Familial Cancer

, Volume 4, Issue 3, pp 227–232 | Cite as

Lynch Syndrome Genes

  • Päivi PeltomäkiEmail author


Since the discovery of the major human genes with DNA mismatch repair (MMR) function in 1993--1995, mutations in four, MSH2, MLH1, MSH6, and PMS2, have been convincingly linked to susceptibility of hereditary nonpolyposis colorectal cancer (HNPCC)/Lynch syndrome. Among these, PMS2 mutations are associated with diverse clinical features, including those of the Turcot syndrome. Two additional MMR genes, MLH3 and PMS1, have also been proposed to play a role in Lynch syndrome predisposition, but the clinical significance of mutations in these genes is less clear. According to the database maintained by the International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer (ICG-HNPCC), current InSiGHT (International Society for Gastrointestinal Hereditary Tumors), approximately 500 different HNPCC-associated MMR gene mutations are known that primarily involve MLH1 (~50%), MSH2 (~40%), and MSH6 (~10%). Examination of HNPCC/Lynch syndrome-associated MMR genes and their mutations has revealed several other important functions for their protein products beyond postreplicative mismatch repair as well as many alternative mechanisms of pathogenicity. Despite these advances, much is yet to be learned about the molecular basis of correlations between genetic changes and clinical features of the disease.


