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Genetic and genomic basis of the mismatch repair system involved in Lynch syndrome

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A Correction to this article was published on 31 July 2019

This article has been updated

Abstract

Lynch syndrome is a cancer-predisposing syndrome inherited in an autosomal-dominant manner, wherein colon cancer and endometrial cancer develop frequently in the family, it results from a loss-of-function mutation in one of four different genes (MLH1, MSH2, MSH6, and PMS2) encoding mismatch repair proteins. Being located immediately upstream of the MSH2 gene, EPCAM abnormalities can affect MSH2 and cause Lynch syndrome. Mismatch repair proteins are involved in repairing of incorrect pairing (point mutations and deletion/insertion of simple repetitive sequences, so-called microsatellites) that can arise during DNA replication. MSH2 forms heterodimers with MSH6 or MSH3 (MutSα, MutSβ, respectively) and is involved in mismatch-pair recognition and initiation of repair. MLH1 forms a complex with PMS2, and functions as an endonuclease. If the mismatch repair system is thoroughly working, genome integrity is maintained completely. Lynch syndrome is a state of mismatch repair deficiency due to a monoallelic abnormality of any mismatch repair genes. The phenotype indicating the mismatch repair deficiency can be frequently shown as a microsatellite instability in tumors. Children with germline biallelic mismatch repair gene abnormalities were reported to develop conditions such as gastrointestinal polyposis, colorectal cancer, brain cancer, leukemia, etc., and so on, demonstrating the need to respond with new concepts in genetic counseling. In promoting cancer genome medicine in a new era, such as by utilizing immune checkpoints, it is important to understand the genetic and genomic molecular background, including the status of mismatch repair deficiency.

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Change history

  • 31 July 2019

    In the original publication, part d of Figure 2 was mistakenly not included.

Abbreviations

MMR:

Mismatch repair

MSI:

Microsatellite instability

PCNA:

Proliferating cellular nuclear antigen

RFC:

Replication factor

CTE:

Congenital tufting enteropathy

CMMR-D:

Constitutional mismatch repair deficiency

CNS:

Central nervous system

IHC:

Immunohistochemical staining

MLPA:

Multiple ligation-dependent probe amplification

CTLA-4:

Cytotoxic T-lymphocyte-associated protein 4

PD-1:

Programmed cell death protein 1

TMB:

Tumor mutational burden

ICI:

Immune checkpoint inhibitor

References

  1. Vogelstein B, Fearon ER, Hamilton SR et al (1988) Genetic alterations during colorectal-tumor development. N Engl J Med 319:525–532

    CAS  PubMed  Google Scholar 

  2. Fearon ER, Vogelstein B (1990) A genetic model for colorectal tumorigenesis. Cell 61:759–767

    CAS  PubMed  Google Scholar 

  3. Bodmer W, Bishop T, Karran P (1994) Genetic steps in colorectal cancer. Nature Genet 6:217–219

    CAS  PubMed  Google Scholar 

  4. Kinzler KW, Vogelstein B (1996) Lessons from hereditary colorectal cancer. Cell 87:159–170

    CAS  PubMed  Google Scholar 

  5. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674

    CAS  PubMed  Google Scholar 

  6. Tamura K, Utsunomiya J, Iwama T et al (2004) Mechanism of carcinogenesis in familial tumors. Int J Clin Oncol 9:232–245

    PubMed  Google Scholar 

  7. Lynch HT, de la Chapelle A (2003) Hereditary colorectal cancer. N Engl J Med 348:919–932

    CAS  PubMed  Google Scholar 

  8. Holliday R (1964) A mechanism for gene conversion in fungi. Genet Res 5:282–304

    Google Scholar 

  9. Modrich P (2016) Mechanisms in E. coli and mismatch repair. Angew Chem Int Ed Engl 55:8490–8501

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Nevers P, Spats HC (1975) Escherichia coli mutants uvr D and uvr E deficient in gene conversion of lambda-heteroduplexes. Mol Gen Genet 139:233–243

    CAS  PubMed  Google Scholar 

  11. Rydberg B (1978) Bromouracil mutagenesis and mismatch repair in mutator strains of Escherichia coli. Mutat Res 52:11–24

