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Milestones of Lynch syndrome: 1895–2015

Nature Reviews Cancer volume 15, pages 181–194 (2015)Cite this article

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Abstract

Lynch syndrome, which is now recognized as the most common hereditary colorectal cancer condition, is characterized by the predisposition to a spectrum of cancers, primarily colorectal cancer and endometrial cancer. We chronicle over a century of discoveries that revolutionized the diagnosis and clinical management of Lynch syndrome, beginning in 1895 with Warthin's observations of familial cancer clusters, through the clinical era led by Lynch and the genetic era heralded by the discovery of causative mutations in mismatch repair (MMR) genes, to ongoing challenges.

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Figure 1: Historical timeline of LS.
Figure 2: Molecular mechanism of MSI.
Figure 3: CRC development in individuals with LS.
Figure 4: Pedigree of an LS family.

References

  1. Warthin, A. S. Heredity with reference to carcinoma as shown by the study of the cases examined in the pathological laboratory of the University of Michigan, 1895–1913. Arch. Intern. Med. 12, 546–555 (1913). This is the first published paper describing what has become known as LS.

    Article  Google Scholar 

  2. Mendel, G. Versuche über Pflanzen-Hybriden. Verh. Naturforsch. Ver. Brünn 4, 3–47 (1866); English translation available in J. R. Hortic. Soc. 26, 1–32 (1901).

    Google Scholar 

  3. Desai, D. C. et al. Recurrent germline mutation in MSH2 arises frequently de novo. J. Med. Genet. 37, 646–652 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Lynch, H. T., Shaw, M. W., Magnuson, C. W., Larsen, A. L. & Krush, A. J. Hereditary factors in cancer: study of two large Midwestern kindreds. Arch. Intern. Med. 117, 206–212 (1966). This paper reopened interest in LS, which had been dormant since the work of Warthin.

    Article  CAS  PubMed  Google Scholar 

  5. Lynch, H. T. & Krush, A. J. Cancer family “G” revisited: 1895–1970. Cancer 27, 1505–1511 (1971).

    Article  CAS  PubMed  Google Scholar 

  6. Douglas, J. A. et al. History and molecular genetics of Lynch syndrome in Family G: a century later. JAMA 294, 2195–2202 (2005).

    Article  CAS  PubMed  Google Scholar 

  7. Lynch, H. T. & Krush, A. J. The cancer family syndrome and cancer control. Surg. Gynecol. Obstet. 132, 247–250 (1971). This report details early cancer diagnosis through increased surveillance in CFS.

    CAS  PubMed  Google Scholar 

  8. Boland, C. R. & Troncale, F. J. Familial colonic cancer without antecedent polyposis. Ann. Intern. Med. 100, 700–701 (1984). This was the first paper to suggest the term LS for CFS.

    Article  CAS  PubMed  Google Scholar 

  9. Tempero, M. A., Jacobs, M. M., Lynch, H. T., Graham, C. L. & Blotcky, A. J. Serum and hair selenium levels in hereditary nonpolyposis colorectal cancer. Biol. Trace Element Res. 6, 51–55 (1984).

    Article  CAS  Google Scholar 

  10. Kalady, M. F., Kravochuck, S., LaGuardia, L., O'Malley, M. & Church, J. M. Adenomas in Lynch syndrome: don't be fooled by the “non” in hereditary nonpolyposis colorectal cancer. Fam Cancer 12 (Suppl. 2), 53 (2013). This is a recent study demonstrating an excess of adenomas in LS.

    Google Scholar 

  11. Boland, C. R. Evolution of the nomenclature for the hereditary colorectal cancer syndromes. Fam. Cancer 4, 211–218 (2005). In the context of the developing nomenclature for LS, this paper gives a succinct summary of the history of hereditary CRC until that time.

    Article  PubMed  Google Scholar 

  12. Jass, J. R. Hereditary non-polyposis colorectal cancer: The rise and fall of a confusing term. World J. Gastroenterol. 12, 4943–4950 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lynch, P. M., Lynch, H. T. & Harris, R. E. Hereditary proximal colonic cancer. Dis. Colon Rectum 20, 661–668 (1977). This was the first paper to note the predilection for the proximal colon of LS-associated CRCs.

    Article  CAS  PubMed  Google Scholar 

  14. Lanspa, S. J. et al. Surveillance in Lynch syndrome: how aggressive? Am. J. Gastroenterol. 89, 1978–1980 (1994). This paper calls for complete colonoscopy in surveillance for LS-associated CRCs.

    CAS  PubMed  Google Scholar 

  15. Rondagh, E. J. A. et al. Nonpolypoid colorectal neoplasms: a challenge in endoscopic surveillance of patients with Lynch syndrome. Endoscopy 45, 257–264 (2013).

    Article  CAS  PubMed  Google Scholar 

  16. Watson, P. & Lynch, H. T. The tumor spectrum in HNPCC. Anticancer Res. 14, 1635–1640 (1994).

    CAS  PubMed  Google Scholar 

  17. Watson, P. et al. The risk of extra-colonic, extra-endometrial cancer in the Lynch syndrome. Int. J. Cancer 123, 444–449 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lynch, H. T., Lynch, P. M., Pester, J. & Fusaro, R. M. The cancer family syndrome: rare cutaneous phenotypic linkage of Torre's syndrome. Arch. Intern. Med. 141, 607–611 (1981). This paper was the first to demonstrate that Muir–Torre syndrome is a variant of LS.

    Article  CAS  PubMed  Google Scholar 

  19. Kastrinos, F. et al. Risk of pancreatic cancer in families with Lynch syndrome. JAMA 302, 1790–1795 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Win, A. K. et al. Colorectal and other cancer risks for carriers and noncarriers from families with a DNA mismatch repair gene mutation: a prospective cohort study. J. Clin. Oncol. 30, 958–964 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Bauer, C. M. et al. Hereditary prostate cancer as a feature of Lynch syndrome. Fam. Cancer 10, 37–42 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Raymond, V. M. et al. Adrenocortical carcinoma is a Lynch syndrome-associated cancer. J. Clin. Oncol. 31, 3012–3018 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Vasen, H. F. A., Mecklin, J.-P., Meera Khan, P. & Lynch, H. T. The International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer (ICG-HNPCC). Dis. Colon Rectum 34, 424–425 (1991). This paper is the source of the Amsterdam I Criteria for LS.

