Current Colorectal Cancer Reports

, Volume 3, Issue 1, pp 10–15 | Cite as

Hereditary nonpolyposis colon cancer: Revised Bethesda criteria, immunohistochemistry, microsatellite instability, germline analysis, and emerging issues in genetic testing



Clinical criteria aid in the decision to pursue genetic testing for suspected cases of hereditary nonpolyposis colon cancer (HNPCC) and continue to be refined. Sequence analysis offers the greatest opportunity for definitive germline mutation testing; however, prescreening through microsatellite instability and/or immunohistochemistry offers a cost effective alternative, and recent studies suggest both are complementary. BRAF mutations and hMLH1 promoter methylation appear to have negative predictive value for identifying individuals with HNPCC, but further studies are needed. We review strategies for the evaluation of suspected HNPCC, as well as emerging issues in testing.


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References and Recommended Reading

  1. 1.
    Wijen J, Khan PM, Vasen H, et al.: Hereditary nonpolyposis colorectal cancer families not complying with the Amsterdam criteria show extremely low frequency of mismatch repair gene mutations. Am J Hum Genet 1997, 61:329–335.Google Scholar
  2. 2.
    Rodriguez-Bigas MA, Boland CR, Hamilton SR, et al.: A National Cancer Institute workshop on hereditary nonpolyposis colorectal cancer syndrome: meeting highlights and Bethesda guidelines. J Natl Cancer Inst 1997, 89:1758–1762.PubMedCrossRefGoogle Scholar
  3. 3.
    Umar A, Boland CR, Terdiman JP, et al.: Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch Syndrome) and microsatellite instability. J Natl Cancer Inst 2004, 96:261–268.PubMedCrossRefGoogle Scholar
  4. 4.
    Wolf B, Gruber S, Henglmueller S, et al.: Efficiency of the revised Bethesda guidelines (2003) for the detection of mutations in mismatch repair genes in HNPCC patients. Int J Cancer 2006, 118:1465–1470.PubMedCrossRefGoogle Scholar
  5. 5.
    Rodríguez-Moranta F, Castells A, Andreu M, et al.: Clinical performance of original and revised Bethesda guidelines for the identification of MSH2/MLH1 gene carriers in patients with newly diagnosed colorectal cancer: proposal of a new and simpler set of recommendations. Am J Gastroenterol 2006, 101:1104–1111.PubMedCrossRefGoogle Scholar
  6. 6.
    Piñol V, Castells A, Andreu M, et al.: Accuracy of revised Bethesda guidelines, microsatellite instability, and immunohistochemistry for the identification of patients with hereditary nonpolyposis colorectal cancer. JAMA 2005, 293:1986–1994.PubMedCrossRefGoogle Scholar
  7. 7.
    Peltomaki P, Vasen H: Mutations predisposing to hereditary nonpolyposis colorectal cancer: database and results of a collaborative study. The International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer. Gastroenterology 1997, 113:1146–1158.PubMedCrossRefGoogle Scholar
  8. 8.
    Bronner CE, Baker SM, Morrison PT, et al.: Mutation in the DNA mismatch repair gene homologue hMHLH1 is associated with hereditary non-polyposis colon cancer. Nature 1994, 368:258–261.PubMedCrossRefGoogle Scholar
  9. 9.
    Fishel R, Lescoe MK, Rao M, et al.: The human mutator gene homology MSH2 and its association with hereditary non-polyposis colorectal cancer. Cell 1993, 75:1027–1038.PubMedCrossRefGoogle Scholar
  10. 10.
    Jiricny J: Mediating mismatch repair. Nat Genet 2000, 24:6–8.PubMedCrossRefGoogle Scholar
  11. 11.
    Peltomaki P, Vasen HF, et al.: Mutations predisposing to hereditary nonpolyposis colorectal cancer: database and results of a collaborative study. The International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer. Gastroenterology 1997, 113:1146–1158.PubMedCrossRefGoogle Scholar
  12. 12.
    Lynch HT, Lynch J: Lynch syndrome: genetics, natural history, genetic counseling, and prevention. J Clin Oncol 2000, 18:19S–31S.PubMedGoogle Scholar
  13. 13.
