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Hereditary Nonpolyposis Colorectal Cancer

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Molecular Pathology in Clinical Practice

Abstract

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant colon cancer syndrome. The first description of a cancer-prone family with HNPCC dates back to the late 1800s.1 However, it was not until the work of Lynch in the 1970s that a more complete clinical picture of this disorder began to emerge.2,3 The diagnosis of HNPCC has, until recently, been based primarily on family history. As a result, reliably differentiating patients with HNPCC from those with sporadic cancer has been difficult. However, the constellation of several clinical characteristics, in addition to family history, may raise suspicion of HNPCC.

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References

  1. Lynch HT, Smyrk TC, Watson P, et al. Genetics, natural history, tumor spectrum, and pathology of hereditary nonpolyposis colorectal cancer: an updated review. Gastroenterology. 1993;104:1535–1549.

    PubMed  CAS  Google Scholar 

  2. Lynch HT, Shaw MW, Magnuson CW, Larsen AL, Krush AJ. Hereditary factors in cancer. Study of two large midwestern kindreds. Arch Intern Med. 1966;117:206–212.

    Article  PubMed  CAS  Google Scholar 

  3. Lynch HT, Krush AJ. Cancer family “G” revisited: 1895–1970. Cancer. 1971;27:1505–1511.

    Article  PubMed  CAS  Google Scholar 

  4. Lynch HT, de la Chapelle A. Genetic susceptibility to non-polyposis colorectal cancer. J Med Genet. 1999;36:801–818.

    PubMed  CAS  Google Scholar 

  5. Watson P, Lynch HT. The tumor spectrum in HNPCC. Anticancer Res. 1994;14:1635–1639.

    PubMed  CAS  Google Scholar 

  6. Lynch HT, Fusaro RM, Roberts L, Voorhees GJ, Lynch JF. Muir-Torre syndrome in several members of a family with a variant of the Cancer Family Syndrome. Br J Dermatol. 1985;113:295–301.

    Article  PubMed  CAS  Google Scholar 

  7. Jass JR, Stewart SM. Evolution of hereditary non-polyposis colorectal cancer. Gut. 1992;33:783–786.

    Article  PubMed  CAS  Google Scholar 

  8. Jass JR. Colorectal adenoma progression and genetic change: is there a link? Ann Med. 1995;27:301–306.

    Article  PubMed  CAS  Google Scholar 

  9. Alexander J, Watanabe T, Wu TT, Rashid A, Li S, Hamilton SR. Histopathological identification of colon cancer with microsatellite instability. Am J Pathol. 2001;158:527–535.

    PubMed  CAS  Google Scholar 

  10. Aarnio M, Mustonen H, Mecklin JP, Jarvinen HJ. Prognosis of colorectal cancer varies in different high-risk conditions. Ann Med. 1998;30:75–80.

    PubMed  CAS  Google Scholar 

  11. Frei JV. Hereditary nonpolyposis colorectal cancer (Lynch syndrome II). Diploid malignancies with prolonged survival. Cancer. 1992;69:1108–1111.

    Article  PubMed  CAS  Google Scholar 

  12. Kouri M, Laasonen A, Mecklin JP, Jarvinen H, Franssila K, Pyrhonen S. Diploid predominance in hereditary nonpolyposis colorectal carcinoma evaluated by flow cytometry. Cancer. 1990;65:1825–1829.

    Article  PubMed  CAS  Google Scholar 

  13. Dolcetti R, Viel A, Doglioni C, et al. High prevalence of activated intraepithelial cytotoxic T lymphocytes and increased neoplastic cell apoptosis in colorectal carcinomas with microsatellite instability. Am J Pathol. 1999;154:1805–1813.

    PubMed  CAS  Google Scholar 

  14. Gryfe R, Kim H, Hsieh ET, et al. Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med. 2000;342:69–77.

    Article  PubMed  CAS  Google Scholar 

  15. Vasen HF, Mecklin JP, Khan PM, Lynch HT. The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC). Dis Colon Rectum. 1991;34:424–425.

    Article  PubMed  CAS  Google Scholar 

  16. Aaltonen LA, Salovaara R, Kristo P, et al. Incidence of hereditary nonpolyposis colorectal cancer and the feasibility of molecular screening for the disease. N Engl J Med. 1998;338:1481–1487.

    Article  PubMed  CAS  Google Scholar 

  17. Cunningham JM, Cheong-Yong K, Christensen E, et al. The frequency of hereditary defective mismatch repair in a prospective series of unselected colorectal carcinomas. Am J Hum Genet. 2001;69:780–790.