    Article  CAS  PubMed  Google Scholar 

  24. Vasen, H. F. A., Watson, P., Mecklin, J.-P. & Lynch, H. T. & ICG-HNPCC. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative Group on HNPCC. Gastroenterology 116, 1453–1456 (1999). This is the source of the revised Amsterdam II Criteria.

    Article  CAS  PubMed  Google Scholar 

  25. Boland, C. R. 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. 58, 5248–5257 (1998).

    CAS  PubMed  Google Scholar 

  26. Rodriguez-Bigas, M. A. et al. A National Cancer Institute workshop on hereditary nonpolyposis colorectal cancer syndrome: meeting highlights and Bethesda Guidelines. J. Natl Cancer Inst. 89, 1758–1762 (1997).

    Article  CAS  PubMed  Google Scholar 

  27. Umar, A. et al. Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J. Natl Cancer Inst. 96, 261–268 (2004). This is the source of the Revised Bethesda Guidelines for MSI testing.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Blackwell, L. J., Wang, S. & Modrich, P. DNA chain length dependence of formation and dynamics of hMutSα.hMutLα.heteroduplex complexes. J. Biol. Chem. 276, 33233–33240 (2001).

    Article  CAS  PubMed  Google Scholar 

  29. Farabaugh, P. J., Schmeissner, U., Hofer, M. & Miller, J. H. Genetic studies of the lac repressor. VII. On the molecular nature of spontaneous hotspots in the lacI gene of Escherichia coli. J. Mol. Biol. 126, 847–857 (1978).

    Article  CAS  PubMed  Google Scholar 

  30. Streisinger, G. & Owen, J. E. Mechanisms of spontaneous and induced frameshift mutation in bacteriophage T4. Genetics 109, 633–659 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Levinson, G. & Gutman, G. A. High frequencies of short frameshifts in poly-CA/TG tandem repeats borne by bacteriophage M13 in Escherichia coli K-12. Nucleic Acids Res. 15, 5323–5338 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  33. Strand, M., Prolla, T. A., Liskay, R. M. & Petes, T. D. Destabilization of tracts of simple repetitive DNA in yeast by mutations affecting DNA mismatch repair. Nature 365, 274–276 (1993).

    Article  CAS  PubMed  Google Scholar 

  34. Aaltonen, L. A. et al. Clues to the pathogenesis of familial colorectal cancer. Science 260, 812–816 (1993). This was the first study to link MSI with LS.

    Article  CAS  PubMed  Google Scholar 

  35. Ionov, Y. M., Peinado, M. A., Malkhosyan, S., Shibata, D. & Perucho, M. Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 363, 558–561 (1993).

    Article  CAS  PubMed  Google Scholar 

  36. Thibodeau, S. N., Bren, G. & Schaid, D. Microsatellite instability in cancer of the proximal colon. Science 260, 816–819 (1993).

    Article  CAS  PubMed  Google Scholar 

  37. Parsons, R. et al. Hypermutability and mismatch repair deficiency in RER+ tumor cells. Cell 75, 1227–1236 (1993). This is an early description of hypermutability in MSI.

    Article  CAS  PubMed  Google Scholar 

  38. Jass, J. R. Natural history of hereditary non-polyposis colorectal cancer. J. Tumor Marker Oncol. 10, 65–71 (1995).

    Google Scholar 

  39. Lengauer, C., Kinzler, K. W. & Vogelstein, B. Genetic instabilities in human cancers. Nature 396, 643–649 (1998).

    Article  CAS  PubMed  Google Scholar 

  40. Jass, J. R. et al. Pathology of hereditary non-polyposis colorectal cancer. Anticancer Res. 14, 1631–1634 (1994). This was the first comprehensive listing of pathological features found in LS-associated CRCs.

    CAS  PubMed  Google Scholar 

  41. Watson, P. et al. Colorectal carcinoma survival among hereditary nonpolyposis colorectal cancer family members. Cancer 83, 259–266 (1998). This study documents the survival advantage of LS-associated CRC compared with sporadic CRC.

    Article  CAS  PubMed  Google Scholar 

  42. Deschoolmeester, V. et al. Tumor infiltrating lymphocytes: an intriguing player in the survival of colorectal cancer patients. BMC Immunol. 11, 19 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Hamilton, S. R. in Cancers of the Colon and Rectum: A Multidisciplinary Approach to Diagnosis and Management Ch. 6 (eds Benson, A. B, Chakravarthy, A., Hamilton, S. R., Sigurdson, E. & Thomas, C. Jr) 115–128 (Demos Medical Publishing, 2014). This book chapter gives an up-to-date understanding of pathological features in CRC.

    Google Scholar 

  44. Bartley, A. N. et al. Colorectal adenoma stem-like cell populations: associations with adenoma characteristics and metachronous colorectal neoplasia. Cancer Prev. Res. 6, 1162–1170 (2013).

    Article  CAS  Google Scholar 

  45. Peltomäki, P. et al. Genetic mapping of a locus predisposing to human colorectal cancer. Science 260, 810–812 (1993). This was the first study to show a germline mutation as a cause of LS.

    Article  PubMed  Google Scholar 

  46. Lindblom, A., Tannergard, P., Werelius, B. & Nordenskjold, M. Genetic mapping of a second locus predisposing to hereditary nonpolyposis colorectal cancer. Nature Genet. 5, 279–282 (1993). This study links LS to a second locus.

    Article  CAS  PubMed  Google Scholar 

  47. Fishel, R. et al. The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 75, 1027–1038 (1993).

    Article  CAS  PubMed  Google Scholar 

  48. Leach, F. S. et al. Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell 75, 1215–1225 (1993). References 47 and 48 document the discovery of the connection between MSH2 and LS.

    Article  CAS  PubMed  Google Scholar 

  49. Papadopoulos, N. et al. Mutation of a mutL homolog in hereditary colon cancer. Science 263, 1625–1629 (1994).

    Article  CAS  PubMed  Google Scholar 

  50. Bronner, C. E. et al. Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary nonpolyposis colon cancer. Nature 368, 258–261 (1994). References 49 and 50 document the discovery of the connection between MLH1 and LS.

    Article  CAS  PubMed  Google Scholar 

  51. Nicolaides, N. C. et al. Mutations of two PMS homologues in hereditary nonpolyposis colon cancer. Nature 371, 75–80 (1994). This study was the first to link the PMS genes to LS.