    Berends MJ, Wu Y, Sijmons RH, et al.: Molecular and clinical characteristics of MSH6 variants: an analysis of 25 index carriers of a germline variant. Am J Hum Genet 2002, 70:26–37.PubMedCrossRefGoogle Scholar
  14. 14.
    Lawes DA, SenGupta SB, Boulos PB: Pathogenesis and clinical management of hereditary nonpolyposis colorectal cancer. Br J Surg 2002, 89:1357–1369.PubMedCrossRefGoogle Scholar
  15. 15.
    Nicolaides NC, Papadopoulos N, Liu B, et al.: Mutations of two PMS homologues in hereditary nonpolyposis colon cancer. Nature 1994, 371:75–80.PubMedCrossRefGoogle Scholar
  16. 16.
    Kiu B, Parsons R, Papadopoulos N, et al.: Analysis of mismatch repair genes in hereditary non-polyposis colorectal cancer patients. Nat Med 1996, 2:169–174.CrossRefGoogle Scholar
  17. 17.
    Wang Q, Lasset C, Desseigne F, et al.: Prevalence of germline mutations of hMLH1, hMSH2, hPMS1, hPMS2, and hMSH6 genes in 75 French kindreds with nonpolyposis colorectal cancer. Hum Genet 1999, 105:79–85.PubMedCrossRefGoogle Scholar
  18. 18.
    Watanabe A, Ikejima M, Suzuki N, et al.: Genomic organization and expression of the human MSH3 gene. Genomics 1996, 31:311–318.PubMedCrossRefGoogle Scholar
  19. 19.
    De Rosa M, Fasano C, Panariello L, et al.: Evidence for a recessive inheritance of Turcot’s syndrome caused by compound heterozygous mutations within the PMS2 gene. Oncogene 2000, 19:1719–1723.PubMedCrossRefGoogle Scholar
  20. 20.
    Miyaki M, Nishio M, Kikuchi-Yanoshita R, et al.: Drastic genetic instability of tumors and normal tissues in Turcot syndrome. Oncogene 1997, 15:2877–2881.PubMedCrossRefGoogle Scholar
  21. 21.
    Liu T, Yan H, Kuismanen S, et al.: The role of hPMS1 and hPMS2 in predisposing to colorectal cancer. Cancer Res 2001, 61:7798–7802.PubMedGoogle Scholar
  22. 22.
    Wu Y, Berends M, Post J, et al.: Germline mutations EX01 gene patients with hereditary nonpolyposis colorectal cancer (HNPCC) atypical HNPCC forms. Gastroenterology 2001, 120:1580–1587.PubMedCrossRefGoogle Scholar
  23. 23.
    Thompson E, Meldrum CJ, Crooks R, et al.: Hereditary non-polyposis colorectal cancer and the role of hPMS2 and hEX01 mutations. Clin Genet 2004, 65:215–255.PubMedCrossRefGoogle Scholar
  24. 24.
    Truninger K, Menigatti M, Luz J, et al.: Immunohistochemical analysis reveals high frequency of PMS2 defects in colorectal cancer. Gastroenterology 2005, 128:1160–1171.PubMedCrossRefGoogle Scholar
  25. 25.
    Baudhuin LM, Mai M, French AJ, et al.: Analysis of hMLH1 and hm SH2 gene dosage alterations in hereditary nonpolyposis colorectal cancer patients by novel methods. J Mol Diagn 2005, 7:226–235.PubMedGoogle Scholar
  26. 26.
    Nakagawa H, Lockman JC, Frankel WL, et al.: Mismatch repair gene PMSH2: disease-causing germline mutations are frequent in patients whose tumors stain negative for PMSH2 protein, but paralogous genes obscure mutation detection and interpretation. Cancer Res. 2004, 64:4721–4727.PubMedCrossRefGoogle Scholar
  27. 27.
    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.PubMedCrossRefGoogle Scholar
  28. 28.
    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.PubMedCrossRefGoogle Scholar
  29. 29.
    Plaschke J, Engel C, Kruger S, et al.: Lower incidence of colorectal cancer and later age of disease onset in 27 families with pathogenic MSH6 germline mutations compared with families with MLH1 or MSH2 mutations: the German Hereditary Nonpolyposis Colorectal Cancer Consortium. J Clin Oncol 2004, 22:4486–4494.PubMedCrossRefGoogle Scholar
  30. 30.