    Article  PubMed  CAS  Google Scholar 

  18. Vasen HF, Watson P, Mecklin JP, Lynch HT. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology. 1999;116:1453–1456.

    Article  PubMed  CAS  Google Scholar 

  19. Boland CR, Thibodeau SN, Hamilton SR, 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. 1998;58:5248–5257.

    PubMed  CAS  Google Scholar 

  20. Thibodeau SN, Bren G, Schaid D. Microsatellite instability in cancer of the proximal colon [comments]. Science. 1993;260:816–819.

    Article  PubMed  CAS  Google Scholar 

  21. Ionov Y, Peinado MA, malkhosyan S, Shibata D, Perucho M. Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature. 1993;363:558–561.

    Article  PubMed  CAS  Google Scholar 

  22. Aaltonen LA, Peltomaki P, Leach FS, et al. Clues to the pathogenesis of familial colorectal cancer. Science. 1993;260:812–816.

    Article  PubMed  CAS  Google Scholar 

  23. Lander ES, Linton LM, Birren B, et al. Initial sequencing and analysis of the human genome. Nature. 2001;409:860–921.

    Article  PubMed  CAS  Google Scholar 

  24. Strand M, Prolla TA, Liskay RM, Petes TD. Destabilization of tracts of simple repetitive DNA in yeast by mutations affecting DNA mismatch repair. Nature. 1993;365:274–276.

    Article  PubMed  CAS  Google Scholar 

  25. Peltomaki P, Aaltonen LA, Sistonen P, et al. Genetic mapping of a locus predisposing to human colorectal cancer. Science. 1993;260:810–812.

    Article  PubMed  CAS  Google Scholar 

  26. Fishel R, Lescoe MK, Rao MR, et al. The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell. 1993;75:1027–1038.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  28. Fishel R, Kolodner RD. Identification of mismatch repair genes and their role in the development of cancer. Curr Opin Genet Dev. 1995;5:382–395.

    Article  PubMed  CAS  Google Scholar 

  29. Buermeyer AB, Deschenes SM, Baker SM, Liskay RM. Mammalian DNA mismatch repair. Annu Rev Genet. 1999;33:533–564.

    Article  PubMed  CAS  Google Scholar 

  30. Malkhosyan S, McCarty A, Sawai H, Perucho M. Differences in the spectrum of spontaneous mutations in the hprt gene between tumor cells of the microsatellite mutator phenotype. Mutat Res. 1996;316:249–259.

    PubMed  CAS  Google Scholar 

  31. Ohzeki S, Tachibana A, Tatsumi K, Kato T. Spectra of spontaneous mutations at the hprt locus in colorectal carcinoma cell lines defective in mismatch repair. Carcinogenesis. 1997;18:1127–1133.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  33. Papadopoulos N, Nicolaides NC, Wei YF, et al. Mutation of a mutL homolog in hereditary colon cancer. Science. 1994;263:1625–1629.

    Article  PubMed  CAS  Google Scholar 

  34. Miyaki M, Konishi M, Tanaka K, et al. Germline mutation of MSH6 as the cause of hereditary nonpolyposis colorectal cancer. Nat Genet. 1997;17:271–272.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  36. Wu Y, Berends MJ, Sijmons RH, et al. A role for MLH3 in hereditary nonpolyposis colorectal cancer. Nat Genet. 2001;29:137–138.

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  38. Wijnen J, de Leeuw W, Vasen H, et al. Familial endometrial cancer in female carriers of MSH6 germline mutations. Nat Genet. 1999;23:142–144.

    Article  PubMed  CAS  Google Scholar 

  39. Wu Y, Berends MJ, Mensink RG, et al. Association of hereditary nonpolyposis colorectal cancer-related tumors displaying low microsatellite instability with MSH6 germline mutations. Am J Hum Genet. 1999;65:1291–1298.

    Article  PubMed  CAS  Google Scholar 

  40. Beck NE, Tomlinson IP, Homfray T, et al. Use of SSCP analysis to identify germline mutations in HNPCC families fulfilling the Amsterdam criteria. Hum Genet. 1997;99:219–224.

    Article  PubMed  CAS  Google Scholar 

  41. Wagner A, Barrows A, Wijnen JT, 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. 2003;72:1088–1100.

    Article  PubMed  CAS  Google Scholar 

  42. Lindor NM, Rabe MS, Peterson GM, et al. Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency. JAMA. 2005;293:1979–1985.