    Article  CAS  PubMed  Google Scholar 

  52. Liu, T. et al. The role of hPMS1 and hPMS2 in predisposing to colorectal cancer. Cancer Res. 61, 7798–7802 (2001).

    CAS  PubMed  Google Scholar 

  53. Miyaki, M. et al. Germline mutation of MSH6 as the cause of hereditary nonpolyposis colorectal cancer. Nature Genet. 17, 271–272 (1997). This paper shows the involvement of MSH6 in LS.

    Article  CAS  PubMed  Google Scholar 

  54. Lipkin, S. M. et al. MLH3: a DNA mismatch repair gene associated with mammalian microsatellite instability. Nature Genet. 24, 27–34 (2000). This paper connects MLH3 with MSI.

    Article  CAS  PubMed  Google Scholar 

  55. Wu, Y. et al. A role for MLH3 in hereditary nonpolyposis colorectal cancer. Nature Genet. 29, 137–138 (2001).

    Article  CAS  PubMed  Google Scholar 

  56. Liu, H. X. et al. The role of hMLH3 in familial colorectal cancer. Cancer Res. 63, 1894–1899 (2003).

    CAS  PubMed  Google Scholar 

  57. Korhonen, M. K., Vuorenmaa, E. & Nyström, M. The first functional study of MLH3 mutations found in cancer patients. Genes Chromosomes Cancer 47, 803–809 (2008).

    Article  CAS  PubMed  Google Scholar 

  58. Ou, J. et al. Biochemical characterization of MLH3 missense mutations does not reveal an apparent role of MLH3 in Lynch syndrome. Genes Chromosomes Cancer 48, 340–350 (2009).

    Article  CAS  PubMed  Google Scholar 

  59. Rasmussen, L. J. et al. Pathological assessment of mismatch repair gene variants in Lynch syndrome. Hum. Mutat. 33, 1617–1625 (2012).

    Article  CAS  PubMed  Google Scholar 

  60. Nystrom-Lahti, M. et al. Founding mutations and Alu-mediated recombination in hereditary colon cancer. Nature Med. 1, 1203–1206 (1995).

    Article  CAS  PubMed  Google Scholar 

  61. Marshall, B., Isidro, G. & Boavida, M. G. Insertion of a short Alu sequence into the hMSH2 gene following a double cross over next to sequences with chi homology. Gene 174, 175–179 (1996).

    Article  CAS  PubMed  Google Scholar 

  62. Wijnen, J. et al. MSH2 genomic deletions are a frequent cause of HNPCC. Nature Genet. 20, 326–328 (1998). This study shows the use of Southern blotting to identify genomic rearrangements in MSH2.

    Article  CAS  PubMed  Google Scholar 

  63. Yan, H. et al. Conversion of diploidy to haploidy: individuals susceptible to multigene disorders may now be spotted more easily. Nature 403, 723–724 (2000).

    Article  CAS  PubMed  Google Scholar 

  64. Charbonnier, F. et al. MSH2 in contrast to MLH1 and MSH6 is frequently inactivated by exonic and promoter rearrangements in hereditary nonpolyposis colorectal cancer. Cancer Res. 62, 848–853 (2002).

    CAS  PubMed  Google Scholar 

  65. Gille, J. J. et al. Genomic deletions of MSH2 and MLH1 in colorectal cancer families detected by a novel mutation detection approach. Br. J. Cancer 87, 892–897 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Plazzer, J. P. et al. The InSiGHT database: utilizing 100 years of insights into Lynch syndrome. Fam. Cancer 12, 175–180 (2013).

    Article  CAS  PubMed  Google Scholar 

  67. Wagner, A. et al. Molecular 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 gene. Am. J. Hum. Genet. 72, 1088–1100 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Lynch, H. T. et al. A founder mutation of the MSH2 gene and hereditary nonpolyposis colorectal cancer in the United States. JAMA 291, 718–724 (2004). This paper describes the discovery of a widespread founder mutation in the United States.

    Article  CAS  PubMed  Google Scholar 

  69. Clendenning, M. et al. Long-range PCR facilitates the identification of PMS2-specific mutations. Hum. Mutat. 27, 490–495 (2006).

    Article  CAS  PubMed  Google Scholar 

  70. Vaughn, C. P. et al. Clinical analysis of PMS2: mutation detection and avoidance of pseudogenes. Hum. Mutat. 31, 588–593 (2010).

    CAS  PubMed  Google Scholar 

  71. Vaughn, C. P., Baker, C. L., Samowitz, W. S. & Swensen, J. J. The frequency of previously undetectable deletions involving 3′ exons of the PMS2 gene. Genes Chromosomes Cancer 52, 107–112 (2013).

    Article  CAS  PubMed  Google Scholar 

  72. Wimmer, K. & Wernstedt, A. PMS2 gene mutational analysis: direct cDNA sequencing to circumvent pseudogene interference. Methods Mol. Biol. 1167, 289–302 (2014).

    Article  CAS  PubMed  Google Scholar 

  73. Pritchard, C. C. et al. ColoSeq provides comprehensive Lynch and polyposis syndrome mutational analysis using massively parallel sequencing. J. Mol. Diagn. 14, 357–366 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Gazzoli, I., Loda, M., Garber, J., Syngal, S. & Kolodner, R. D. A hereditary nonpolyposis colorectal carcinoma case associated with hypermethylation of the MLH1 gene in normal tissue and loss of heterozygosity of the unmethylated allele in the resulting microsatellite instability-high tumor. Cancer Res. 62, 3925–3928 (2002).

    CAS  PubMed  Google Scholar 

  75. Hitchins, M. P. The role of epigenetics in Lynch syndrome. Fam. Cancer 12, 189–205 (2013). This is a recent review of the role of epigenetics in LS.

    Article  PubMed  Google Scholar 

  76. Hitchins, M. et al. MLH1 germline epimutations as a factor in hereditary nonpolyposis colorectal cancer. Gastroenterology 129, 1392–1399 (2005). This was the first description of MLH1 epimutations in LS.

    Article  CAS  PubMed  Google Scholar 

  77. Hitchins, M. et al. Dominantly inherited constitutional epigenetic silencing of MLH1 in a cancer-affected family is linked to a single nucleotide variant within the 5′UTR. Cancer Cell 20, 200–213 (2011). This paper describes a dominantly inherited epimutation in MLH1.

