An Overview of the Lynch Syndrome (Hereditary Non-polyposis Colorectal Cancer)

  • Hans F. A. VasenEmail author
  • J. C. H. Hardwick
Part of the M.D. Anderson Solid Tumor Oncology Series book series (MDA, volume 5)


Environmental factors play a dominant role in the etiology of most colo­rectal cancers. However, in about 5% of all cases, CRC is associated with a highly penetrant dominant syndrome. The most common of these is Lynch syndrome (hereditary non-polyposis colorectal cancer; HNPCC). It is characterized by the development of colorectal cancer, endometrial cancer and various other cancers and is caused by a mutation in one of the mismatch repair (MMR) genes: MLH1, MSH2, MSH6 or PMS2. The MMR-defect leads to instability at microsatellites of tumour-DNA (microsatellite instability (MSI)) which can be found in >90% of CRC associated with Lynch syndrome. Currently, mainly clinical criteria (Bethesda criteria) are used to select patients with CRC for molecular genetic (MSI-analysis) and/or immunohistochemical analysis of the tumour and those with evidence of MSI or loss of MMR expression are offered mutation analysis. Because, there is increasing evidence that MSI/IHC is an important prognostic factor and may predict the response to chemotherapy, these tests might in future be performed on a much larger scale, if not in all CRC cases.

Identification of Lynch syndrome families is important as it allows to offer preventative measures. Many studies have shown that colonoscopic surveillance leads to a substantial reduction of the risk of CRC and also reduction of the mortality associated with CRC. Also surveillance for endometrial cancer may lead to detection of premalignant lesions and early cancers.

Knowledge on the effectiveness of surveillance for the other LS-associated cancer is limited.

The life time risk of developing one of associated cancers (stomach, ureter, renal pelvis, small bowel, the bile ducts and tumors of the brain) is relatively low (less than 15%) and may be associated with the underlying MMR defect. In the decision making on which surveillance protocol should be recommended, a reasonable approach might be to first discuss all the various cancer risks with the patient, then discuss which screenings are indicated scientifically.

In this chapter, the clinical features, diagnostic criteria and management of the syndrome will be discussed in detail.


Overview Lynch syndrome Hereditary Non-polyposis Colorectal cancer HNPCC 


  1. 1.
    Warthin AS. Heredity with reference to carcinoma. Arch Int Med. 1913;12:546–555.CrossRefGoogle Scholar
  2. 2.
    Lynch HT, Krush AJ. Cancer family “G” revisited: 1895–1970. Cancer. 1971;27:1505–11.PubMedCrossRefGoogle Scholar
  3. 3.
    Mecklin JP, Jarvinen HJ, Peltokallio P. Cancer family syndrome. Genetic analysis of 22 Finnish kindreds. Gastroenterology. 1986;90:328–33.PubMedGoogle Scholar
  4. 4.
    Ponz DL, Sassatelli R, Sacchetti C, Zanghieri G, Scalmati A, Roncucci L. Familial aggregation of tumors in the three-year experience of a population-based colorectal cancer registry. Cancer Res. 1989;49:4344–8.Google Scholar
  5. 5.
    Vasen HF, Hartog Jager FC, Menko FH, Nagengast FM. Screening for hereditary non-polyposis colorectal cancer: a study of 22 kindreds in The Netherlands. Am J Med. 1989;86:278–81.PubMedCrossRefGoogle Scholar
  6. 6.
    Vasen HF, Mecklin JP, Khan PM, Lynch HT. The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC). Dis Colon Rectum. 1991;34:424–5.PubMedCrossRefGoogle Scholar
  7. 7.
    Lynch HT, de la Chapelle A. Hereditary colorectal cancer. N Engl J Med. 2003;348:919–32.PubMedCrossRefGoogle Scholar
  8. 8.
    Peltomaki P, Vasen H. Mutations associated with HNPCC predisposition – update of ICG-HNPCC/INSiGHT mutation database. Dis Markers. 2004;20:269–76.PubMedGoogle Scholar
  9. 9.
    Lynch HT, Harris RE, Organ Jr CH, Guirgis HA, Lynch PM, Lynch JF, et al. The surgeon, genetics, and cancer control: the Cancer Family syndrome. Ann Surg. 1977;185:435–40.PubMedCrossRefGoogle Scholar
  10. 10.
    Boland CR, Troncale FJ. Familial colonic cancer without antecedent polyposis. Ann Intern Med. 1984;100:700–1.PubMedCrossRefGoogle Scholar
  11. 11.