hereditary nonpolyposis colorectal cancer MLH1 MLH3 MSH2 MSH6 PMS2 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Cox, EC 1976Bacterial mutator genes and the control of spontaneous mutation.Annu Rev Genet1013556CrossRefPubMedGoogle Scholar
  2. Strand, M, Prolla, TA, Liskay, RM, Petes, TD 1993Destabilization of tracts of simple repetitive DNA in yeast by mutations affecting DNA mismatch repair.Nature3652746CrossRefPubMedGoogle Scholar
  3. Kolodner, RD, Marsischky, GT 1999Eukaryotic DNA mismatch repair.Curr Opin Genet Devel98996CrossRefGoogle Scholar
  4. Jiricny, J, Nyström-Lahti, M 2000Mismatch repair defects in cancer.Curr Opin Genet Devel1015761CrossRefGoogle Scholar
  5. Marti, TM, Kunz, C, Fleck, O 2002DNA mismatch repair and mutation avoidance pathways.J Cell Physiol1912841CrossRefPubMedGoogle Scholar
  6. Peltomäki, P, Vasen, H 2004Mutations associated with HNPCC predisposition–Update of ICG-HNPCC/InSiGHT mutation database.Dis Markers2026976PubMedGoogle Scholar
  7. Fishel, R 2001The selection for mismatch repair defects in hereditary nonpolyposis colorectal cancer: Revising the mutator hypothesis.Cancer Res61736974PubMedGoogle Scholar
  8. Peltomäki, P, Aaltonen, LA, Sistonen, P,  et al. 1993Genetic mapping of a locus predisposing to human colorectal cancer.Science26081012PubMedGoogle Scholar
  9. Fishel, R, Lescoe, MK, Rao, MRS,  et al. 1993The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer.Cell75102738CrossRefPubMedGoogle Scholar
  10. Leach, FS, Nicolaides, NC, Papadopoulos, N,  et al. 1993Mutations of a MutS homolog in hereditary non-polyposis colorectal cancer.Cell75121525CrossRefPubMedGoogle Scholar
  11. Drummond, JT, Li, G-M, Longley, MJ, Modrich, P 1995Isolation of an hMSH2-p160 heterodimer that restores DNA mismatch repair to tumor cells.Science268190912PubMedGoogle Scholar
  12. Palombo, F, Gallinari, P, Iaccarino, I,  et al. 1995GTBP, a 160-kilodalton protein essential for mismatch-binding activity in human cells.Science26819124PubMedGoogle Scholar
  13. Iaccarino, I, Marra, G, Palombo, F, Jiricny, J 1998hMSH2 and hMSH6 play distinct roles in mismatch binding and contribute differently to the ATPase activity of hMutSα.EMBO J17267786CrossRefPubMedGoogle Scholar
  14. Schmutte, C, Marinescu, RC, Copeland, NG,  et al. 1998Refined chromosomal localization of the mismatch repair and hereditary nonpolyposis colorectal cancer genes hMSH2 and hMSH6.Cancer Res5850236PubMedGoogle Scholar
  15. Edelmann, W, Yang, K, Umar, A,  et al. 1997Mutation in the mismatch repair gene Msh6 causes cancer susceptibility.Cell9146777CrossRefPubMedGoogle Scholar
  16. Akiyama, Y, Sato, H, Yamada, T,  et al. 1997Germ-line mutation of the hMSH6/GTBP gene in an atypical hereditary nonpolyposis colorectal cancer kindred.Cancer Res5739203PubMedGoogle Scholar
  17. Miyaki, M, Konishi, M, Tanaka, K,  et al. 1997Germline mutation of MSH6 as the cause of hereditary nonpolyposis colorectal cancer.Nat Genet172712PubMedGoogle Scholar
  18. Wu, Y, Berends, MJW, Mensink, RGJ,  et al. 1999Association of hereditary nonpolyposis colorectal cancer-related tumors displaying low microsatellite instability with MSH6 germline mutations.Am J Hum Genet6512918CrossRefPubMedGoogle Scholar
  19. Fujii, H, Shimada, T 1989Isolation and characterization of cDNA clones derived from the divergently transcribed gene in the region upstream from the human dihydrofolate reductase gene.J Biol Chem2641005764PubMedGoogle Scholar
  20. Watanabe, A, Ikejima, M, Suzuki, N, Shimada, T 1996Genomic organization and expression of the human MSH3 gene.Genomics313118CrossRefPubMedGoogle Scholar
  21. Marsischky, GT, Kolodner, RD 1996Redundancy of Saccharomyces cerevisiae MSH3 and MSH6 in MSH2-dependent mismatch repair.Genes Dev1040720PubMedGoogle Scholar
  22. Genschel, J, Littman, SJ, Drummond, JT, Modrich, P 1998Isolation of MutSβ from human cells and comparison of the mismatch repair specificities of MutSβ and MutSα.J Biol Chem27319895901CrossRefPubMedGoogle Scholar
  23. Malkhosyan, S, Rampino, N, Yamamoto, H, Perucho, M 1996Frameshift mutator mutations.Nature382499500CrossRefPubMedGoogle Scholar