    Article  CAS  PubMed  Google Scholar 

  78. Morak, M. et al. Biallelic MLH1 SNP cDNA expression or constitutional promoter methylation can hide genomic rearrangements causing Lynch syndrome. J. Med. Genet. 48, 513–519 (2011).

    Article  CAS  PubMed  Google Scholar 

  79. Kwok, C. T. et al. The MLH1 c.-27C>A and c.85G>T variants are linked to dominantly inherited MLH1 epimutation and are borne on a European ancestral haplotype. Eur. J. Hum. Genet. 22, 617–624 (2014).

    Article  CAS  PubMed  Google Scholar 

  80. Chan, T. L. et al. Heritable germline epimutation of MSH2 in a family with hereditary nonpolyposis colorectal cancer. Nature Genet. 38, 1178–1183 (2006).

    Article  CAS  PubMed  Google Scholar 

  81. Ligtenberg, M. J. L. et al. Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3′ exons of TACSTD1. Nature Genet. 41, 112–117 (2009). This paper describes the effect of EPCAM deletions on MSH2.

    Article  CAS  PubMed  Google Scholar 

  82. Zhang, Y. et al. Reconstitution of 5′-directed human mismatch repair in a purified system. Cell 122, 693–705 (2005).

    Article  CAS  PubMed  Google Scholar 

  83. Constantin, N., Dzantiev, L., Kadyrov, F. A. & Modrich, P. Human mismatch repair: reconstitution of a nick-directed bidirectional reaction. J. Biol. Chem. 280, 39752–39761 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Hsieh, P. & Yamane, K. DNA mismatch repair: Molecular mechanism, cancer, and ageing. Mech. Ageing Dev. 129, 391–407 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Kunkel, T. A. & Erie, D. A. DNA mismatch repair. Ann. Rev. Biochem. 74, 681–710 (2005).

    Article  CAS  PubMed  Google Scholar 

  86. Acharya, S. et al. hMSH2 forms specific mispair-binding complexes with hMSH3 and hMSH6. Proc. Natl Acad. Sci. USA 93, 13629–13634 (1996).

    Article  CAS  PubMed  Google Scholar 

  87. de Wind, N. et al. HNPCC-like cancer predisposition in mice through simultaneous loss of Hsh3 and Msh6 mismatch-repair protein functions. Nature Genet. 23, 359–362 (1999).

    Article  CAS  PubMed  Google Scholar 

  88. Edelmann, W. et al. The DNA mismatch repair genes Msh3 and Msh6 cooperate in intestinal tumor suppression. Cancer Res. 60, 803–807 (2000).

    CAS  PubMed  Google Scholar 

  89. Gradia, S., Acharya, S. & Fishel, R. The human mismatch recognition complex hMSH2–hMSH6 functions as a novel molecular switch. Cell 91, 995–1005 (1997).

    Article  CAS  PubMed  Google Scholar 

  90. Gradia, S. et al. hMSH2–hMSH6 forms a hydrolysis-independent sliding clamp on mismatched DNA. Mol. Cell 3, 255–261 (1999).

    Article  CAS  PubMed  Google Scholar 

  91. Acharya, S., Foster, P. L., Brooks, P. & Fishel, R. The coordinated functions of the E. coli MutS and MutL proteins in mismatch repair. Mol. Cell 12, 233–246 (2003).

    Article  CAS  PubMed  Google Scholar 

  92. Geng, H. et al. Biochemical analysis of the human mismatch repair proteins hMutSα MSH2(G674A)–MSH6 and MSH2–MSH6(T1219D). J. Biol. Chem. 287, 9777–9791 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Chen, P. C. et al. Contributions by MutL homologues Mlh3 and Pms2 to DNA mismatch repair and tumor suppression in the mouse. Cancer Res. 65, 8662–8670 (2005).

    Article  CAS  PubMed  Google Scholar 

  94. Kadyrov, F. A., Dzantiev, L., Constantin, N. & Modrich, P. Endonucleolytic function of MutLα in human mismatch repair. Cell 126, 297–308 (2006).

    Article  CAS  PubMed  Google Scholar 

  95. Pluciennik, A. et al. PCNA function in the activation and strand direction of MutLα endonuclease in mismatch repair. Proc. Natl Acad. Sci. USA 107, 16066–16071 (2010).

    Article  PubMed  Google Scholar 

  96. Dzantiev, L. et al. A defined human system that supports bidirectional mismatch-provoked excision. Mol. Cell 15, 31–41 (2004).

    Article  CAS  PubMed  Google Scholar 

  97. Holmes, J. J., Clark, S. & Modrich, P. Strand-specific mismatch correction in nuclear extracts of human and Drosophila melanogaster cell lines. Proc. Natl Acad. Sci. USA 87, 5837–5841 (1990).

    Article  CAS  PubMed  Google Scholar 

  98. Kadyrov, F. et al. A possible mechanism for exonuclease 1-independent eukaryotic mismatch repair. Proc. Natl Acad. Sci. USA 106, 8495–8500 (2009).

    Article  PubMed  Google Scholar 

  99. Hemminki, A. et al. Loss of the wild type MLH1 gene is a feature of hereditary nonpolyposis colorectal cancer. Nature Genet. 8, 405–410 (1994).

    Article  CAS  PubMed  Google Scholar 

  100. Knudson, A. G. Jr Hereditary cancer, oncogenes, and antioncogenes. Cancer Res. 45, 1437–1443 (1985). This paper is important historically, as it contains Knudson's two-hit hypothesis of carcinogenesis.

    CAS  PubMed  Google Scholar 

  101. Fishel, R. & Kolodner, R. D. Identification of mismatch repair genes and their role in the development of cancer. Curr. Opin. Genet. Dev. 5, 382–395 (1995).

    Article  CAS  PubMed  Google Scholar 

  102. Loeb, L. A., Springgate, C. F. & Battula, N. Errors in DNA replication as a basis of malignant changes. Cancer Res. 34, 2311–2321 (1974).

    CAS  PubMed  Google Scholar 

  103. Markowitz, S. et al. Inactivation of the type II TGF-β receptor in colon cancer cells with microsatellite instability. Science 268, 1336–1338 (1995).

    Article  CAS  PubMed  Google Scholar 

  104. Markowitz, S. D. & Roberts, A. B. Tumor suppressor activity of the TGF-β pathway in human cancers. Cytokine Growth Factor Rev. 7, 93–102 (1996).