    Umar A, Boland CR, Terdiman JP, Syngal S, de la Chapelle A, Ruschoff J, et al. Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst. 2004;96:261–8.PubMedCrossRefGoogle Scholar
  12. 12.
    Desai DC, Lockman JC, Chadwick RB, Gao X, Percesepe A, Evans DG, et al. Recurrent germline mutation in MSH2 arises frequently de novo. J Med Genet. 2000;37:646–52.PubMedCrossRefGoogle Scholar
  13. 13.
    Kraus C, Kastl S, Gunther K, Klessinger S, Hohenberger W, Ballhausen WG. A proven de novo germline mutation in HNPCC. J Med Genet. 1999;36:919–21.PubMedGoogle Scholar
  14. 14.
    Park JG, Park YJ, Wijnen JT, Vasen HF. Gene-environment interaction in hereditary nonpolyposis colorectal cancer with implications for diagnosis and genetic testing. Int J Cancer. 1999;82:516–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Watson P, Lynch HT. Extracolonic cancer in hereditary nonpolyposis colorectal cancer. Cancer. 1993;71:677–85.PubMedCrossRefGoogle Scholar
  16. 16.
    Vasen HF, Wijnen JT, Menko FH, Kleibeuker JH, Taal BG, Griffioen G, et al. Cancer risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis. Gastroenterology. 1996;110:1020–7.PubMedCrossRefGoogle Scholar
  17. 17.
    Vasen HF, Sanders EA, Taal BG, Nagengast FM, Griffioen G, Menko FH, et al. The risk of brain tumours in hereditary non-polyposis colorectal cancer (HNPCC). Int J Cancer. 1996;65:422–5.PubMedCrossRefGoogle Scholar
  18. 18.
    Sijmons RH, Kiemeney LA, Witjes JA, Vasen HF. Urinary tract cancer and hereditary nonpolyposis colorectal cancer: risks and screening options. J Urol. 1998;160:466–70.PubMedCrossRefGoogle Scholar
  19. 19.
    Aarnio M, Sankila R, Pukkala E, Salovaara R, Aaltonen LA, de la Chapelle A, et al. Cancer risk in mutation carriers of DNA-mismatch-repair genes. Int J Cancer. 1999;81:214–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Scott RJ, McPhillips M, Meldrum CJ, Fitzgerald PE, Adams K, Spigelman AD, et al. Hereditary nonpolyposis colorectal cancer in 95 families: differences and similarities between mutation-positive and mutation-negative kindreds. Am J Hum Genet. 2001;68:118–27.PubMedCrossRefGoogle Scholar
  21. 21.
    Vasen HF, Morreau H, Nortier JW. Is breast cancer part of the tumor spectrum of hereditary nonpolyposis colorectal cancer? Am J Hum Genet. 2001;68:1533–5.PubMedCrossRefGoogle Scholar
  22. 22.
    Soravia C, van der Klift H, Brundler MA, Blouin JL, Wijnen J, Hutter P, et al. Prostate cancer is part of the hereditary non-polyposis colorectal cancer (HNPCC) tumor spectrum. Am J Med Genet. 2003;121:159–62.CrossRefGoogle Scholar
  23. 23.
    Aarnio M, Mecklin JP, Aaltonen LA, Nystrom-Lahti M, Jarvinen HJ. Life-time risk of different cancers in hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Int J Cancer. 1995;64:430–3.PubMedCrossRefGoogle Scholar
  24. 24.
    Vasen HF, Stormorken A, Menko FH, Nagengast FM, Kleibeuker JH, Griffioen G, 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. 2001;19:4074–80.PubMedGoogle Scholar
  25. 25.
    Dunlop MG, Farrington SM, Carothers AD, Wyllie AH, Sharp L, Burn J, et al. Cancer risk associated with germline DNA mismatch repair gene mutations. Hum Mol Genet. 1997;6:105–10.PubMedCrossRefGoogle Scholar
  26. 26.
    Hendriks YM, Wagner A, Morreau H, Menko F, Stormorken A, Quehenberger F, et al. Cancer risk in hereditary nonpolyposis colorectal cancer due to MSH6 mutations: impact on counseling and surveillance. Gastroenterology. 2004;127:17–25.PubMedCrossRefGoogle Scholar
  27. 27.
    Quehenberger F, Vasen HF, van Houwelingen HC. Risk of colorectal and endometrial cancer for carriers of mutations of the hMLH1 and hMSH2 gene: correction for ascertainment. J Med Genet. 2005;42:491–6.PubMedCrossRefGoogle Scholar
  28. 28.