    CAS  PubMed  Google Scholar 

  12. Glickman BW, Radman M (1980) Escherichia coli mutator mutants deficient in methylation-instructed DNA mismatch correction. Proc Natl Acad Sci USA 77:1063–1067

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Lauhe RS, Su SS, Morich P (1987) Requirement for d(GATC) sequences in Escherichia coli mutHLS mismatch correction. Proc Natl Acad Sci USA 84:1482–1486

    Google Scholar 

  14. Su SS, Morrich P (1986) Escherichia coli mutS-encoded protein binds to Mismatched DNA base pairs. Proc Natl Acad Sci USA 83:5057–5061

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Meselson M (1988) Methyl-directed repair of DNA mismatches. In: Low KB (ed) Recombination of the genetic material. Academic Press, San Diego, pp 91–113

    Google Scholar 

  16. Modrich P (1989) Methyl-directed DNA mismatch correction. J Biol Chem 264:6597–6600

    CAS  PubMed  Google Scholar 

  17. Grilley M, Holmes J, Yashar B et al (1990) Mechanisms of DNA-mismatch correction. Mutat Res 236:253–267

    CAS  PubMed  Google Scholar 

  18. Modrich P (1991) Mechanisms and biological effects of mismatch repair. Annu Rev Genet 25:229–253

    CAS  PubMed  Google Scholar 

  19. Ligtenberg MJL, Kuiper RP, Chan TL et al (2009) Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3-prime exons of TACSTD1. Nature Genet 41:112–117

    CAS  PubMed  Google Scholar 

  20. Fishel R, Lescoe MK, Rao MRS et al (1993) The human mutator gene homolog MSH2 and its association. Cell 75:1027–1038

    CAS  PubMed  Google Scholar 

  21. Leach FS, Nicolaides NC, Papadopoulos N et al (1993) Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell 75:1215–1225

    CAS  PubMed  Google Scholar 

  22. Kolodner RD, Hall NR, Lipford J et al (1994) Structure of the human MSH2 locus and analysis of two Muir-Torre kindreds for msh2 mutations. Genomics 24:516–526

    CAS  PubMed  Google Scholar 

  23. Fishel R, Ewel A, Lee S et al (1993) Binding of mismatched microsatellite DNA sequences by the human MSH2 protein. Science 266:1403–1405

    Google Scholar 

  24. Papadopoulos N, Nicolaides NC, Wei Y-F et al (1994) Mutation of a mutL homolog in hereditary colon cancer. Science 263:1625–1629

    CAS  PubMed  Google Scholar 

  25. Bronner CE, Baker SM, Morrison PT et al (1994) Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer. Nature 368:258–261

    CAS  PubMed  Google Scholar 

  26. Han H-J, Maruyama M, Baba S et al (1995) Genomic structure of human mismatch repair gene, hMLH1, and its mutation analysis in patients with hereditary non-polyposis colorectal cancer (HNPCC). Hum Molec Genet 4:237–242

    CAS  PubMed  Google Scholar 

  27. Drummond JT, Li G-M, Longley MJ et al (1995) Isolation of an hMSH2-p160 heterodimer that restores DNA mismatch repair to tumor cells. Science 268:1909–1912

    CAS  PubMed  Google Scholar 

  28. Palombo F, Gallinari P, Iaccarino I et al (1995) GTBP, a 160-kilodalton protein essential for mismatch-binding activity in human cells. Science 268:1912–1914

    CAS  PubMed  Google Scholar 

  29. Miyaki M, Konishi M, Tanaka K et al (1997) Germline mutation of MSH6 as the cause of hereditary nonpolyposis colorectal cancer. Nature Genet 17:271–272

    CAS  PubMed  Google Scholar 

  30. Akiyama Y, Sato H, Yamada T et al (1997) Germ-line mutation of the hMSH6/GTBP gene in an atypical hereditary nonpolyposis colorectal cancer kindred. Cancer Res 57:3920–3923

    CAS  PubMed  Google Scholar 

  31. Nicolaides NC, Papadopoulos N, Liu B et al (1994) Mutations of two PMS homologues in hereditary nonpolyposis colon cancer. Nature 371:75–80