    Article  CAS  PubMed  Google Scholar 

  105. Huang, J. et al. APC mutations in colorectal tumors with mismatch repair deficiency. Proc. Natl Acad. Sci. USA 93, 9049–9054 (1996).

    Article  CAS  PubMed  Google Scholar 

  106. Rampino, N. et al. Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype. Science 275, 967–969 (1997).

    Article  CAS  PubMed  Google Scholar 

  107. Duval, A. & Hamelin, R. Mutations at coding repeat sequences in mismatch repair-deficient human cancers: toward a new concept of target genes for instability. Cancer Res. 62, 2447–2454 (2002).

    CAS  PubMed  Google Scholar 

  108. Mori, Y. et al. Instabilotyping: comprehensive identification of frameshift mutations caused by coding region microsatellite instability. Cancer Res. 61, 6046–6049 (2001).

    CAS  PubMed  Google Scholar 

  109. Percesepe, A. et al. Mismatch repair genes and mononucleotide tracts as mutation targets in colorectal tumors with different degrees of microsatellite instability. Oncogene 17, 157–163 (1998).

    Article  CAS  PubMed  Google Scholar 

  110. Cancer Genome Atlas Network Comprehensive molecular characterization of human colon and rectal cancer. Nature 487, 330–337 (2012).

  111. Ricciardone, M. D. et al. Human MLH1 deficiency predisposes to hematological malignancy and neurofibromatosis type I. Cancer Res. 59, 290–293 (1999).

    CAS  PubMed  Google Scholar 

  112. Wang, Q. et al. Neurofibromatosis and early onset of cancers in hMLH1-deficient children. Cancer Res. 59, 294–297 (1999).

    CAS  PubMed  Google Scholar 

  113. Bougeard, G. et al. Diversity of the clinical presentation of the MMR gene biallelic mutations. Fam. Cancer 13, 131–135 (2014).

    Article  CAS  PubMed  Google Scholar 

  114. Vasen, H. F. A. et al. Cancer risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis. Gastroenterology 110, 1020–1027 (1996).

    Article  CAS  PubMed  Google Scholar 

  115. Vasen, H. F. A. et al. MSH2 mutation carriers are at higher risk of cancer than MLH1 mutation carriers: a study of hereditary nonpolyposis colorectal cancer families. J. Clin. Oncol. 19, 4074–4080 (2001).

    Article  CAS  PubMed  Google Scholar 

  116. Peltomäki, P., Gao, X. & Mecklin, J. P. Genotype and phenotype in hereditary nonpolyposis colon cancer: a study of families with different versus shared predisposing mutations. Fam. Cancer 1, 9–15 (2001).

    Article  PubMed  Google Scholar 

  117. Mangold, E. et al. A genotype-phenotype correlation in HNPCC: strong predominance of MSH2 mutations in 41 patients with Muir–Torre syndrome. J. Med. Genet. 41, 567–572 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Wagner, A. et al. Atypical HNPCC owing to MSH6 germline mutations: analysis of a large Dutch pedigree. J. Med. Genet. 38, 318–322 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Hendriks, Y. M. C. et al. Cancer risk in hereditary nonpolyposis colorectal cancer due to MSH6 mutations: impact on counseling and surveillance. Gastroenterology 127, 17–25 (2004). This paper details the clinical impact of MSH6 mutations.

    Article  CAS  PubMed  Google Scholar 

  120. Wu, Y. et al. Association of hereditary nonpolyposis colorectal cancer-related tumors displaying low microsatellite instability with MSH6 germline mutations. Am. J. Hum. Genet. 65, 1291–1298 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Berends, M. J. W. et al. Molecular and clinical characteristics of MSH6 variants: an analysis of 25 index carriers of a germline variant. Am. J. Hum. Genet. 70, 26–37 (2002).

    Article  CAS  PubMed  Google Scholar 

  122. Verma, L. et al. Mononucleotide microsatellite instability and germline MSH6 mutation analysis in early onset colorectal cancer. J. Med. Genet. 36, 678–682 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Nakagawa, H. et al. Mismatch 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 Res. 64, 4721–4727 (2004).

    Article  CAS  PubMed  Google Scholar 

  124. Worthley, D. L. et al. Familial mutations in PMS2 can cause autosomal dominant hereditary nonpolyposis colorectal cancer. Gastroenterology 128, 1431–1436 (2005).

    Article  CAS  PubMed  Google Scholar 

  125. Hendriks, Y. M. et al. Heterozygous mutations in PMS2 cause hereditary nonpolyposis colorectal carcinoma (Lynch syndrome). Gastroenterology 130, 312–322 (2006).

    Article  CAS  PubMed  Google Scholar 

  126. Senter, L. et al. The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations. Gastroenterology 135, 419–428 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Kempers, M. J. E. et al. Risk of colorectal and endometrial cancers in EPCAM deletion-positive Lynch syndrome: a cohort study. Lancet Oncol. 12, 49–55 (2011).

    Article  PubMed  Google Scholar 

  128. Lynch, H. et al. Lynch syndrome associated extracolonic tumors are rare in two extended families with the same EPCAM deletion. Am. J. Gastroenterol. 106, 1829–1836 (2011). This paper describes the effect of an EPCAM deletion on two large families, including a family in the United States.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Halvarsson, B. et al. Phenotypic heterogeneity in hereditary non-polyposis colorectal cancer: identical germline mutations associated with variable tumour morphology and immunohistochemical expression. J. Clin. Pathol. 60, 781–786 (2007).

    Article  CAS  PubMed  Google Scholar 

  130. Wimmer, K. & Etzler, J. Constitutional mismatch repair-deficiency syndrome: have we so far seen only the tip of the iceberg? Hum. Genet. 124, 105–122 (2008).

    Article  PubMed  Google Scholar 

  131. Johannesma, P. C. et al. Childhood brain tumours due to germline bi-allelic mismatch repair gene mutations. Clin. Genet. 80, 243–255 (2011).

    Article  CAS  PubMed  Google Scholar 

  132. Gylling, A. H. et al. Differential cancer predisposition in Lynch syndrome: insights from molecular analysis of brain and urinary tract tumors. Carcinogenesis 29, 1351–1359 (2008).

    Article  CAS  PubMed  Google Scholar 

  133. Hampel, H. et al. Feasibility of screening for Lynch syndrome among patients with colorectal cancer. J. Clin. Oncol. 26, 5783–5788 (2008). This study shows that LS is common enough to justify the genetic testing of all CRCs.