    Hampel H, de la Chapelle A, Stephens JA, Pukkala E, Sankila R, Aaltonen LA, et al. Cancer risk in hereditary nonpolyposis colorectal cancer syndrome: later age of onset. Gastroenterology. 2005;129:415–21.PubMedGoogle Scholar
  29. 29.
    Jenkins MA, Baglietto L, Dowty JG, Van Vliet CM, Smith L, Mead LJ, et al. Cancer risks for mismatch repair gene mutation carriers: a population-based early onset case-family study. Clin Gastroenterol Hepatol. 2006;4:489–98.PubMedCrossRefGoogle Scholar
  30. 30.
    Buttin BM, Powell MA, Mutch DG, Babb SA, Huettner PC, Edmonston TB, et al. Penetrance and expressivity of MSH6 germline mutations in seven kindreds not ascertained by family history. Am J Hum Genet. 2004;74:1262–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Lin KM, Shashidharan M, Ternent CA, Thorson AG, Blatchford GJ, Christensen MA, et al. Colorectal and extracolonic cancer variations in MLH1/MSH2 hereditary nonpolyposis colorectal cancer kindreds and the general population. Dis Colon Rectum. 1998;41:428–33.PubMedCrossRefGoogle Scholar
  32. 32.
    Hendriks YM, Jagmohan-Changur S, van der Klift HM, Morreau H, van Puijenbroek M, Tops C, et al. Heterozygous mutations in PMS2 cause hereditary nonpolyposis colorectal carcinoma (Lynch syndrome). Gastroenterology. 2006;130:312–22.PubMedCrossRefGoogle Scholar
  33. 33.
    Moisio AL, Sistonen P, Mecklin JP, Jarvinen H, Peltomaki P. Genetic polymorphisms in carcinogen metabolism and their association to hereditary nonpolyposis colon cancer. Gastroenterology. 1998;115:1387–94.PubMedCrossRefGoogle Scholar
  34. 34.
    Kong S, Amos CI, Luthra R, Lynch PM, Levin B, Frazier ML. Effects of cyclin D1 polymorphism on age of onset of hereditary nonpolyposis colorectal cancer. Cancer Res. 2000;60:249–52.PubMedGoogle Scholar
  35. 35.
    Heinimann K, Scott RJ, Chappuis P, Weber W, Muller H, Dobbie Z, et al. N-acetyltransferase 2 influences cancer prevalence in hMLH1/hMSH2 mutation carriers. Cancer Res. 1999;59:3038–40.PubMedGoogle Scholar
  36. 36.
    Frazier ML, O’Donnell FT, Kong S, Gu X, Campos I, Luthra R, et al. Age-associated risk of cancer among individuals with N-acetyltransferase 2 (NAT2) mutations and mutations in DNA mismatch repair genes. Cancer Res. 2001;61:1269–71.PubMedGoogle Scholar
  37. 37.
    Bala S, Peltomaki P. CYCLIN D1 as a genetic modifier in hereditary nonpolyposis colorectal cancer. Cancer Res. 2001;61:6042–5.PubMedGoogle Scholar
  38. 38.
    Jones JS, Chi X, Gu X, Lynch PM, Amos CI, Frazier ML. p53 polymorphism and age of onset of hereditary nonpolyposis colorectal cancer in a Caucasian population. Clin Cancer Res. 2004;10:5845–9.PubMedCrossRefGoogle Scholar
  39. 39.
    Jones JS, Amos CI, Pande M, Gu X, Chen J, Campos IM, et al. DNMT3b polymorphism and hereditary nonpolyposis colorectal cancer age of onset. Cancer Epidemiol Biomarkers Prev. 2006;15:886–91.PubMedCrossRefGoogle Scholar
  40. 40.
    Maillet P, Chappuis PO, Vaudan G, Dobbie Z, Muller H, Hutter P, et al. A polymorphism in the ATM gene modulates the penetrance of hereditary non-polyposis colorectal cancer. Int J Cancer. 2000;88:928–31.PubMedCrossRefGoogle Scholar
  41. 41.
    Sotamaa K, Liyanarachchi S, Mecklin JP, Jarvinen H, Aaltonen LA, Peltomaki P, et al. p53 codon 72 and MDM2 SNP309 polymorphisms and age of colorectal cancer onset in Lynch syndrome. Clin Cancer Res. 2005;11:6840–4.PubMedCrossRefGoogle Scholar
  42. 42.