  24. de, Wind N, Dekker, M, Claij, N,  et al. 1999HNPCC-like cancer predisposition in mice through simultaneous loss of Msh3 and Msh6 mismatch-repair protein functions.Nat Genet2335962CrossRefPubMedGoogle Scholar
  25. Plaschke, J, Kruger, S, Jeske, B,  et al. 2004Loss of MSH3 protein expression is frequent in MLH1-deficient colorectal cancer and is associated with disease progression.Cancer Res6486470PubMedGoogle Scholar
  26. Huang, J, Kuismanen, SA, Liu, T,  et al. 2001MSH6 and MSH3 are rarely involved in genetic predisposition to non-polypotic colon cancer.Cancer Res61161923PubMedGoogle Scholar
  27. Ohmiya, N, Matsumoto, S, Yamamoto, H,  et al. 2001Germline and somatic mutations in hMSH6 and hMSH3 in gastrointestinal cancers of the microsatellite mutator phenotype.Gene27230113CrossRefPubMedGoogle Scholar
  28. Paquis-Flucklinger, V, Santucci-Darmanin, S, Paul, R 1997Cloning and expression analysis of a meiosis-specific MutS homolog: The human MSH4 gene.Genomics4418894CrossRefPubMedGoogle Scholar
  29. Winand, NJ, Panzer, JA, Kolodner, RD 1998Cloning and characterization of the human and Caenorhabditis elegans homologs of the Saccharomyces cerevisiae MSH5 gene.Genomics536980CrossRefPubMedGoogle Scholar
  30. Kubota, T, Dakeishi, M, Nozaki, J,  et al. 2000Probable involvement of a germ-line mutation of an unknown mismatch repair gene in a Japanese Muir–Torre syndrome phenotype.J Dermatol Sci2311725CrossRefPubMedGoogle Scholar
  31. Mason, PA, Matheson, EC, Hall, AG, Lightowlers, RN 2003Mismatch repair activity in mammalian mitochondria.Nucl Acids Res3110528CrossRefPubMedGoogle Scholar
  32. Lindblom, A, Tannergård, P, Werelius, B, Nordenskjöld, M 1993Genetic mapping of a second locus predisposing to hereditary non-polyposis colon cancer.Nat Genet527982Google Scholar
  33. Tannergård, P, Zabarovsky, E, Stanbridge, E,  et al. 1994Sublocalization of a locus at 3p21.3-23 predisposing to hereditary nonpolyposis colon cancer.Hum Genet942104PubMedGoogle Scholar
  34. Papadopoulos, N, Nicolaides, NC, Wei, Y-F 1994Mutation of a mutL homolog is associated with hereditary colon cancer.Science26316259PubMedGoogle Scholar
  35. Bronner, CE, Baker, SM, Morrison, PT,  et al. 1994Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer.Nature36825861CrossRefPubMedGoogle Scholar
  36. Nicolaides, NC, Papadopoulos, N, Liu, B,  et al. 1994Mutations in two PMS homologues in hereditary nonpolyposis colon cancer.Nature3717580Google Scholar
  37. Hamilton, SR, Liu, B, Parsons, RE,  et al. 1995The molecular basis of Turcot’s syndrome.N Engl J Med33283947CrossRefPubMedGoogle Scholar
  38. Miyaki, M, Nishio, J, Konishi, M,  et al. 1997Drastic genetic instability of tumors and normal tissues in Turcot syndrome.Oncogene15287781CrossRefPubMedGoogle Scholar
  39. De, Rosa M, Fasano, C, Panariello, L,  et al. 2000Evidence for a recessive inheritance of Turcot’s syndrome caused by compound heterozygous mutations within the PMS2 gene.Oncogene19171923CrossRefPubMedGoogle Scholar
  40. Liu, T, Yan, H, Kuismanen, S,  et al. 2001The role of hPMS1 and hPMS2 in predisposing to colorectal cancer.Cancer Res617798802PubMedGoogle Scholar
  41. Nakagawa, H, Lockman, JC, Frankel, WL,  et al. 2004Mismatch repair gene PMS2: Disease-causing germline mutations are frequent in patients whose tumors stain negative for PMS2 protein, but paralogous genes obscure mutation detection and interpretation.Cancer Res6447217PubMedGoogle Scholar
  42. De, Vos M, Hayward, BE, Picton, S,  et al. 2004Novel PMS2 pseudogenes can conceal recessive mutations causing a distinctive childhood cancer syndrome.Am J Hum Genet7495464CrossRefPubMedGoogle Scholar
  43. Harfe, BD, Jinks-Robertson, S 2000DNA mismatch repair and genetic instability.Annu Rev Genet343599CrossRefPubMedGoogle Scholar
  44. Shimodaira, H, Yoshioka-Yamashita, A, Kolodner, RD, Wang, JY 2003Interaction of mismatch repair protein PMS2 and the p53-related transcription factor p73 in apoptosis response to cisplatin.Proc Natl Acad Sci USA10024205CrossRefPubMedGoogle Scholar