    CAS  PubMed  Google Scholar 

  32. De Vos M, Hayward BE, Picton S et al (2004) Novel PMS2 pseudogenes can conceal recessive mutations causing a distinctive childhood cancer syndrome. Am J Hum Genet 74:954–964

    PubMed  PubMed Central  Google Scholar 

  33. Ban C, Juno M, Yang W (1999) Transformation of MutL by ATP binding and hydrolysis: a switch in DNA mismatch repair. Cell 97:85–97

    CAS  PubMed  Google Scholar 

  34. Tran PT, Liskay RM (2000) Functional studies on the candidate ATPase domains of Saccharomyces cerevisiae MutLalpha. Mol Cell Biol 20:6390–6398

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Räschle M, Dufner P, Marra G et al (2002) Mutations within the hMLH1 and hPMS2 subunits of the human MutLalpha mismatch repair factor affect its ATPase activity, but not its ability to interact with hMutSalpha. J Biol Chem 277:21810–21820

    PubMed  Google Scholar 

  36. Guerrette S, Acharya S, Fishel R (1999) The interaction of the human MutL homologues in hereditary nonpolyposis colon cancer. J Biol Chem 274:6336–6341

    CAS  PubMed  Google Scholar 

  37. Kondo E, Horii A, Fukushige S (2001) The interaction domains of three MutL heterodimers in man: hMLH1 interacts with 36 homologous amino acid residues within hMLH3, hPMS1 and hPMS2. Nucleic Acids Res 29:1695–1708

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Reenan RA, Kolodner RD (1992) Isolation and characterization of two Saccharomyces cerevisiae genes encoding homologs of the bacterial HexA and MutS mismatch repair proteins. Genetics 132:963–973

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Li GM, Modrich P (1995) Restoration of mismatch repair to nuclear extracts of H6 colorectal tumor cells by a heterodimer of human MutL homologs. Proc Natl Acad Sci USA 92:1950–1954

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Johnson RE, Kovvali GK, Guzder SN et al (1996) Evidence for involvement of yeast proliferating cell nuclear antigen in DNA mismatch repair. J Biol Chem 271:27987–27990

    CAS  PubMed  Google Scholar 

  41. Umar A, Buermeyer AB, Simon JA et al (1996) Requirement for PCNA in DNA mismatch repair at a step preceding DNA resynthesis. Cell 87:65–73

    CAS  PubMed  Google Scholar 

  42. Tishkoff DX, Boerger AL, Bertrand P et al (1997) Identification and characterization of Saccharomyces cerevisiae EXO1, a gene encoding an exonuclease that interacts with MSH2. Proc Natl Acad Sci USA 94:7487–7492

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Longley MJ, Pierce AJ, Modrich P (1997) DNA polymerase delta is required for human mismatch repair in vitro. J Biol Chem 272:10917–10921

    CAS  PubMed  Google Scholar 

  44. Schmutte C, Marinescu RC, Sadoff MM et al (1998) Human exonuclease I interacts with the mismatch repair protein hMSH2. Cancer Res 58:4537–4542

    CAS  PubMed  Google Scholar 

  45. Tishkoff DX, Amin NS, Viars CS et al (1998) Identification of a human gene encoding a homologue of Saccharomyces cerevisiae EXO1, an exonuclease implicated in mismatch repair and recombination. Cancer Res 58:5027–5031

    CAS  PubMed  Google Scholar 

  46. Lin YL, Shivji MK, Chen C et al (1998) The evolutionarily conserved zinc finger motif in the largest subunit of human replication protein A is required for DNA replication and mismatch repair but not for nucleotide excision repair. J Biol Chem 273:1453–1461

    CAS  PubMed  Google Scholar 

  47. Gu L, Hong Y, McCulloch S et al (1998) ATP-dependent interaction of human mismatch repair proteins and dual role of PCNA in mismatch repair. Nucleic Acids Res 26:1173–1178

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Zhang Y, Yuan F, Presnell SR et al (2005) Reconstitution of 5′-directed human mismatch repair in a purified system. Cell 122:693–705

    CAS  PubMed  Google Scholar 

  49. Genschel J, Littman SJ, Drummond JT et al (1998) Isolation of MutSbeta from human cells and comparison of the mismatch repair specificities of MutSbeta and MutSalpha. J Biol Chem 273(31):19895–19901