    Kruger S, Bier A, Engel C, Mangold E, Pagenstecher C, von Knebel DM, et al. The p53 codon 72 variation is associated with the age of onset of hereditary non-polyposis colorectal cancer (HNPCC). J Med Genet. 2005;42:769–73.PubMedCrossRefGoogle Scholar
  43. 43.
    Kruger S, Silber AS, Engel C, Gorgens H, Mangold E, Pagenstecher C, et al. Arg462Gln sequence variation in the prostate-cancer-susceptibility gene RNASEL and age of onset of hereditary non-polyposis colorectal cancer: a case-control study. Lancet Oncol. 2005;6:566–72.PubMedCrossRefGoogle Scholar
  44. 44.
    Kruger S, Engel C, Bier A, Mangold E, Pagenstecher C, Doeberitz MK, et al. Absence of association between cyclin D1 (CCND1) G870A polymorphism and age of onset in hereditary nonpolyposis colorectal cancer. Cancer Lett. 2006;236:191–7.PubMedCrossRefGoogle Scholar
  45. 45.
    Zecevic M, Amos CI, Gu X, Campos IM, Jones JS, Lynch PM, et al. IGF1 gene polymorphism and risk for hereditary nonpolyposis colorectal cancer. J Natl Cancer Inst. 2006;98:139–43.PubMedCrossRefGoogle Scholar
  46. 46.
    Felix R, Bodmer W, Fearnhead NS, van der Merwe L, Goldberg P, Ramesar RS. GSTM1 and GSTT1 polymorphisms as modifiers of age at diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC) in a homogeneous cohort of individuals carrying a single predisposing mutation. Mutat Res. 2006;602:175–81.PubMedCrossRefGoogle Scholar
  47. 47.
    Pistorius S, Gorgens H, Kruger S, Engel C, Mangold E, Pagenstecher C, et al. The German Hnpcc-Consortium. N-acetyltransferase (NAT) 2 acetylator status and age of onset in patients with hereditary nonpolyposis colorectal cancer (HNPCC). Cancer Lett. 2006;241:150–7.PubMedCrossRefGoogle Scholar
  48. 48.
    Campbell PT, Edwards L, McLaughlin JR, Green J, Younghusband HB, Woods MO. Cytochrome P450 17A1 and catechol O-methyltransferase polymorphisms and age at Lynch syndrome colon cancer onset in Newfoundland. Clin Cancer Res. 2007;13:3783–8.PubMedCrossRefGoogle Scholar
  49. 49.
    Talseth BA, Meldrum C, Suchy J, Kurzawski G, Lubinski J, Scott RJ. MDM2 SNP309 T > G alone or in combination with the TP53 R72P polymorphism does not appear to influence disease expression and age of diagnosis of colorectal cancer in HNPCC patients. Int J Cancer. 2007;120:563–5.PubMedCrossRefGoogle Scholar
  50. 50.
    ten Kate GL, Kleibeuker JH, Nagengast FM, Craanen M, Cats A, Menko FH, et al. Is surveillance of the small bowel indicated for Lynch syndrome families? Gut. 2007;56:1198–201.PubMedCrossRefGoogle Scholar
  51. 51.
    Menko FH, te Meerman GJ, Sampson JR. Variable age of onset in hereditary nonpolyposis colorectal cancer: clinical implications. Gastroenterology. 1993;104:946–7.PubMedGoogle Scholar
  52. 52.
    Voskuil DW, Vasen HF, Kampman E, van’t Veer P. Colorectal cancer risk in HNPCC families: development during lifetime and in successive generations. National Collaborative Group on HNPCC. Int J Cancer. 1997;72:205–9.PubMedCrossRefGoogle Scholar
  53. 53.
    Tsai YY, Petersen GM, Booker SV, Bacon JA, Hamilton SR, Giardiello FM. Evidence against genetic anticipation in familial colorectal cancer. Genet Epidemiol. 1997;14:435–46.PubMedCrossRefGoogle Scholar
  54. 54.
    de Jong AE, van Puijenbroek M, Hendriks Y, Tops C, Wijnen J, Ausems MG, et al. Microsatellite instability, immunohistochemistry, and additional PMS2 staining in suspected hereditary nonpolyposis colorectal cancer. Clin Cancer Res. 2004;10:972–80.PubMedCrossRefGoogle Scholar
  55. 55.
    de Vos tot Nederveen Cappel WH, Buskens E, van Duijvendijk P, Cats A, Menko FH, Griffioen G, et al. Decision analysis in the surgical treatment of colorectal cancer due to a mismatch repair gene defect. Gut. 2003;52:1752–5.CrossRefGoogle Scholar
  56. 56.
    de Jong AE, Morreau H, van Puijenbroek M, Eilers PH, Wijnen J, Nagengast FM, et al. The role of mismatch repair gene defects in the development of adenomas in patients with HNPCC. Gastroenterology. 2004;126:42–8.PubMedCrossRefGoogle Scholar
  57. 57.