  45. Prolla, TA, Baker, SM, Harris, AC,  et al. 1998Tumour susceptibility and spontaneous mutation in mice deficient in Mlh1, Pms1 and Pms2 DNA mismatch repair.Nat Genet182769CrossRefPubMedGoogle Scholar
  46. Räschle, M, Marra, G, Nyström-Lahti, M,  et al. 1999Identification of hMutLβ, a heterodimer of hMLH1 and hPMS1.J Biol Chem53236875CrossRefGoogle Scholar
  47. Lipkin, SM, Wang, V, Jacoby, R, Banerjee-Basu, S,  et al. 2000MLH3: A DNA mismatch repair gene associated with mammalian microsatellite instability.Nat Genet242735CrossRefPubMedGoogle Scholar
  48. Flores-Rozas, H, Kolodner, RD 1998The Saccharomyces cerevisiae MLH3 gene functions in MSH3-dependent suppression of frameshift mutations.Proc Natl Acad Sci USA95124049CrossRefPubMedGoogle Scholar
  49. Lipkin, SM, Moens, PB, Wang, V,  et al. 2002Meiotic arrest and aneuploidy in MLH3-deficient mice.Nat Genet3138590PubMedGoogle Scholar
  50. Wu, Y, Berends, MJW, Sijmons, RH,  et al. 2001A role for MLH3 in hereditary nonpolyposis colorectal cancer.Nat Genet291378CrossRefPubMedGoogle Scholar
  51. Liu, HX, Zhou, X-L, Liu, T,  et al. 2003The role of hMLH3 in familial colorectal cancer.Cancer Res6318949PubMedGoogle Scholar
  52. Loukola, A, Vilkki, S, Singh, J 2000Germline and somatic mutation analysis of MLH3 in MSI-positive colorectal cancer.Am J Pathol15734752PubMedGoogle Scholar
  53. Lipkin, SM, Wang, V, Stoler, DL,  et al. 2001Germline and somatic mutation analyses in the DNA mismatch repair gene MLH3: Evidence for somatic mutation in colorectal cancers.Hum Mut1738996CrossRefPubMedGoogle Scholar
  54. Hienonen, T, Laiho, P, Salovaara, R,  et al. 2003Little evidence for involvement of MLH3 in colorectal cancer predisposition.Int J Cancer1062926CrossRefPubMedGoogle Scholar
  55. Ionov, Y, Peinado, MA, Malkhosyan, S,  et al. 1993Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis.Nature36355861CrossRefPubMedGoogle Scholar
  56. Thibodeau, SN, Bren, G, Schaid, D 1993Microsatellite instability in cancer of the proximal colon.Science2608169PubMedGoogle Scholar
  57. Aaltonen, LA, Peltomäki, P, Leach, FS,  et al. 1993Clues to the pathogenesis of familial colorectal cancer.Science2608126PubMedGoogle Scholar
  58. Boland, CR, Thibodeau, SN, Hamilton, SR,  et al. 1998A 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 Res58524857PubMedGoogle Scholar
  59. Chang, DK, Ricciardello, L, Goel, A,  et al. 2000Steady-state regulation of the human DNA mismatch repair system.J Biol Chem2751842431Google Scholar
  60. Schweizer, P, Moisio, A-L, Kuismanen, SA,  et al. 2001Lack of MSH2 and MSH6 characterizes endometrial but not colon carcinomas in hereditary nonpolyposis colorectal cancer.Cancer Res6128135PubMedGoogle Scholar
  61. Plaschke, J, Krüger, S, Pistorius, S,  et al. 2002Involvement of hMSH6 in the development of hereditary and sporadic colorectal cancer revealed by immunostaining is based on germline mutations, but rarely on somatic inactivation.Int J Cancer976438CrossRefPubMedGoogle Scholar
  62. Buttin, BM, Powell, MA, Mutch, DG,  et al. 2004Penetrance and expressivity of MSH6 germline mutations in seven kindreds not ascertained by family history.Am J Hum Genet7412629CrossRefPubMedGoogle Scholar
  63. Hendriks, YMC, Wagner, A, Morreau, H,  et al. 2004Cancer risk in hereditary nonpolyposis colorectal cancer due to MSH6 mutations: Impact on counseling and surveillance.Gastroenterology1271725CrossRefPubMedGoogle Scholar
  64. Berends, MJW, Wu, Y, Sijmons, RH,  et al. 2002Molecular and clinical characteristics of MSH6 variants: An analysis of 25 index carriers of a germline variant.Am J Hum Genet702637CrossRefPubMedGoogle Scholar
  65. Wijnen, J, de, Leeuw W, Vasen, H,  et al. 1999Familial endometrial cancer in female carriers of MSH6 germline mutations.Nat Genet231424CrossRefPubMedGoogle Scholar
  66. Verma, L, Kane, MF, Brassett, C,  et al. 1999Mononucleotide microsatellite instability and germline MSH6 mutation analysis in early onset colorectal cancer.J Med Genet3667882PubMedGoogle Scholar