    CAS  PubMed  Google Scholar 

  50. Iyer RR, Pluciennik A, Genschel J et al (2010) MutLalpha and proliferating cell nuclear antigen share binding sites on MutSbeta. J Biol Chem 285(15):11730–11739

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Plotz G, Raedle J, Brieger A et al (2003) N-terminus of hMLH1 confers interaction of hMutLalpha and hMutLbeta with hMutSalpha. Nucleic Acids Res 31(12):3217–3226

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Dahal BK, Kadyrova LY, Delfino KR et al (2017) Involvement of DNA mismatch repair in the maintenance of heterochromatic DNA stability in Saccharomyces cerevisiae. PLoS Genet 13(10):e1007074

    PubMed  PubMed Central  Google Scholar 

  53. Villahermosa D, Christensen O, Knapp K et al (2017) Schizosaccharomyces pombe MutSα and MutLα maintain stability of tetra-nucleotide repeats and Msh3 of hepta-nucleotide repeats. G3 (Bethesda) 7(5):1463–1473

    CAS  Google Scholar 

  54. Prolla TA, Baker SM, Harris AC et al (1998) Tumour susceptibility and spontaneous mutation in mice deficient in Mlh1, Pms1 and Pms2 DNA mismatch repair. Nat Genet 18(3):276–279

    CAS  PubMed  Google Scholar 

  55. Jäger AC, Rasmussen M, Bisgaard HC et al (2001) HNPCC mutations in the human DNA mismatch repair gene hMLH1 influence assembly of hMutLalpha and hMLH1-hEXO1 complexes. Oncogene 20(27):3590–3595

    PubMed  Google Scholar 

  56. Cannavo E, Marra G, Sabates-Bellver J et al (2005) Expression of the MutL homologue hMLH3 in human cells and its role in DNA mismatch repair. Cancer Res 65(23):10759–10766

    CAS  PubMed  Google Scholar 

  57. Kadyrov FA, Dzantiev L, Constantin N et al (2006) Endonucleolytic function of MutLalpha in human mismatch repair. Cell 126(2):297–308

    CAS  PubMed  Google Scholar 

  58. Peng M, Litman R, Xie J, Sharma S, Brosh RM Jr, Cantor SB (2007) The FANCJ/MutLalpha interaction is required for correction of the cross-link response in FA-J cells. EMBO J 26(13):3238–3249

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Pluciennik A, Dzantiev L, Iyer RR et al (2010) PCNA function in the activation and strand direction of MutLα endonuclease in mismatch repair. Proc Natl Acad Sci USA 107(37):16066–16071

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Kunkel TA, Erie DA (2005) DNA mismatch repair. Annu Rev Biochem 74:681–710

    CAS  PubMed  Google Scholar 

  61. Li GM (2008) Mechanisms and functions of DNA mismatch repair. Cell Res 18(1):85–98

    CAS  PubMed  Google Scholar 

  62. Kunkel TA, Erie DA (2015) Eukaryotic mismatch repair in relation to DNA replication. Annu Rev Genet 49:291–313

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Marti TM, Kunz C, Fleck O (2002) DNA mismatch repair and mutation avoidance pathways. J Cell Physiol 191(1):28–41

    CAS  PubMed  Google Scholar 

  64. Friedberg EC (2003) DNA damage and repair. Nature 421(6921):436–440

    PubMed  Google Scholar 

  65. Martin SA, Lord CJ, Ashworth A (2010) Therapeutic targeting of the DNA mismatch repair pathway. Clin Cancer Res 16(21):5107–5113

    CAS  PubMed  Google Scholar 

  66. Boland CR, Goel A (2010) Microsatellite instability in colorectal cancer. Gastroenterology 138(6):2073–2087

    CAS  PubMed  Google Scholar 

  67. Fishel R (2015) Mismatch repair. J Biol Chem 290(44):26395–26403

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Groothuizen FS, Sixma TK (2016) The conserved molecular machinery in DNA mismatch repair enzyme structures. DNA Repair (Amst) 38:14–23

    CAS  Google Scholar 

  69. Hingorani MM (2016) Mismatch binding, ADP-ATP exchange and intramolecular signaling during mismatch repair. DNA Repair (Amst) 38:24–31