    Jass JR, Stewart SM, Stewart J, Lane MR. Hereditary non-polyposis colorectal cancer – morphologies, genes and mutations. Mutat Res. 1994;310:125–33.PubMedCrossRefGoogle Scholar
  58. 58.
    Vasen HF, Nagengast FM, Khan PM. Interval cancers in hereditary non-polyposis colorectal cancer (Lynch syndrome). Lancet. 1995;345:1183–4.PubMedCrossRefGoogle Scholar
  59. 59.
    Sankila R, Aaltonen LA, Jarvinen HJ, Mecklin JP. Better survival rates in patients with MLH1-associated hereditary colorectal cancer. Gastroenterology. 1996;110:682–7.PubMedCrossRefGoogle Scholar
  60. 60.
    Boks DE, Trujillo AP, Voogd AC, Morreau H, Kenter GG, Vasen HF. Survival analysis of endometrial carcinoma associated with hereditary nonpolyposis colorectal cancer. Int J Cancer. 2002;102:198–200.PubMedCrossRefGoogle Scholar
  61. 61.
    de Leeuw WJ, Dierssen J, Vasen HF, Wijnen JT, Kenter GG, Meijers-Heijboer H, et al. Prediction of a mismatch repair gene defect by microsatellite instability and immunohistochemical analysis in endometrial tumours from HNPCC patients. J Pathol. 2000;192:328–35.PubMedCrossRefGoogle Scholar
  62. 62.
    van den Bos M, van den Hoven M, Jongejan E, van der Leij F, Michels M, Schakenraad S, et al. More differences between HNPCC-related and sporadic carcinomas from the endometrium as compared to the colon. Am J Surg Pathol. 2004;28:706–11.PubMedCrossRefGoogle Scholar
  63. 63.
    Crijnen TE, Janssen-Heijnen ML, Gelderblom H, Morreau J, Nooij MA, Kenter GG, et al. Survival of patients with ovarian cancer due to a mismatch repair defect. Fam Cancer. 2005;4:301–5.PubMedCrossRefGoogle Scholar
  64. 64.
    Aarnio M, Salovaara R, Aaltonen LA, Mecklin JP, Jarvinen HJ. Features of gastric cancer in hereditary non-polyposis colorectal cancer syndrome. Int J Cancer. 1997;74:551–5.PubMedCrossRefGoogle Scholar
  65. 65.
    Rodriguez-Bigas MA, Vasen HF, Lynch HT, Watson P, Myrhoj T, Jarvinen HJ, et al. Characteristics of small bowel carcinoma in hereditary nonpolyposis colorectal carcinoma. International Collaborative Group on HNPCC. Cancer. 1998;83:240–4.PubMedCrossRefGoogle Scholar
  66. 66.
    Schulmann K, Brasch FE, Kunstmann E, Engel C, Pagenstecher C, Vogelsang H, et al. HNPCC-associated small bowel cancer: clinical and molecular characteristics. Gastroenterology. 2005;128:590–9.PubMedCrossRefGoogle Scholar
  67. 67.
    Hamilton SR, Liu B, Parsons RE, Papadopoulos N, Jen J, Powell SM, et al. The molecular basis of Turcot’s syndrome. N Engl J Med. 1995;332:839–47.PubMedCrossRefGoogle Scholar
  68. 68.
    de Jong AE. Shift in mortality due to surveillance in the Lynch syndrome. Gastroenterology. 2006;130: 665–71.PubMedCrossRefGoogle Scholar
  69. 69.
    Ponti G, Ponz de Leon M. Muir–Torre syndrome. Lancet Oncol. 2005;6:980–7.PubMedCrossRefGoogle Scholar
  70. 70.
    Hackman P, Tannergard P, Osei-Mensa S, Chen J, Kane MF, Kolodner R, et al. A human compound heterozygote for two MLH1 missense mutations. Nat Genet. 1997;17:135–6.PubMedCrossRefGoogle Scholar
  71. 71.
    Trimbath JD, Petersen GM, Erdman SH, Ferre M, Luce MC, Giardiello FM. Cafe-au-lait spots and early onset colorectal neoplasia: a variant of HNPCC? Fam Cancer. 2001;1:101–5.PubMedCrossRefGoogle Scholar
  72. 72.