    Kolodner R, Tytell JD, Schmeits JL, et al.: Germline MSH6 mutations in colorectal cancer families. Cancer Res 1999, 59:5068–5074.PubMedGoogle Scholar
  31. 31.
    Wijnen J, de Leeuw W, Vasen H, et al.: Familial endometrial cancer in female carriers of MSH6 germline mutations. Nat Gen 1999, 23:142–144.CrossRefGoogle Scholar
  32. 32.
    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.PubMedGoogle Scholar
  33. 33.
    Charbonnier F, Olschwang S, Wang Q, et al.: MSH2 in contrast to MLH1 and MSH6 is frequently inactivated by exonic and promoter rearrangements in hereditary nonpolyposis colorectal cancer. Cancer Res 2002, 62:848–853.PubMedGoogle Scholar
  34. 34.
    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.PubMedCrossRefGoogle Scholar
  35. 35.
    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.PubMedCrossRefGoogle Scholar
  36. 36.
    Baudhuin LM, Ferber MJ, Winters JL, et al.: Characterization of hMLH1 and hMSHS2 gene dosage alterations in Lynch syndrome patients. Gastroenterology 2005, 129:846–854.PubMedCrossRefGoogle Scholar
  37. 37.
    Grabowski M, Mueller-Koch Y, Grasbon-Frodl E, et al.: Deletions account for 17% of pathogenic germline alterations in MLH1 and MSH2 in hereditary nonpolyposis colorectal cancer (HNPCC) families. Genet Test 2005, 9:138–146.PubMedCrossRefGoogle Scholar
  38. 38.
    Mangold E, Pagenstecher C, Friedl W, et al.: Spectrum and frequencies of mutations in MSH2 and MLH1 identified in 1721 German families suspected of hereditary nonpolyposis colorectal cancer. Int J Cancer 2005, 116:692–702.PubMedCrossRefGoogle Scholar
  39. 39.
    Giardiello FM, Brensinger JD, Petersen GM: AGA technical review on hereditary colorectal cancer and genetic testing. Gastroenterology 2001, 121:198.PubMedCrossRefGoogle Scholar
  40. 40.
    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.PubMedGoogle Scholar
  41. 41.
    Aaltonen LA, Peltomaki P, Leach FS, et al.: Clues to the pathogenesis of familial colorectal cancer. Science 1993, 260:812–816.PubMedCrossRefGoogle Scholar
  42. 42.
    Ionov Y, Peinado MA, Malkhosyan S, et al.: Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 1993, 363:558–561.PubMedCrossRefGoogle Scholar
  43. 43.
    Loukola A, de la Chapelle A, Aaltonen LA: Strategies for screening for hereditary non-polyposis colorectal cancer. J Med Genet 1999, 36:819–822.PubMedGoogle Scholar
  44. 44.
    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, 21:1481–1487.CrossRefGoogle Scholar
  45. 45.
    Ribic CM, Sargent DJ, Moore MJ, et al.: Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med 2003, 349:247–257.PubMedCrossRefGoogle Scholar
  46. 46.
    Southey MC, Jenkins MA, Mead L, et al.: Use of molecular tumor characteristics to prioritize mismatch repair gene testing in early-onset colorectal cancer. J Clin Oncol 2005, 23:6524–6532.PubMedCrossRefGoogle Scholar
  47. 47.
    Kievit W, de Bruin JH, Adang EM, et al.: Current clinical selection strategies for identification of hereditary nonpolyposis colorectal cancer families are inadequate: a meta-analysis. Clin Genet 2004, 65:308–316.PubMedCrossRefGoogle Scholar
  48. 48.
    Lynch HT, Riley BD, Weissman SM: Hereditary nonpolyposis colorectal carcinoma (HNPCC) and HNPCC-like families: problems in diagnosis, surveillance, and management. Cancer 2004, 100:53–64.PubMedCrossRefGoogle Scholar
  49. 49.
    de la Chapelle A: Microsatellite instability phenotype of tumors: genotyping or immunohistochemistry? The jury is still out. J Clin Oncol 2002, 20:897–899.Google Scholar
  50. 50.
    Hampel H, Frankel WL, Martin E, et al.: Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med 2005, 352:1851–1860.PubMedCrossRefGoogle Scholar
  51. 51.