    CAS  Google Scholar 

  70. Kadyrova LY, Kadyrov FA (2016) Endonuclease activities of MutLα and its homologs in DNA mismatch repair. DNA Repair (Amst) 38:42–49

    CAS  Google Scholar 

  71. Peltomäki P (2016) Update on Lynch syndrome genomics. Fam Cancer 15:385–393

    PubMed  PubMed Central  Google Scholar 

  72. Liu D, Keijzers G, Rasmussen LJ (2017) DNA mismatch repair and its many roles in eukaryotic cells. Mutat Res 773:174–187

    CAS  Google Scholar 

  73. Lee JB, Cho WK, Park J et al (2014) Single-molecule views of MutS on mismatched DNA. DNA Repair 20:82–93

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Plotz G, Raedle J, Brieger A et al (2002) hMutSalpha forms an ATP-dependent complex with hMutLalpha and hMutLbeta on DNA. Neucleic Acids Res 30(3):711–718

    CAS  Google Scholar 

  75. Plotz G, Piiper A, Wormek M et al (2006) Analysis of the human MutLalpha.MutSalpha. Biochem Biophys Res Commun. 340(3):852–859

    CAS  PubMed  Google Scholar 

  76. Friedhoff P, Li P, Gotthardt J (2016) Protein-protein interactions in DNA mismatch repair. DNA Repair 38:50–57

    CAS  PubMed  Google Scholar 

  77. Jeon Y, Kim D, Martin-Lopez JV et al (2016) Dynamic control of strand excision during human DNA mismatch repair. Proc Natl Acad Sci USA 113(12):3281–3286

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Fishel R (1998) Mismatch repair, molecular switches, and signal transduction. Genes Dev 12(14):2096–2101

    CAS  PubMed  Google Scholar 

  79. Ban C, Junop M, Yang W (1999) Transformation of MutL by ATP binding and hydrolysis: a switch in DNA mismatch repair. Cell 97(1):85–97

    CAS  PubMed  Google Scholar 

  80. Spampinato C, Modrich P (2000) The MutL ATPase is required for mismatch repair. J Biol Chem 275(13):9863–9869

    CAS  PubMed  Google Scholar 

  81. Lamers MH, Winterwerp HH, Sixma TK (2003) The alternating ATPase domains of MutS control DNA mismatch repair. ENBO J 22(3):746–756

    CAS  Google Scholar 

  82. Kolodner RD, Marsischky GT (1999) Eukaryotic DNA mismatch repair. Curr Opin Genet Dev 9(1):89–96

    CAS  PubMed  Google Scholar 

  83. Peltomäki P (2001) Deficient DNA mismatch repair: a common etiologic factor for colon cancer. Hum Mol Genet 10(7):735–740

    PubMed  Google Scholar 

  84. Bellacosa A (2001) Functional interactions and signaling properties of mammalian DNA mismatch repair proteins. Cell Death Differ 8(11):1076–1092

    CAS  PubMed  Google Scholar 

  85. Scmidt MHM, Pearson CE (2016) Disease associated repeat instability and mismatch repair. DNA Repair 38:117–126

    Google Scholar 

  86. Campregher C, Schmid G, Ferk F et al (2012) MSH3-deficiency initiates EMAST without oncogenic transformation of human colon epithelialcells. PLoS One 7(11):e50541. https://doi.org/10.1371/journal.pone.0050541(Epub 2012 Nov 27)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Tseng-Rogenski SS, Chung H, Wilk M et al (2012) Oxidative stress induces nuclear-to-cytosol shift of hMSH3, a potential mechanism for EMAST in colorectal cancer cells. PLoS One 7(11):e50616. https://doi.org/10.1371/journal.pone.0050616(Epub 2012 Nov 30)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Watson MMC, Berg M, Søreide K (2014) Prevalence and implications of elevated microsatellite alterations at selected tetranucleotides in cancer. Br J Cancer 111(5):823–827

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Carethers JM, Koi M, Tseng-Rogenski SS (2015) EMAST is a form of microsatellite instability that is initiated by inflammation and modulates colorectal cancer progression. Genes 6(2):185–205