    Article  PubMed  CAS  Google Scholar 

  43. Lynch HT, Smyrk T, Lynch J. An update of HNPCC (Lynch syndrome). Cancer Genet Cytogenet. 1997;93:84–99.

    Article  PubMed  CAS  Google Scholar 

  44. Nystrom-Lahti M, Wu Y, Moisio AL, et al. DNA mismatch repair gene mutations in 55 kindreds with verified or putative hereditary nonpolyposis colorectal cancer. Hum Mol Genet. 1996;5:763–769.

    Article  PubMed  CAS  Google Scholar 

  45. Lewis CM, Neuhausen SL, Daley D, et al. Genetic heterogeneity and unmapped genes for colorectal cancer. Cancer Res. 1996;56:1382–1388.

    PubMed  CAS  Google Scholar 

  46. Huang J, Kuismanen SA, Liu T, et al. MSH6 and MSH3 are rarely involved in genetic predisposition to nonpolypotic colon cancer. Cancer Res. 2001;61:1619–1623.

    PubMed  CAS  Google Scholar 

  47. Baudhuin LM, Burgart LJ, Leontovich O, et al. Use of microsatellite instability and immunohistochemistry testing for the identification of individuals at risk for Lynch syndrome. Familial Cancer. 2005;4:255–265.

    Article  PubMed  Google Scholar 

  48. Bhattacharyya NP, Skandalis A, Ganesh A, Groden J, Meuth M. Mutator phenotypes in human colorectal carcinoma cell lines. Proc Natl Acad Sci U S A. 1994;91:6319–6323.

    Article  PubMed  CAS  Google Scholar 

  49. Thibodeau SN, French AJ, Cunningham JM, et al. Microsatellite instability in colorectal cancer: different mutator phenotypes and the principal involvement of hMLH1. Cancer Res. 1998;58:1713–1718.

    PubMed  CAS  Google Scholar 

  50. Zhou XP, Hoang JM, Li YJ, et al. Determination of the replication error phenotype in human tumors without the requirement for matching normal DNA by analysis of mononucleotide repeat microsatellites. Genes Chromosomes Cancer. 1998;21:101–107.

    Article  PubMed  CAS  Google Scholar 

  51. Umar A, Boland CR, Terdiman JP, et al. Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Nat Cancer Inst. 2004;96:261–267.

    Article  PubMed  CAS  Google Scholar 

  52. Pastrello C, Baglioni S, Tibiletti MG, Papi L, Fornasarig M, Morabito A, Agostini M, Genuardi M, Viel A: Stability of BAT26 in tumours of hereditary nonpolyposis colorectal cancer patients with MSH2 intragenic deletion, Eur J Hum Genet. 2006,14:63–68.

    PubMed  CAS  Google Scholar 

  53. Konishi M, Kikuchi-Yanoshita R, Tanaka K, et al. Molecular nature of colon tumors in hereditary nonpolyposis colon cancer, familial polyposis, and sporadic colon cancer. Gastroenterology. 1996;111:307–317.

    Article  PubMed  CAS  Google Scholar 

  54. Jass JR, Biden KG, Cummings MC, et al. Characterisation of a subtype of colorectal cancer combining features of the suppressor and mild mutator pathways. J Clin Pathol. 1999;52:455–460.

    Article  PubMed  CAS  Google Scholar 

  55. Cunningham JM, Boardman LA, Burgart LJ, Thibodeau SN. Microsatellite instability in colon cancers. In: Wells R, Warren S, eds. Genetic Instabilities and Hereditary Neurological Diseases. Academic Press, San Diego, CA; 1998:791–807.

    Google Scholar 

  56. Kane MF, Loda M, Gaida GM, 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. 1997;57:808–811.

    PubMed  CAS  Google Scholar 

  57. Cunningham JM, Christensen ER, Tester DJ, et al. Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability. Cancer Res. 1998;58:3455–3460.

    PubMed  CAS  Google Scholar 

  58. Dietmaier W, Wallinger S, Bocker T, Kullmann F, Fishel R, Ruschoff J. Diagnostic microsatellite instability: definition and correlation with mismatch repair protein expression. Cancer Res. 1997;57:4749–4756.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  60. Ganguly A, Rock MJ, Prockop DJ. Conformation-sensitive gel electrophoresis for rapid detection of single-base differences in double-stranded PCR products and DNA fragments: evidence for solvent-induced bends in DNA heteroduplexes [published erratum appears in Proc Natl Acad Sci U S A. 1994;91:5217]. Proc Natl Acad Sci U S A. 1993;90:10325–10329.