    Article  PubMed  PubMed Central  Google Scholar 

  134. Evaluation of Genomic, Applications in Practice and Prevention (EGAPP) Working Group. 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, 35–41 (2009).

  135. Giardiello, F. M. et al. Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-Society Task Force on Colorectal Cancer. Dis. Colon Rectum 57, 1025–1048 (2014). This is a current and authoritative consensus statement on genetic testing and management of LS.

    Article  PubMed  Google Scholar 

  136. Boland, C. R. & Goel, A. Microsatellite instability in colorectal cancer. Gastroenterology 138, 2073–2087 (2010). This review gives an excellent overview of MSI in CRC.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Kane, M. F. et al. Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. Cancer Res. 57, 808–811 (1997).

    CAS  PubMed  Google Scholar 

  138. Veigl, M. L. et al. Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers. Proc. Natl Acad. Sci. USA 95, 8698–8702 (1998).

    Article  CAS  PubMed  Google Scholar 

  139. Cunningham, J. M. et al. Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability. Cancer Res. 58, 3455–3460 (1998).

    CAS  PubMed  Google Scholar 

  140. Deng, G. et al. BRAF mutation is frequently present in sporadic colorectal cancer with methylated hMLH1, but not in hereditary nonpolyposis colorectal cancer. Clin. Cancer Res. 10, 191–195 (2004).

    Article  CAS  PubMed  Google Scholar 

  141. McGivern, A. et al. Promoter hypermethylation frequency and BRAF mutations distinguish hereditary non-polyposis colon cancer from sporadic MSI-H colon cancer. Fam. Cancer 3, 101–107 (2004).

    Article  CAS  PubMed  Google Scholar 

  142. Domingo, E. et al. BRAF screening as a low-cost effective strategy for simplifying HNPCC genetic testing. J. Med. Genet. 41, 664–668 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Hegde, M. et al. ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis). Genet. Med. 16, 101–116 (2014).

    Article  CAS  PubMed  Google Scholar 

  144. Heinen, C. D. & Rasmussen, L. J. Determining the functional significance of mismatch repair gene missense variants using biochemical and cellular assays. Heredit. Cancer Clin. Practice 10, 9 (2012).

    Article  CAS  Google Scholar 

  145. Thompson, B. A. et al. Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database. Nature Genet. 46, 107–115 (2014). This paper details a scheme for classifying MMR gene variants.

    Article  CAS  PubMed  Google Scholar 

  146. Warren, J. J. et al. Structure of the human MutSα DNA lesion recognition complex. Mol. Cell 26, 579–592 (2007).

    Article  CAS  PubMed  Google Scholar 

  147. Lerman, C. et al. What you don't know can hurt you: adverse psychologic effects in members of BRCA1-linked and BRCA2-linked families who decline genetic testing. J. Clin. Oncol. 16, 1650–1654 (1998).

    Article  CAS  PubMed  Google Scholar 

  148. Eliezer, D., Hadley, D. W. & Koehly, L. M. Exploring psychological responses to genetic testing for Lynch Syndrome within the family context. Psychooncol. 23, 1292–1299 (2014).

    Article  Google Scholar 

  149. Aktan-Collan, K. et al. Predictive genetic testing for hereditary non-polyposis colorectal cancer: Uptake and long-term satisfaction. Int. J. Cancer (Pred Oncol.) 89, 44–50 (2000).

    Article  CAS  Google Scholar 

  150. Potti, A. et al. Genomic signatures to guide the use of chemotherapeutics. Nature Med. 12, 1294–1300 (2006).

    Article  CAS  PubMed  Google Scholar 

  151. Heinen, C. D. Translating mismatch repair mechanism into cancer care. Curr. Drug Targets 15, 53–64 (2014).

    Article  CAS  PubMed  Google Scholar 

  152. Jiricny, J. The multifaceted mismatch-repair system. Nature Rev. Mol. Cell Biol. 7, 335–346 (2006).

    Article  CAS  Google Scholar 

  153. Karran, P. & Marinus, M. G. Mismatch correction at O6-methylguanine residues in E. coli DNA. Nature 296, 868–869 (1982).

    Article  CAS  PubMed  Google Scholar 

  154. Kat, A. et al. An alkylation-tolerant, mutator human cell line is deficient in strand specific mismatch repair. Proc. Natl Acad. Sci. USA 90, 6424–6428 (1993).

    Article  CAS  PubMed  Google Scholar 

  155. Stojic, L., Brun, R. & Jiricny, J. Mismatch repair and DNA damage signalling. DNA Repair 3, 1091–1101 (2004).

    Article  CAS  PubMed  Google Scholar 

  156. Carethers, J. M. et al. Use of 5-fluorouracil and survival in patients with microsatellite-unstable colorectal cancer. Gastroenterology 126, 394–401 (2004). This is an early report on the possible difference in response to 5-fluorouracil based on MSI.

    Article  CAS  PubMed  Google Scholar 

  157. Jover, R. et al. The efficacy of adjuvant chemotherapy with 5-fluorouracil in colorectal cancer depends on the mismatch repair status. Eur. J. Cancer 45, 365–373 (2009).

    Article  CAS  PubMed  Google Scholar 

  158. Sinicrope, F. A. & Sargent, D. J. Molecular pathways: microsatellite instability in colorectal cancer: prognostic, predictive, and therapeutic implications. Clin. Cancer Res. 18, 1506–1512 (2012). This paper discusses the clinical implications of MSI, including the possible effect on chemotherapy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Meyers, M. et al. DNA mismatch repair-dependent response to fluoropyrimidine-generated damage. J. Biol. Chem. 280, 5516–5526 (2005).

    Article  CAS  PubMed  Google Scholar 

  160. Liu, A., Yoshioka, K., Salerno, V. & Hsieh, P. The mismatch repair-mediated cell cycle checkpoint response to fluorodeoxyuridine. Cell Biochem. 105, 245–254 (2008).

    Article  CAS  Google Scholar 

  161. Kim, J. H. & Kang, G. H. Molecular and prognostic heterogeneity of microsatellite-unstable colorectal cancer. World J. Gastroenterol. 20, 4230–4241 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Bertagnolli, M. M. et al. Microsatellite instability predicts improved response to adjuvant therapy with irinotecan, fluorouracil, and leucovorin in stage III colon cancer: Cancer and Leukemia Group Protocol 89803. J. Clin. Oncol. 27, 1814–1821 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Fallik, D. et al. Microsatellite instability is a predictive factor of the tumor response to irinotecan in patients with advanced colorectal cancer. Cancer Res. 63, 5738–5744 (2003).