    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. Fam Cancer 2005, 4:255–265.PubMedCrossRefGoogle Scholar
  52. 52.
    Engel C, Forberg J, Holinski-Feder E, et al.: Novel strategy for optimal sequential application of clinical criteria, immunohistochemistry and microsatellite analysis in the diagnosis of hereditary nonpolyposis colorectal cancer. Int J Cancer 2006, 118:115–122.PubMedCrossRefGoogle Scholar
  53. 53.
    Cunningham JM, Kim CY, Christensen ER, 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.PubMedCrossRefGoogle Scholar
  54. 54.
    Yuen ST, Chan TL, Ho JW, et al.: Germline somatic and epigenetic events underlying mismatch repair deficiency in colorectal and HNPCC-related cancers. Oncogene 2002, 21:7585–7592.PubMedCrossRefGoogle Scholar
  55. 55.
    Raedle J, Trojan J, Brieger A, et al.: Bethesda guidelines: relation to microsatellite instability and MLH1 promoter methylation in patients with colorectal cancer. Ann Intern Med 2001, 135:566–576.PubMedGoogle Scholar
  56. 56.
    Davies H, Bignell GR, Cox C, et al.: Mutations of the BRAF gene in human cancer. Nature 2002, 417:949–954.PubMedCrossRefGoogle Scholar
  57. 57.
    Sommerer F, Vieth M, Markwarth A, et al.: Mutations of BRAF and KRAS2 in the development of Barrett’s adenocarcinoma. Oncogene 2004, 23:554–558.PubMedCrossRefGoogle Scholar
  58. 58.
    Yuen ST, Davies H, Chan TL, et al.: Similarity of the phenotypic patterns associated with BRAF and KRAS mutations in colorectal neoplasia. Cancer Res 2002, 62:6451–6455.PubMedGoogle Scholar
  59. 59.
    Chan TL, Wei Z, Suet LY, Siu YT: BRAF and KRAS mutations in colorectal hyperplastic polyps and serrated adenomas. Cancer Res 2003, 63:4878–4881.PubMedGoogle Scholar
  60. 60.
    Rajagopalan H, Bardelli A, Lengauer C, et al.: Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature 2002, 418:934.PubMedCrossRefGoogle Scholar
  61. 61.
    Aaltonen LA, Peltomaki P, Mecklin JP, et al.: Replication errors in benign and malignant tumors from hereditary nonpolyposis colorectal cancer patients. Cancer Res 1994, 54:1645–1648.PubMedGoogle Scholar
  62. 62.
    Domingo E, Espin E, Armengol M, et al.: Activated BRAF targets proximal colon tumors with mismatch repair deficiency and MLH1 inactivation. Genes Chromosomes Cancer 2004, 39:138–142.PubMedCrossRefGoogle Scholar
  63. 63.
    Deng G, Bell I, Crawley S, et al.: BRAF mutation is frequently present in sporadic colorectal cancer with methylated hMLH1, but not in hereditary nonpolyposis colorectal cancer. Clin Cancer Res 2004, 10:191–195.PubMedCrossRefGoogle Scholar
  64. 64.
    Domingo E, Niessen RC, Oliveira C, et al.: BRAF-V600E is not involved in the colorectal tumorigenesis of HNPCC in patients with functional MLH1 and MSH2 genes. Oncogene 2005, 24:3995–3998.PubMedCrossRefGoogle Scholar
  65. 65.
    Domingo E, Laiho P, Ollikainen M, et al.: BRAF screening as a low-cost effective strategy for simplifying HNPCC genetic testing. J Med Genet 2004, 41:664–668.PubMedCrossRefGoogle Scholar
  66. 66.
    Wang L, Cunningham JM, Winters JL, et al.: BRAF mutations in colon cancer are not likely attributed to defective DNA mismatch repair. Cancer Res 2003, 63:5209–5212.PubMedGoogle Scholar
  67. 67.
    Cao Y, Oieretti M, Marshall J, et al.: Challenges in the differentiation between attenuated familial adenom atous polyposis and hereditary nonpolyposis colorectal cancer: case report with review of the literature. Am J Gastroenterol 2002, 97:1822–1827.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  1. 1.Division of Gastroenterology, Hepatology and NutritionUniversity of UtahSalt Lake CityUSA

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