impact of molecular genetic diagnosis, genetic counseling, and management of hereditary cancer, Part I: Studies of cancer in familiesCancer86244956PubMedGoogle Scholar
  26. 26.
    Caldes, T, Godino, J, Hoya, M 2002Prevalence of germline mutations of MLH1 and MSH2 in hereditary nonpolyposis colorectal cancer families from SpainInt J Cancer987749CrossRefPubMedGoogle Scholar
  27. 27.
    Ban, C, Yang, W 1998Crystal structure and ATPase activity of MutL: Implications for DNA repair and mutagenesisCell9554152CrossRefPubMedGoogle Scholar
  28. 28.
    Ban, C, Junop, M, Yang, W 1999Transformation of MutL by ATP binding and hydrolysis: A switch in DNA mismatch repairCell978597CrossRefPubMedGoogle Scholar
  29. 29.
    Prodromou, C, Panaretou, B, Chohan, S 2000The ATPase cycle of Hsp90 drives a molecular ‘clamp’ via transient dimerization of the N-terminal domainsEMBO J.19438392CrossRefPubMedGoogle Scholar
  30. 30.
    Brino, L, Urzhumtsev, A, Mousli, M 2000Dimerization of Escherichia coli DNA-gyrase B provides a structural mechanism for activating the ATPase catalytic centerJ Biol Chem275946875CrossRefPubMedGoogle Scholar
  31. 31.
    Hackman, P, Tannergard, P, Osei-Mensa, S 1997A human compound heterozygote for two MLH1 missense mutationsNat Genet171356CrossRefPubMedGoogle Scholar
  32. 32.
    Wang, Q, Lasset, C, Desseigne, F 1999Neurofibromatosis and early onset of cancers in hMLH1-deficient childrenCancer Res592947PubMedGoogle Scholar
  33. 33.
    Ricciardone, MD, Ozcelik, T, Cevher, B 1999Human MLH1 deficiency predisposes to hematological malignancy and neurofibromatosis type 1Cancer Res59290PubMedGoogle Scholar
  34. 34.
    Vilkki, S, Tsao, JL, Loukola, A 2001Extensive somatic microsatellite␣mutations in normal human tissueCancer Res6145414PubMedGoogle Scholar
  35. 35.
    Nystrom-Lahti, M, Sistonen, P, Mecklin, JP 1994Close linkage to chromosome 3p and conservation of ancestral founding haplotype in hereditary nonpolyposis colorectal cancer familiesProc Natl Acad Sci USA9160548PubMedGoogle Scholar
  36. 36.
    Moisio, AL, Sistonen, P, Weissenbach, J 1996Age and origin of two common MLH1 mutations predisposing to hereditary colon cancerAm J Hum Genet59124351PubMedGoogle Scholar
  37. 37.
    Hutter, P, Couturier, A, Membrez, V 1998Excess of hMLH1 germline mutations in Swiss families with hereditary non-polyposis colorectal cancerInt J Cancer786804CrossRefPubMedGoogle Scholar
  38. 38.
    Wagner, A, Barrows, A, Wijnen, JT 2003Molecular analysis of hereditary nonpolyposis colorectal cancer in the United States: high mutation detection rate among clinically selected families and characterization of an American founder genomic deletion of the MSH2 geneAm J Hum Genet7210881100CrossRefPubMedGoogle Scholar
  39. 39.
    Lynch, HT, Coronel, SM, Okimoto, R 2004A founder mutation of the MSH2 gene and hereditary nonpolyposis colorectal cancer in the United StatesJAMA29171824CrossRefPubMedGoogle Scholar
  40. 40.
    Han, HJ, Yuan, Y, Ku, JL 1996Germline mutations of hMLH1 and hMSH2 genes in Korean hereditary nonpolyposis colorectal cancerJ Natl Cancer Inst8813179PubMedGoogle Scholar
  41. 41.
    Bai, YQ, Akiyama, Y, Nagasaki, H 1999Predominant germ-line mutation of the hMSH2 gene in Japanese hereditary non-polyposis colorectal cancer kindredsInt J Cancer825125CrossRefPubMedGoogle Scholar
  42. 42.
    Wang, Q, Lasset, C, Desseigne, F 1999Prevalence of germline mutations of hMLH1, hMSH2, hPMS1, hPMS2, and hMSH6 genes in 75 French kindreds with nonpolyposis colorectal cancerHum Genet1057985CrossRefPubMedGoogle Scholar
  43. 43.
    Taylor, CF, Charlton, RS, Burn, J 2003Genomic deletions in MSH2 or MLH1 are a frequent cause of hereditary non-polyposis colorectal cancer: identification of novel and recurrent deletions by MLPAHum Mut2242833PubMedGoogle Scholar

Copyright information

© Springer 2005

Authors and Affiliations

  • Alejandro Giraldo
    • 1
    • 2
  • Andrea Gómez
    • 1
  • Gustavo Salguero
    • 1
  • Herbert García
    • 1
  • Fabio Aristizábal
    • 3
  • Óscar Gutiérrez
    • 1
  • Luis Alberto Ángel
    • 1
  • Jorge Padrón
    • 4
  • Carlos Martínez
    • 5
  • Humberto Martínez
    • 6
  • Omar Malaver
    • 7
  • Luis Flórez
    • 8
  • Rosa Barvo
    • 9
  1. 1.School of Medicine and Genetics Institute, Of. 214, Instituto de GenéticaUniversidad Nacional de ColombiaBogotáColombia
  2. 2.Arthur Stanley Gillow FoundationBogotáColombia
  3. 3.Department of Pharmacy and Biotechnology InstituteUniversidad Nacional de ColombiaBogotáColombia
  4. 4.School of MedicineUniversidad del RosarioBogotáColombia
  5. 5.Coloproctology UnitHospital Militar CentralBogotáColombia
  6. 6.Department of SurgeryHospital de la PolicíaColombia
  7. 7.Department of SurgeryClínica San Pedro ClaverBogotáColombia
  8. 8.Department of SurgeryHospital de San JoséBogotáColombia
  9. 9.Gastroenterology UnitClinica La AsunciónBarranquillaColombia

Personalised recommendations