    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;116:1453–6.PubMedCrossRefGoogle Scholar
  73. 73.
    Rodriguez-Bigas MA, Boland CR, Hamilton SR, Henson DE, Jass JR, Khan PM, et al. A National Cancer Institute Workshop on Hereditary Nonpolyposis Colorectal Cancer Syndrome: meeting highlights and Bethesda guidelines. J Natl Cancer Inst. 1997;89:1758–62.PubMedCrossRefGoogle Scholar
  74. 74.
    Pinol V, Castells A, Andreu M, Castellvi-Bel S, Alenda C, Llor X, et al. Accuracy of revised Bethesda guidelines, microsatellite instability, and immunohistochemistry for the identification of patients with hereditary nonpolyposis colorectal cancer. JAMA. 2005;293:1986–94.PubMedCrossRefGoogle Scholar
  75. 75.
    Wijnen JT, Vasen HF, Khan PM, Zwinderman AH, van der Klift H, Mulder A, et al. Clinical findings with implications for genetic testing in families with clustering of colorectal cancer. N Engl J Med. 1998;339:511–8.PubMedCrossRefGoogle Scholar
  76. 76.
    Jenkins MA, Hayashi S, O’Shea AM, Burgart LJ, Smyrk TC, Shimizu D, et al. Pathology features in Bethesda guidelines predict colorectal cancer microsatellite instability: a population-based study. Gastroenterology. 2007;133:48–56.PubMedCrossRefGoogle Scholar
  77. 77.
    Aaltonen LA, Peltomaki P, Leach FS, Sistonen P, Pylkkanen L, Mecklin JP, et al. Clues to the pathogenesis of familial colorectal cancer. Science. 1993;260:812–6.PubMedCrossRefGoogle Scholar
  78. 78.
    Hendriks Y, Franken P, Dierssen JW, De Leeuw W, Wijnen J, Dreef E, et al. Conventional and tissue microarray immunohistochemical expression analysis of mismatch repair in hereditary colorectal tumors. Am J Pathol. 2003;162:469–77.PubMedCrossRefGoogle Scholar
  79. 79.
    Debniak T, Kurzawski G, Gorski B, Kladny J, Domagala W, Lubinski J. Value of pedigree/clinical data, immunohistochemistry and microsatellite instability analyses in reducing the cost of determining hMLH1 and hMSH2 gene mutations in patients with colorectal cancer. Eur J Cancer. 2000;36:49–54.PubMedCrossRefGoogle Scholar
  80. 80.
    Cunningham JM, Kim CY, Christensen ER, Tester DJ, Parc Y, Burgart LJ, et al. The frequency of hereditary defective mismatch repair in a prospective series of unselected colorectal carcinomas. Am J Hum Genet. 2001;69:780–90.PubMedCrossRefGoogle Scholar
  81. 81.
    Scartozzi M, Bianchi F, Rosati S, Galizia E, Antolini A, Loretelli C, et al. Mutations of hMLH1 and hMSH2 in patients with suspected hereditary nonpolyposis colorectal cancer: correlation with microsatellite instability and abnormalities of mismatch repair protein expression. J Clin Oncol. 2002;20:1203–8.PubMedCrossRefGoogle Scholar
  82. 82.
    Engel C, Forberg C, Holinski-Feder E, Pagenstecher C, Plaschke J, Kloor M, 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;118:115–22.PubMedCrossRefGoogle Scholar
  83. 83.
    Southey MC, Jenkins MA, Mead L, Whitty J, Trivett M, Tesoriero AA, et al. Use of molecular tumor characteristics to prioritize mismatch repair gene testing in early-onset colorectal cancer. J Clin Oncol. 2005;23:6524–32.PubMedCrossRefGoogle Scholar
  84. 84.
    Niessen RC, Berends MJ, Wu Y, Sijmons RH, Hollema H, Ligtenberg MJ, et al. Identification of mismatch repair gene mutations in young colorectal cancer patients and patients with multiple HNPCC-associated tumours. Gut. 2006;55(12):1781–8.PubMedCrossRefGoogle Scholar
  85. 85.
    Hampel H, Frankel WL, Martin E, Arnold M, Khanduja K, Kuebler P, et al. Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med. 2005;352:1851–60.PubMedCrossRefGoogle Scholar
  86. 86.
    Barnetson RA, Tenesa A, Farrington SM, Nicholl ID, Cetnarskyj R, Porteous ME, et al. Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer. N Engl J Med. 2006;354:2751–63.PubMedCrossRefGoogle Scholar
  87. 87.