  67. Plaschke, J, Kruppa, C, Tischler, R,  et al. 2000Sequence analysis of the mismatch repair gene hMSH6 in the germline of patients with familial and sporadic colorectal cancer.Int J Cancer8560613CrossRefPubMedGoogle Scholar
  68. Risinger, JI, Umar, A, Glaab, WE,  et al. 1998Single gene complementation of the hPMS2 defect in HEC-1-A endometrial carcinoma cells.Cancer Res58297881PubMedGoogle Scholar
  69. Parsons, R, Li, G-M, Longley, M,  et al. 1995Mismatch repair deficiency in phenotypically normal cells.Science26873840PubMedGoogle Scholar
  70. Vasen, HFA, Mecklin, J-P, Khan, PM, Lynch, HT 1991The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC).Dis Colon Rectum344245CrossRefPubMedGoogle Scholar
  71. Aarnio, M, Mecklin, J-P, Aaltonen, LA,  et al. 1995Life-time risk of different cancers in hereditary non-polyposis colorectal cancer (HNPCC) syndrome.Int J Cancer (Pred Oncol)644303Google Scholar
  72. Dunlop, MG, Farrington, SM, Carothers, AD,  et al. 1997Cancer risk associated with germline DNA-mismatch-repair gene mutation.Hum Mol Genet610510CrossRefPubMedGoogle Scholar
  73. Vasen, HFA, Stormorken, A, Menko, FH,  et al. 2001MSH2 mutation carriers are at higher risk of cancer than MLH1 mutation carriers: A study of hereditary nonpolyposis colorectal cancer families.J Clin Oncol19407480PubMedGoogle Scholar
  74. Peltomäki, P, Gao, X, Mecklin, J-P 2001Genotype and phenotype in hereditary nonpolyposis colon cancer: A study of families with different vs.shared predisposing mutations. Fam Cancer1915CrossRefGoogle Scholar
  75. Wagner, A, Hendriks, Y, Meijers-Heijboer, EJ,  et al. 2001Atypical HNPCC owing to MSH6 germline mutations: Analysis of a large Dutch pedigree.J Med Genet3831822Google Scholar
  76. Vasen, HFA, Wijnen, JT, Menko, FH,  et al. 1996Cancer risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis.Gastroenterology11010207PubMedGoogle Scholar
  77. Mangold, E, Pagenstecher, C, Leister, M,  et al. 2004A genotype–phenotype correlation in HNPCC: Strong predominance of msh2 mutations in 41 patients with Muir–Torre syndrome.J Med Genet4156772CrossRefPubMedGoogle Scholar
  78. Stefansson, I, Akslen, LA, MacDonald, N,  et al. 2002Loss of hMSH2 and hMSH6 expression is frequent in sporadic endometrial carcinomas with microsatellite instability: A population-based study.Clin Cancer Res813843PubMedGoogle Scholar
  79. Bellacosa, A 2001Functional interactions and signaling properties of mammalian DNA mismatch repair proteins.Cell Death Differ8107692CrossRefPubMedGoogle Scholar
  80. Shimodaira, H, Filosi, N, Shibata, H,  et al. 1998Functional analysis of human MLH1 mutations in Saccharomyces cerevisiae.Nat Genet193849CrossRefPubMedGoogle Scholar
  81. Ellison, AR, Lofing, J, Bitter, GA 2001Functional analysis of human MLH1 and MSH2 missense variants and hybrid human-yeast MLH1 proteins in Saccharomyces cerevisiae.Hum Mol Genet101889900CrossRefPubMedGoogle Scholar
  82. Nyström-Lahti, M, Perrera, C, Raschle, M 2005Functional analysis of MLH1 mutations linked to hereditary nonpolyposis colon cancerGenes Chrom Cancer 331607Google Scholar
  83. Trojan, J, Zeuzem, S, Randolph, A,  et al. 2002Functional analysis of hMLH1 variants and HNPCC-related mutations using a human expression system.Gastroenterology1222119CrossRefPubMedGoogle Scholar
  84. Kariola, R, Raevaara, T, Lönnqvist, KE, Nyström-Lahti, M 2002Functional analysis of MSH6 mutations linked to kindreds with putative hereditary non-polyposis colorectal cancer syndrome.Hum Mol Genet11130310CrossRefPubMedGoogle Scholar
  85. Raevaara, TE, Vaccaro, C, Abdel-Rahman, WM,  et al. 2003Pathogenicity of the hereditary colorectal cancer mutation hMLH1 del616 linked to shortage of the functional protein.Gastroenterology1255019CrossRefPubMedGoogle Scholar
  86. Cejka, P, Stojik, L, Mojas, N,  et al. 2003Methylation-induced G2/M arrest requires a full complement of the mismatch repair protein hMLH1.EMBO J22224554CrossRefPubMedGoogle Scholar

Copyright information

© Springer 2005

Authors and Affiliations

  1. 1.Department of Medical Genetics, Biomedicum HelsinkiUniversity of HelsinkiFinland

Personalised recommendations