    Article  PubMed  CAS  Google Scholar 

  61. Orita M, Iwahana H, Kanazawa H, Hayashi K, Sekiya T. Detection of polymorphisms of human DNA by gel electrophoresis as singlestrand conformation polymorphisms. Proc Natl Acad Sci U S A. 1989;86:2766–2770.

    Article  PubMed  CAS  Google Scholar 

  62. Lerman LS, Silverstein K, Grinfeld E. Searching for gene defects by denaturing gradient gel electrophoresis. Cold Spring Harb Symp Quant Biol. 1986;51:285–297.

    PubMed  CAS  Google Scholar 

  63. Underhill PA, Jin L, Lin AA, et al. Detection of numerous Y chromosome biallelic polymorphisms by denaturing high-performance liquid chromatography. Genome Res. 1997;7:996–1005.

    PubMed  CAS  Google Scholar 

  64. Powell SM, Petersen GM, Krush AJ, et al. Molecular diagnosis of familial adenomatous polyposis. N Engl J Med. 1993;329:1982–1987.

    Article  PubMed  CAS  Google Scholar 

  65. Frischmeyer PA, Dietz HC. Nonsense-mediated mRNA decay in health and disease. Hum Mol Genet. 1999;8:1893–1900.

    Article  PubMed  CAS  Google Scholar 

  66. Wijnen J, van der Klift H, Vasen H, et al. MSH2 genomic deletions are a frequent cause of HNPCC. Nat Genet. 1998;20:326–328.

    Article  PubMed  CAS  Google Scholar 

  67. Wang Y, Friedl W, Lamberti C, et al. Hereditary nonpolyposis colorectal cancer: frequent occurrence of large genomic deletions in MSH2 and MLH1 genes. Int J Cancer. 2003;103:636–641.

    Article  PubMed  CAS  Google Scholar 

  68. Baudhuin LM, Mai M, French AJ, et al. Analysis of hMLH1 and hMSH2 gene dosage alterations in hererditary nonpolyposis colorectal cancer patients by novel methods. J Mol Diagn. 2005;7:26–235.

    Google Scholar 

  69. Gille JJ, Hogervorst FB, Pals G, et al. Genomic deletions of MSH2 and MLH1 in colorectal cancer families detected by a novel mutation detection approach. Br J Cancer. 2002;87:892–897.

    Article  PubMed  CAS  Google Scholar 

  70. Yan H, Papadopoulos N, Marra G, et al. Conversion of diploidy to haploidy. Nature. 2000;403:723–724.

    Article  PubMed  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. Clinical Cytogenetics Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA

    Erik C. Thorland PhD (Co-Director)

  2. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA

    Stephen N. Thibodeau PhD (Co-Director Molecular Genetics)

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  1. Erik C. Thorland PhD
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  2. Stephen N. Thibodeau PhD
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Editors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University and New York Presbyterian Hospital, New York, NY, 10021, USA

    Debra G. B. Leonard MD, PhD (Professor and Vice Chair for Laboratory Medicine) (Professor and Vice Chair for Laboratory Medicine)

  2. Hematology, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Adam Bagg MD (Director) (Director)

  3. Department of Pathology and Laboratory Medicine, Emory University Hospital, Atlanta, GA, 30322, USA

    Angela M. Caliendo MD, PhD (Vice Chair and Associate Professor) (Vice Chair and Associate Professor)

  4. Northwestern University Feinberg School of Medicine, Evanston, IL, 60201

    Karen L. Kaul MD, PhD (Professor) (Professor)

  5. Department of Pathology and Laboratory Medicine, Evanston Northwestern Healthcare, Evanston, IL, 60201, USA

    Karen L. Kaul MD, PhD (Professor) (Professor)

  6. Molecular Pathology Laboratory, Department of Pathology and Laboratory Medicine, University of Pennsylvania Health System, Philadelphia, PA, 19104, USA

    Vivianna M. Van Deerlin MD, PhD (Director) (Director)

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Thorland, E.C., Thibodeau, S.N. (2007). Hereditary Nonpolyposis Colorectal Cancer. In: Leonard, D.G.B., Bagg, A., Caliendo, A.M., Kaul, K.L., Van Deerlin, V.M. (eds) Molecular Pathology in Clinical Practice. Springer, New York, NY. https://doi.org/10.1007/978-0-387-33227-7_19

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  • DOI: https://doi.org/10.1007/978-0-387-33227-7_19

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