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Venderbosch S, van Lent-van Vliet S, de Haan AF et al (2015) EMAST is associated with a poor prognosis in microsatellite instable metastatic colorectal cancer. PLoS One 10(4):e0124538. https://doi.org/10.1371/journal.pone.0124538.eCollection

    Article  PubMed  PubMed Central  Google Scholar 

  91. Dollé E, Theise ND, Schmelzer E et al (2015) EpCAM and the biology of hepatic stem/progenitor cells. Am J Physiol Gastrointest Liver Physiol 308:G233–G250

    PubMed  Google Scholar 

  92. Huang L, Yang Y, Yang F et al (2018) Functions of EpCAM in physiological processes and diseases. Int J Mol Med 42(4):1771–1785

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Kovacs ME, Papp J, Szentirmay Z et al (2009) Deletions removing the last exon of TACSTD1 constitute a distinct class of mutations predisposing to Lynch syndrome. Hum Mutat 30(2):197–203

    CAS  PubMed  Google Scholar 

  94. Sivagnanam M, Mueller JL, Lee H et al (2008) Identification of EpCAM as the gene for congenital tufting enteropathy. Gastroenterol 135(2):429–437

    CAS  Google Scholar 

  95. Reifen RM, Cutz E, Griffiths AM et al (1994) Tufting enteropathy: a newly recognized clinicopathological entity associated with refractory diarrhea in infants. J Pediatr Gastroenterol Nutr 18(3):379–385

    CAS  PubMed  Google Scholar 

  96. Goulet O, Salomon J, Ruemmele F et al (2007) Intestinal epithelial dysplasia (tufting enteropathy). Orphanet J Rare Dis 2(1):20

    PubMed  PubMed Central  Google Scholar 

  97. Pathak SJ, Mueller JL, Okamoto K et al (2019) EPCAM mutation update: variants associated with congenital tufting enteropathy and Lynch syndrome. Hum Mutat 40(2):142–161

    CAS  PubMed  Google Scholar 

  98. Wimmer K, Kratz CP, Vasen HFA et al (2014) Diagnostic criteria for constitutional mismatch repair deficiency syndrome: suggestions of the European consortium ‘care for CMMRD’ (C4CMMRD). J Med Genet 51(6):355–365

    CAS  PubMed  Google Scholar 

  99. Ricciardone MD, Ozçelik T, Cevher B et al (1999) Human MLH1 deficiency predisposes to hematological malignancy and neurofibromatosis type 1. Cancer Res 59(2):290–293

    CAS  PubMed  Google Scholar 

  100. Wang Q, Lasset C, Desseigne F et al (1999) Neurofibromatosis and early onset of cancers in hMLH1-deficient children. Cancer Res 59(2):294–297

    CAS  PubMed  Google Scholar 

  101. Turcot J, Despres JP, St Pierre F et al (1959) Malignant tumors of the central nervous system associated with familial polyposis of the colon: report of two cases. Dis Colon Rectum 2:465–468

    CAS  PubMed  Google Scholar 

  102. Hamilton SR, Liu B, Parsons RE et al (1995) The molecular basis of Turcot’s syndrome. N Engl J Med 332(13):839–847

    CAS  PubMed  Google Scholar 

  103. Lavoine N, Colas C, Muleris M et al (2015) Constitutional mismatch repair deficiency syndrome: clinical description in a French cohort. J Med Genet 52(11):770–778

    CAS  PubMed  Google Scholar 

  104. Turcot J, Despres JP, St Pierre F (1959) Malignant tumors of the central nervous system associated with familial polyposis of the colon: report of two cases. Dis Colon Rectum 2(5):465–468

    CAS  PubMed  Google Scholar 

  105. Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group (2009) Recommendations from the EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives. Genet Med 11(1):35–41

    Google Scholar 

  106. Giardiello FM, Allen JI, Axilbund JE et al (2014) Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multisociety Task Force on colorectal cancer. Am J Gastroenterol 109(8):1159–1179

    PubMed  Google Scholar 

  107. Syngal S, Brand RE, Church JM et al (2015) ACG clinical guideline: genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol 110(2):223–262

