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Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis

INTRODUCTION

Lynch syndrome is the most common cause of inherited colorectal cancer (CRC). It is characterized by a significantly increased risk for CRC and endometrial cancer as well as a risk of several other malignancies. This topic will review the genetic basis, clinical manifestations, and diagnosis of Lynch syndrome. Surveillance strategies for individuals with Lynch syndrome are discussed separately. (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Screening and management of patients and families".)

TERMINOLOGY

Hereditary nonpolyposis colorectal cancer (HNPCC) refers to patients and/or families who fulfill the Amsterdam I or II criteria for Lynch syndrome (table 1). (See 'Amsterdam criteria' below.)

Lynch syndrome refers to patients and families with a germline mutation in one of the DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2) or the EPCAM gene.

EPIDEMIOLOGY

Approximately 70 to 80 percent of patients with colorectal cancer (CRC) have sporadic disease, but the remaining 20 to 30 percent have a familial or inherited component that might be causative. Lynch syndrome is the most common inherited CRC susceptibility syndrome and accounts for approximately 3 percent of newly diagnosed cases of CRC and 2 percent of endometrial cancer.

GENETICS

Lynch syndrome is an autosomal dominant disorder that is caused by a germline mutation in one of several DNA mismatch repair (MMR) genes or loss of expression of MSH2 due to deletion in the EPCAM gene (previously called TACSTD1). The MMR genes that are associated with Lynch syndrome include:

                       