    Chen S, Wang W, Lee S, Nafa K, Lee J, Romans K, et al. Prediction of germline mutations and cancer risk in the Lynch syndrome. JAMA. 2006;296:1479–87.PubMedCrossRefGoogle Scholar
  88. 88.
    Lerman C, Hughes C, Trock BJ, Myers RE, Main D, Bonney A, et al. Genetic testing in families with hereditary nonpolyposis colon cancer. JAMA. 1999;281:1618–22.PubMedCrossRefGoogle Scholar
  89. 89.
    Aktan-Collan K, Mecklin JP, Jarvinen H, Nystrom-Lahti M, Peltomaki P, Soderling I, et al. Predictive genetic testing for hereditary non-polyposis colorectal cancer: uptake and long-term satisfaction. Int J Cancer. 2000;89:44–50.PubMedCrossRefGoogle Scholar
  90. 90.
    Wagner A, Tops C, Wijnen JT, Zwinderman K, van der Meer C, Kets M, et al. Genetic testing in hereditary non-polyposis colorectal cancer families with a MSH2, MLH1, or MSH6 mutation. J Med Genet. 2002;39:833–7.PubMedCrossRefGoogle Scholar
  91. 91.
    Love RR, Morrissey JF. Colonoscopy in asymptomatic individuals with a family history of colorectal cancer. Arch Intern Med. 1984;144:2209–11.PubMedCrossRefGoogle Scholar
  92. 92.
    Mecklin JP, Jarvinen HJ, Aukee S, Elomaa I, Karjalainen K. Screening for colorectal carcinoma in cancer family syndrome kindreds. Scand J Gastroenterol. 1987;22:449–53.PubMedCrossRefGoogle Scholar
  93. 93.
    Vasen HF, Taal BG, Nagengast FM, Griffioen G, Menko FH, Kleibeuker JH, et al. Hereditary nonpolyposis colorectal cancer: results of long-term surveillance in 50 families. Eur J Cancer. 1995;31A:1145–8.PubMedCrossRefGoogle Scholar
  94. 94.
    Jarvinen HJ, Mecklin JP, Sistonen P. Screening reduces colorectal cancer rate in families with hereditary nonpolyposis colorectal cancer. Gastroenterology. 1995;108:1405–11.PubMedCrossRefGoogle Scholar
  95. 95.
    Jarvinen HJ, Aarnio M, Mustonen H, Aktan-Collan K, Aaltonen LA, Peltomaki P, et al. Controlled 15-year trial on screening for colorectal cancer in families with hereditary nonpolyposis colorectal cancer. Gastroenterology. 2000;118:829–34.PubMedCrossRefGoogle Scholar
  96. 96.
    Arrigoni A, Sprujevnik T, Alvisi V, Rossi A, Ricci G, Pennazio M, et al. Clinical identification and long-term surveillance of 22 hereditary non-polyposis colon cancer Italian families. Eur J Gastroenterol Hepatol. 2005;17:213–9.PubMedCrossRefGoogle Scholar
  97. 97.
    de Vos tot Nederveen Cappel WH, Nagengast FM, Griffioen G, Menko FH, Taal BG, Kleibeuker JH, et al. Surveillance for hereditary nonpolyposis colorectal cancer: a long-term study on 114 families. Dis Colon Rectum. 2002;45:1588–94.CrossRefGoogle Scholar
  98. 98.
    Renkonen-Sinisalo L, Aarnio M, Mecklin JP, Jarvinen HJ. Surveillance improves survival of colorectal cancer in patients with hereditary nonpolyposis colorectal cancer. Cancer Detect Prev. 2000;24:137–42.PubMedGoogle Scholar
  99. 99.
    Stormorken AT, Clark N, Grindedal E, Maehle L, Moller P. Prevention of colorectal cancer by colonoscopic surveillance in families with hereditary colorectal cancer. Scand J Gastroenterol. 2007;42:611–7.PubMedCrossRefGoogle Scholar
  100. 100.
    Lecomte T, Cellier C, Meatchi T, Barbier JP, Cugnenc PH, Jian R, et al. Chromoendoscopic colonoscopy for detecting preneoplastic lesions in hereditary nonpolyposis colorectal cancer syndrome. Clin Gastroenterol Hepatol. 2005;3:897–902.PubMedCrossRefGoogle Scholar
  101. 101.