    PubMed  PubMed Central  Google Scholar 

  108. Boland CR, Thibodeau SN, Hamilton SR 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(22):5248–5257

    CAS  PubMed  Google Scholar 

  109. Ionov Y, Peinado MA, Malkhosyan S et al (1993) Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 363(6429):558–561

    CAS  PubMed  Google Scholar 

  110. Peltomäki P, Aaltonen LA, Sistonen P et al (1993) Genetic mapping of a locus predisposing to human colorectal cancer. Nature 260:810–812

    Google Scholar 

  111. Thibodeau SN, Bren G, Schaid D (1993) Microsatellite instability in cancer of the proximal colon. Nature 260(5109):816–819

    CAS  Google Scholar 

  112. Rodriguez-Bigas MA, Boland CR, Hamilton SR et al (1997) A National Cancer Institute Workshop on Hereditary Nonpolyposis Colorectal Cancer Syndrome: meeting highlights and Bethesda guidelines. J Natl Cancer Inst 89(23):1758–1762

    CAS  PubMed  Google Scholar 

  113. Leach FS, Polyak K, Burrell M et al (1996) Expression of the human mismatch repair gene hMSH2 in normal and neoplastic tissues. Cancer Res 56(2):235–240

    CAS  PubMed  Google Scholar 

  114. Thibodeau SN, French AJ, Roche PC et al (1996) Altered expression of hMSH2 and hMLH1 in tumors with microsatellite instability and genetic alterations in mismatch repair genes. Cancer Res 56(21):4836–4840

    CAS  PubMed  Google Scholar 

  115. Hendriks Y, Franken P, Dierssen JW et al (2003) Conventional and tissue microarray immunohistochemical expression analysis of mismatch repair in hereditary colorectal tumors. Am J Pathol 162(2):469–477

    CAS  PubMed  PubMed Central  Google Scholar 

  116. de Jong AE, van Puijenbroek M, Hendriks Y et al (2004) Microsatellite instability, immunohistochemistry, and additional PMS2 staining in suspected hereditary nonpolyposis colorectal cancer. Clin Cancer res 10(39):972–980

    PubMed  Google Scholar 

  117. Lipkin SM, Wang V, Jacoby R et al (2000) MLH3: a DNA mismatch repair gene associated with mammalian microsatellite instability. Nat Genet 24(1):27–35

    CAS  PubMed  Google Scholar 

  118. Rigau V, Sebbagh N, Olschwang S et al (2003) Microsatellite instability in colorectal carcinoma. The comparison of immunohistochemistry and molecular biology suggests a role for hMSH6 [correction of hMLH6] immunostaining. Arch Pathol Lab Med 127(6):694–700

    CAS  PubMed  Google Scholar 

  119. Hampel H, Frankel WL, Martin E et al (2005) Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med 352(18):1851–1860

    CAS  PubMed  Google Scholar 

  120. Hendriks YMC, de Jong AE, Morreau H et al (2006) Dianostic approach and management of Lynch syndrome (hereditary nonpolyposis colorectal carcinoma): a guide for clinicians. CA Cancer J Clin 56(4):213–225

    PubMed  Google Scholar 

  121. Snowsill T, Coelho H, Huxley N et al (2017) Molecular testing for Lynch syndrome in people with colorectal cancer: systematic reviews and economic evaluation. Health Technol Assess 21(51):1–238

    PubMed  PubMed Central  Google Scholar 

  122. Jin M, Hampel H, Zhou X et al (2013) BRAF V600E mutation analysis simplifies the testing algorithm for Lynch Syndrome. Am J Clin Pathol 140(2):177–183

    CAS  PubMed  Google Scholar 

  123. Lagerstedt-Robinson K, Rohlin A, Aravidis C et al (2016) Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population. Oncol Rep 36(5):2823–2835

    CAS  PubMed  Google Scholar 

  124. Lorans M, Dow E, Macrae FA et al (2018) Update on hereditary colorectal cancer: improving the clinical utility of multigene panel testing. Clin Colorectal Cancer 17(2):e293–e305. https://doi.org/10.1016/j.clcc.2018.01.001(Epub 2018 Jan 11)

    Article  PubMed  Google Scholar 

  125. Gallego CJ, Shirts BH, Bennette CS et al (2015) Next-generations sequencing panels for the diagnosis of colorectal cancer and polyposis syndromes: a cost-effectiveness analysis. J Clin Oncol 33(18):2084–2091