    CAS  PubMed  Google Scholar 

  164. Braun, M. S. et al. Predictive biomarkers of chemotherapy efficacy in colorectal cancer: results from the UK MRC FOCUS trial. J. Clin. Oncol. 26, 2690–2698 (2008).

    Article  CAS  PubMed  Google Scholar 

  165. Kim, J. E. et al. Association between deficient mismatch repair system and efficacy to irinotecan-containing chemotherapy in metastatic colon cancer. Cancer Sci. 102, 1706–1711 (2011).

    Article  CAS  PubMed  Google Scholar 

  166. Martin, S. A., Hewish, M., Sims, D., Lord, C. J. & Ashworth, A. Parallel high-throughput RNA interference screens identify PINK1 as a potential therapeutic target for the treatment of DNA mismatch repair-deficient cancers. Cancer Res. 71, 1836–1848 (2011).

    Article  CAS  PubMed  Google Scholar 

  167. Martin, S. A. et al. DNA polymerases as potential therapeutic targets for cancers deficient in the DNA mismatch repair proteins MSH2 or MLH1. Cancer Cell 17, 235–248 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Burn, J. et al. Effect of aspirin or resistant starch on colorectal neoplasia in the Lynch syndrome. N. Engl. J. Med. 359, 2567–2578 (2008).

    Article  CAS  PubMed  Google Scholar 

  169. Burn, J. et al. Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet 378, 2081–2087 (2011). This study on the efficacy of aspirin for chemoprevention shows the importance of long-term follow-up in such studies.

    Article  PubMed  PubMed Central  Google Scholar 

  170. Mcilhatton, M. A. et al. Aspirin and low-dose nitric oxide-donating aspirin increase life span in a Lynch syndrome mouse model. Cancer Prev. Res. 4, 684–693 (2011).

    Article  CAS  Google Scholar 

  171. Laghi, L., Bianchi, P., Roncalli, M. & Malesci, A. Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J. Natl Cancer Inst. 96, 1402–1403 (2004).

    Article  PubMed  Google Scholar 

  172. Järvinen, H. J. et al. Controlled 15-year trial on screening for colorectal cancer in families with hereditary nonpolyposis colorectal cancer. Gastroenterology 118, 829–834 (2000). This was one of the first, and still one of the best, studies demonstrating the real advantage of colonoscopy screening in LS families.

    Article  PubMed  Google Scholar 

  173. Lynch, H. T., Lynch, P. M. & Harris, R. E. Minimal genetic findings and their cancer control implications: a family with the cancer family syndrome. JAMA 240, 535–538 (1978).

    Article  CAS  PubMed  Google Scholar 

  174. Schmeler, K. M. et al. Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch syndrome. N. Engl. J. Med. 354, 261–269 (2006). This study gives strong evidence for the advantage of prophylactic gynaecological surgery among female LS mutation carriers.

    Article  CAS  PubMed  Google Scholar 

  175. Ketabi, Z., Gerdes, A.-M., Mosgaard, B., Ladelund, S. & Bernstein, I. The results of gynecologic surveillance in families with hereditary nonpolyposis colorectal cancer. Gynecol. Oncol. 133, 526–530 (2014).

    Article  PubMed  Google Scholar 

  176. Church, J. M. Prophylactic colectomy in patients with hereditary nonpolyposis colorectal cancer. Ann. Med. 28, 479–482 (1996).

    Article  CAS  PubMed  Google Scholar 

  177. Lynch, H. T. Is there a role for prophylactic subtotal colectomy among hereditary nonpolyposis colorectal cancer germline mutation carriers? Dis. Colon Rectum 39, 109–110 (1996).

    Article  CAS  PubMed  Google Scholar 

  178. Scaife, C. L. & Rodriguez-Bigas, M. A. Lynch syndrome: implications for the surgeon. Clin. Colorectal Cancer 3, 92–98 (2003).

    Article  PubMed  Google Scholar 

  179. Natarajan, N., Watson, P., Silva-Lopez, E. & Lynch, H. T. Comparison of extended colectomy and limited resection in patients with Lynch syndrome. Dis. Colon Rectum 53, 77–82 (2010). This study gives evidence for the advantage of extended colectomy over more limited surgery in LS patients.

    Article  PubMed  Google Scholar 

  180. Al-Tassan, N., Chmiel, N. H., Maynard, J. & Fleming, N. Inherited variants of MYH associated with somatic G:C → T:A mutations in colorectal tumors. Nature Genet. 30, 227–232 (2002). This is an early report of effects of MYH variants on CRC.

    Article  CAS  PubMed  Google Scholar 

  181. Morak, M., Laner, A., Bacher, U., Keiling, C. & Holinski-Feder, E. MUTYH-associated polyposis — variability of the clinical phenotype in patients with biallelic and monoallelic MUTYH mutations and report on novel mutations. Clin. Genet. 78, 353–363 (2010).

    Article  CAS  PubMed  Google Scholar 

  182. Jones, N. et al. Increased colorectal cancer incidence in obligate carriers of heterozygous mutations in MUTYH. Gastroenterology 137, 489–494 (2009).

    Article  PubMed  Google Scholar 

  183. Win, A. K. et al. Risk of colorectal cancer for carriers of mutations in MUTYH, with and without a family history of cancer. Gastroenterology 146, 1208–1211 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Morak, M. et al. Biallelic MUTYH mutations can mimic Lynch syndrome. Eur J Hum Genet. 22, 1334–1337 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Lynch, H. T. et al. Attenuated familial adenomatous polyposis (AFAP): a phenotypically and genotypically distinctive variant of FAP. Cancer 76, 2427–2433 (1995). This paper describes attenuated FAP, a syndrome often confused clinically with LS.

    Article  CAS  PubMed  Google Scholar 

  186. Lindor, N. M. et al. Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X. JAMA 293, 1979–1985 (2005). This was one of the first studies to describe familial CRC type X.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Mueller-Koch, Y. et al. Hereditary non-polyposis colorectal cancer: clinical and molecular evidence for a new entity of hereditary colorectal cancer. Gut 54, 1733–1740 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Llor, X. et al. Differential features of colorectal cancers fulfilling Amsterdam criteria without involvement of the mutator pathway. Clin. Cancer Res. 11, 7304–7310 (2005).