    Hurlstone DP, Karajeh M, Cross SS, McAlindon ME, Brown S, Hunter MD, et al. The role of high-magnification-chromoscopic colonoscopy in hereditary nonpolyposis colorectal cancer screening: a prospective “back-to-back” endoscopic study. Am J Gastroenterol. 2005;100:2167–73.PubMedCrossRefGoogle Scholar
  102. 102.
    Lindor NM, Rabe K, Petersen GM, Haile R, Casey G, Baron J, et al. Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X. JAMA. 2005;293:1979–85.PubMedCrossRefGoogle Scholar
  103. 103.
    Dove-Edwin I, Boks D, Goff S, Kenter GG, Carpenter R, Vasen HF, et al. The outcome of endometrial carcinoma surveillance by ultrasound scan in women at risk of hereditary nonpolyposis colorectal carcinoma and familial colorectal carcinoma. Cancer. 2002;94:1708–12.PubMedCrossRefGoogle Scholar
  104. 104.
    Rijcken FE, Mourits MJ, Kleibeuker JH, Hollema H, van der Zee AG. Gynecologic screening in hereditary nonpolyposis colorectal cancer. Gynecol Oncol. 2003;91:74–80.PubMedCrossRefGoogle Scholar
  105. 105.
    Renkonen-Sinisalo L, Butzow R, Leminen A, Lehtovirta P, Mecklin JP, Jarvinen HJ. Surveillance for endometrial cancer in hereditary nonpolyposis colorectal cancer syndrome. Int J Cancer. 2006;120(4):821–4.CrossRefGoogle Scholar
  106. 106.
    Schmeler KM, Lynch HT, Chen LM, Munsell MF, Soliman PT, Clark MB, et al. Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch syndrome. N Engl J Med. 2006;354:261–9.PubMedCrossRefGoogle Scholar
  107. 107.
    Weber T. Clinical surveillance recommendation adopted for HNPCC. 348th ed. Lancet. 2006;348:465.Google Scholar
  108. 108.
    Carethers JM, Chauhan DP, Fink D, Nebel S, Bresalier RS, Howell SB, et al. Mismatch repair proficiency and in vitro response to 5-fluorouracil. Gastroenterology. 1999;117:123–31.PubMedCrossRefGoogle Scholar
  109. 109.
    Jacob S, Aguado M, Fallik D, Praz F. The role of the DNA mismatch repair system in the cytotoxicity of the topoisomerase inhibitors camptothecin and etoposide to human colorectal cancer cells. Cancer Res. 2001;61:6555–62.PubMedGoogle Scholar
  110. 110.
    Liang JT, Huang KC, Lai HS, Lee PH, Cheng YM, Hsu HC, et al. High-frequency microsatellite instability predicts better chemosensitivity to high-dose 5-fluorouracil plus leucovorin chemotherapy for stage IV sporadic colorectal cancer after palliative bowel resection. Int J Cancer. 2002;101:519–25.PubMedCrossRefGoogle Scholar
  111. 111.
    Ribic CM, Sargent DJ, Moore MJ, Thibodeau SN, French AJ, Goldberg RM, et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med. 2003;349:247–57.PubMedCrossRefGoogle Scholar
  112. 112.
    Carethers JM, Smith EJ, Behling CA, Nguyen L, Tajima A, Doctolero RT, et al. Use of 5-fluorouracil and survival in patients with microsatellite-unstable colorectal cancer. Gastroenterology. 2004;126:394–401.PubMedCrossRefGoogle Scholar
  113. 113.
    de Vos tot Nederveen Cappel WH, Meulenbeld HJ, Kleibeuker JH, Nagengast FM, Menko FH, Griffioen G, et al. Survival after adjuvant 5-FU treatment for stage III colon cancer in hereditary nonpolyposis colorectal cancer. Int J Cancer. 2004;109:468–71.CrossRefGoogle Scholar
  114. 114.
    Fallik D, Borrini F, Boige V, Viguier J, Jacob S, Miquel C, et al. Microsatellite instability is a predictive factor of the tumor response to irinotecan in patients with advanced colorectal cancer. Cancer Res. 2003;63:5738–44.PubMedGoogle Scholar
  115. 115.
    Burn J, Bishop DT, Mecklin J-P, et al. Effect of aspirin or resistant starch on colorectal neoplasia in the Lynch syndrome. N Engl J Med. 2008;359:2567–78.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of GastroenterologyUniversity Medical CentreLeidenThe Netherlands
  2. 2.Medical OncologyLeiden University Medical CentreLeidenThe Netherlands
  3. 3.The Netherlands Foundation for the Detection of Hereditary TumoursLeiden University Medical Centre (Poortgebouw)LeidenThe Netherlands

Personalised recommendations