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Espenschied CR, LaDuca H, Li S et al (2017) Multigene panel testing provides a new perspective on Lynch syndrome. J Clin Oncol 35(22):2568–2575

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Yurgelun MB, Kulke MH, Fuchs CS et al (2017) Cancer susceptibility gene mutations in individuals with colorectal cancer. J Clin Oncol 35(10):1086–1095

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Thompson BA, Spurdle AB, Plazzer JP et al (2014) Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database. Nat Genet 46(12):107–115

    CAS  PubMed  Google Scholar 

  129. Roberts ME, Jackson SA, Susswein LR et al (2018) MSH6 and PMS2 germ-line pathogenic variants implicated in Lynch syndrome are associated with breast cancer. Genet Med 20(10):1167–1174

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Plazzer JP, Sijmons RH, Woods MO et al (2013) The InSiGHT database: utilizing 100 years of insights into Lynch syndrome. Fam Cancer 12(2):175–180

    CAS  PubMed  Google Scholar 

  131. Leach DR, Krummel MF, Allison JP (1996) Enhancement of antitumor immunity by CTLA-4 blockade. Science 271(5256):1734–1736

    CAS  PubMed  Google Scholar 

  132. Ishida Y, Agata Y, Shibahara K, Honjo T (1992) Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J 11(11):3887–3895

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Tivol EA, Borriello F, Schweitzer AN et al (1995) Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3(5):541–547

    CAS  PubMed  Google Scholar 

  134. Nishimura H, Nose M, Hiai H et al (1999) Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 11(2):141–151

    CAS  PubMed  Google Scholar 

  135. Topalian SL, Hodi S, Brahmer JR et al (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366(26):2443–2454

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Le DT, Uram JN, Wang H et al (2015) PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 372(26):2509–2520

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Snyder A, Makarov V, Merghoub T et al (2014) Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med 371:2189–2199

    PubMed  PubMed Central  Google Scholar 

  138. Rizvi NA, Hellmann MD, Snyder A et al (2015) Cancer immunology. Mutational landscape determines sensitivity to PD-1blockade in non-small cell lung cancer. Science 348(6230):124–128

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Yarchoan M, Hopkins A, Jaffee EM et al (2018) Tumor mutational burden and response rate to PD-1 inhibition. N Engl J Med 377(25):2500–2501

    Google Scholar 

  140. Charmers ZR, Connelly CF, Fabrizio D et al (2017) Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med 9(1):34. https://doi.org/10.1186/s13073-017-0424-2

    Article  CAS  Google Scholar 

  141. Dudley JC, Lin MT, Le DT et al (2016) Microsatellite instability as a biomarker for PD-1 blockade. Clin Cancer Res 22(4):813–820

    CAS  PubMed  Google Scholar 

  142. Le DT, Durham JN, Smith KN et al (2017) Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357(6349):409–413

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported in part by a grant from the Japanese Ministry of Education, Science, Sports and Culture of Japan (19K07763).

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Authors and Affiliations

  1. Division of Medical Genetics, Master of Science, Graduate School of Science and Engineering Research, Kindai University, Higashiosaka, Japan

    Kazuo Tamura, Motohide Kaneda, Mashu Futagawa, Miho Takeshita, Sanghyuk Kim, Norihito Kawashita & Junko Tatsumi-Miyajima

  2. Division of Clinical Genetics, Gifu University Hospital, Gifu, Japan

    Mina Nakama

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  1. Kazuo Tamura
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  2. Motohide Kaneda
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The original version of this article was revised: In the original publication, Fig. 2d has not been included. Complete Figure 2 is replaced. “MLH1, MSH2, MSH6, PMS2” in legend of figure 2 are made roman. The section, “Effectiveness of immune check point blockades and a hypermutable state (high tumor mutation burden)” is revised to “Effectiveness of immune check point blockades and a hypermutable state (high tumor mutational burden)”.

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Tamura, K., Kaneda, M., Futagawa, M. et al. Genetic and genomic basis of the mismatch repair system involved in Lynch syndrome. Int J Clin Oncol 24, 999–1011 (2019). https://doi.org/10.1007/s10147-019-01494-y

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