    Article  CAS  PubMed  Google Scholar 

  189. Valle, L. et al. Clinicopathologic and pedigree differences in Amsterdam I-positive hereditary nonpolyposis colorectal cancer families according to tumor microsatellite instability status. J. Clin. Oncol. 25, 781–786 (2007).

    Article  CAS  PubMed  Google Scholar 

  190. Nieminen, T. T. et al. BMPR1A mutations in hereditary nonpolyposis colorectal cancer without mismatch repair deficiency. Gastroenterology 141, e23–e26 (2011).

    Article  PubMed  Google Scholar 

  191. Nieminen, T. T. et al. Germline mutation of RPS20, encoding a ribosomal protein, causes predisposition to hereditary nonpolyposis colorectal carcinoma without DNA mismatch repair deficiency. Gastroenterology 147, 595–598 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Lindor, N. M. Familial colorectal cancer type X: the other half of hereditary non-polyposis colon cancer syndrome. Surg. Oncol. Clin. N. Am. 18, 637–645 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  193. Lynch, H. T. et al. Communication and technology in genetic counseling for familial cancer. Clin. Genet. 85, 213–222 (2014). This paper discusses the importance of familial communication in hereditary cancer syndrome families and some of the methods currently available to aid this communication.

    Article  CAS  PubMed  Google Scholar 

  194. Vasen, H. F. A. et al. The tumor spectrum in hereditary non-polyposis colorectal cancer: a study of 24 kindreds in the Netherlands. Int. J. Cancer 46, 31–34 (1990).

    Article  CAS  PubMed  Google Scholar 

  195. Drummond, J. T., Li, G.-M., Longley, M. J. & Modrich, P. Isolation of an hMSH2–p160 heterodimer that restores DNA mismatch repair to tumor cells. Science 268, 1909–1912 (1995).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  197. Watson, P. et al. Carrier risk status changes resulting from mutation testing in hereditary nonpolyposis colorectal cancer and hereditary breast-ovarian cancer. J. Hum. Genet. 40, 591–596 (2003).

    CAS  Google Scholar 

  198. Peltomäki, P. & Vasen, H. Mutations associated with HNPCC predisposition — update of ICG-HNPCC/INSiGHT mutation database. Dis. Markers 20, 269–276 (2004). This paper lists the mutations found to be associated with LS at the time it was written.

    Article  PubMed  PubMed Central  Google Scholar 

  199. Hitchins, M. P. et al. Inheritance of a cancer-associated MLH1 germ-line epimutation. N. Engl. J. Med. 356, 697–705 (2007).

    Article  CAS  PubMed  Google Scholar 

  200. Jass, J. R. & Edgar, S. Unicryptal loss of heterozygosity in hereditary non-polyposis colorectal cancer. Pathology 26, 414–417 (1994).

    Article  CAS  PubMed  Google Scholar 

  201. Yurgelun, M. B. et al. Microsatellite instability and DNA mismatch repair protein deficiency in Lynch syndrome colorectal polyps. Cancer Prev. Res. 5, 574–582 (2012).

    Article  CAS  Google Scholar 

  202. Saeterdal, I. et al. Frameshift-mutation-derived peptides as tumor-specific antigens in inherited and spontaneous colorectal cancer. Proc. Natl Acad. Sci. USA 98, 13255–13260 (2001).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by revenue from Nebraska cigarette taxes awarded to Creighton University by the Nebraska Department of Health and Human Services. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the State of Nebraska or the Nebraska Department of Health and Human Services. H.T.L.'s work is partially funded through the Charles F. and Mary C. Heider Chair in Cancer Research, which he holds at Creighton University. The Creighton work also receives funding from “Kicks for a Cure”. The authors appreciate the intense and constant help provided by LS patients and their families. This clearly has made their research possible.

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Authors and Affiliations

  1. Carrie L. Snyder and Trudy G. Shaw are at the Department of Preventive Medicine and Public Health, Henry T. Lynch, Creighton University, 2500 California Plaza, Omaha, Nebraska 68178, USA.,

    Henry T. Lynch, Carrie L. Snyder & Trudy G. Shaw

  2. Christopher D. Heinen is at the Center for Molecular Medicine, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, Connecticut 06030–3101, USA.,

    Christopher D. Heinen

  3. Megan P. Hitchins is at the Department of Medicine (Oncology), Stanford Cancer Institute, Stanford University, Grant Building S169, 1291 Welch Road, Stanford, California 94305, USA.,

    Megan P. Hitchins

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PowerPoint slides

Glossary

Consanguineous

Related by blood, such as in a marriage between cousins.

Constitutional epimutation

An epigenetic aberration within normal somatic cells that predisposes to disease but neither precludes nor dictates that its origin is in the germ line or that it is distributed evenly throughout somatic tissues.

Delirium tremens

A condition in which an individual with chronic alcoholic history exhibits neurodegenerative features, which include occasional hallucination, fever and other neuroderangement.

Founder mutations

Mutations that are common to multiple families within a given population, with one or more ancestors carrying the mutation.

Muir–Torre syndrome

A variant of Lynch syndrome characterized by cutaneous signs (sebaceous adenomas and carcinomas, as well as multiple keratoacanthomas).

Mutator phenotype

A cancer with a high burden of somatic mutations across the genome (>12 mutations per 106 bases).

Neurofibromatosis

An autosomal dominant inherited syndrome with neurofibromin 1 (NF1) mutation and the presence of neuropathological findings of gliomas, neuroblastomas, 'café au lait' spots and multiple neurofibromas.

Proband

The key family member who is cooperative with respect to his or her diagnosis and who is a signature member of the cancer-prone family.

Signet cell features

Features of signet ring cells, which have intracytoplasmic mucin-filled vacuoles that cause lateral displacement of the nuclei.

Reflex testing

As performed in the context of colorectal cancer (CRC), the automatic testing of all incidence of CRC for microsatellite instability and/or immunohistochemical loss of mismatch repair activity in order to identify cases that warrant mutation testing for Lynch syndrome.

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Lynch, H., Snyder, C., Shaw, T. et al. Milestones of Lynch syndrome: 1895–2015. Nat Rev Cancer 15, 181–194 (2015). https://doi.org/10.1038/nrc3878

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