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Literature review current through: Nov 2014. | This topic last updated: Dec 11, 2014.
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References
Top
  1. Palomaki GE, McClain MR, Melillo S, et al. EGAPP supplementary evidence review: DNA testing strategies aimed at reducing morbidity and mortality from Lynch syndrome. Genet Med 2009; 11:42.
  2. Koessler T, Oestergaard MZ, Song H, et al. Common variants in mismatch repair genes and risk of colorectal cancer. Gut 2008; 57:1097.
  3. Tannergård P, Lipford JR, Kolodner R, et al. Mutation screening in the hMLH1 gene in Swedish hereditary nonpolyposis colon cancer families. Cancer Res 1995; 55:6092.
  4. Kempers MJ, Kuiper RP, Ockeloen CW, et al. Risk of colorectal and endometrial cancers in EPCAM deletion-positive Lynch syndrome: a cohort study. Lancet Oncol 2011; 12:49.
  5. 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. Hampel H, Stephens JA, Pukkala E, et al. Cancer risk in hereditary nonpolyposis colorectal cancer syndrome: later age of onset. Gastroenterology 2005; 129:415.
  7. Lin KM, Shashidharan M, Ternent CA, 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.
  8. Parry S, Win AK, Parry B, et al. Metachronous colorectal cancer risk for mismatch repair gene mutation carriers: the advantage of more extensive colon surgery. Gut 2011; 60:950.
  9. 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.
  10. Sankila R, Aaltonen LA, Järvinen HJ, Mecklin JP. Better survival rates in patients with MLH1-associated hereditary colorectal cancer. Gastroenterology 1996; 110:682.
  11. Aarnio M, Mecklin JP, Aaltonen LA, et al. Life-time risk of different cancers in hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Int J Cancer 1995; 64:430.
  12. Obermair A, Youlden DR, Young JP, et al. Risk of endometrial cancer for women diagnosed with HNPCC-related colorectal carcinoma. Int J Cancer 2010; 127:2678.
  13. Senter L, Clendenning M, Sotamaa K, et al. The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations. Gastroenterology 2008; 135:419.
  14. Talseth-Palmer BA, McPhillips M, Groombridge C, et al. MSH6 and PMS2 mutation positive Australian Lynch syndrome families: novel mutations, cancer risk and age of diagnosis of colorectal cancer. Hered Cancer Clin Pract 2010; 8:5.
  15. Mecklin JP, Järvinen HJ. Tumor spectrum in cancer family syndrome (hereditary nonpolyposis colorectal cancer). Cancer 1991; 68:1109.
  16. Soravia C, van der Klift H, Bründler MA, et al. Prostate cancer is part of the hereditary non-polyposis colorectal cancer (HNPCC) tumor spectrum. Am J Med Genet A 2003; 121A:159.
  17. Win AK, Young JP, Lindor NM, 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 2012; 30:958.
  18. Win AK, Lindor NM, Young JP, et al. Risks of primary extracolonic cancers following colorectal cancer in lynch syndrome. J Natl Cancer Inst 2012; 104:1363.
  19. Engel C, Loeffler M, Steinke V, et al. Risks of less common cancers in proven mutation carriers with lynch syndrome. J Clin Oncol 2012; 30:4409.
  20. Raymond VM, Mukherjee B, Wang F, et al. Elevated risk of prostate cancer among men with Lynch syndrome. J Clin Oncol 2013.
  21. Win AK, Lindor NM, Winship I, et al. Risks of colorectal and other cancers after endometrial cancer for women with Lynch syndrome. J Natl Cancer Inst 2013; 105:274.
  22. Raymond VM, Everett JN, Furtado LV, et al. Adrenocortical carcinoma is a lynch syndrome-associated cancer. J Clin Oncol 2013; 31:3012.
  23. Buerki N, Gautier L, Kovac M, et al. Evidence for breast cancer as an integral part of Lynch syndrome. Genes Chromosomes Cancer 2012; 51:83.
  24. Müller A, Edmonston TB, Corao DA, et al. Exclusion of breast cancer as an integral tumor of hereditary nonpolyposis colorectal cancer. Cancer Res 2002; 62:1014.
  25. Rosty C, Walsh MD, Lindor NM, et al. High prevalence of mismatch repair deficiency in prostate cancers diagnosed in mismatch repair gene mutation carriers from the colon cancer family registry. Fam Cancer 2014; 13:573.
  26. Giardiello FM, Allen JI, Axilbund JE, et al. Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-Society Task Force on colorectal cancer. Gastroenterology 2014; 147:502.
  27. South CD, Hampel H, Comeras I, et al. The frequency of Muir-Torre syndrome among Lynch syndrome families. J Natl Cancer Inst 2008; 100:277.
  28. Ponti G, Ponz de Leon M. Muir-Torre syndrome. Lancet Oncol 2005; 6:980.
  29. Bonadona V, Bonaïti B, Olschwang S, et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA 2011; 305:2304.
  30. Vasen HF, Möslein G, Alonso A, et al. Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer). J Med Genet 2007; 44:353.
  31. Watson P, Vasen HF, Mecklin JP, et al. The risk of extra-colonic, extra-endometrial cancer in the Lynch syndrome. Int J Cancer 2008; 123:444.
  32. Clendenning M, Senter L, Hampel H, et al. A frame-shift mutation of PMS2 is a widespread cause of Lynch syndrome. J Med Genet 2008; 45:340.
  33. Ligtenberg MJ, Kuiper RP, Geurts van Kessel A, Hoogerbrugge N. EPCAM deletion carriers constitute a unique subgroup of Lynch syndrome patients. Fam Cancer 2013; 12:169.
  34. Jenkins MA, Hayashi S, O'Shea AM, et al. Pathology features in Bethesda guidelines predict colorectal cancer microsatellite instability: a population-based study. Gastroenterology 2007; 133:48.
  35. Bessa X, Alenda C, Paya A, et al. Validation microsatellite path score in a population-based cohort of patients with colorectal cancer. J Clin Oncol 2011; 29:3374.
  36. Hampel H, de la Chapelle A. The search for unaffected individuals with Lynch syndrome: do the ends justify the means? Cancer Prev Res (Phila) 2011; 4:1.
  37. American Gastroenterological Association. American Gastroenterological Association medical position statement: hereditary colorectal cancer and genetic testing. Gastroenterology 2001; 121:195.
  38. Barnetson RA, Tenesa A, Farrington SM, et al. Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer. N Engl J Med 2006; 354:2751.
  39. Balmaña J, Stockwell DH, Steyerberg EW, et al. Prediction of MLH1 and MSH2 mutations in Lynch syndrome. JAMA 2006; 296:1469.
  40. Wijnen JT, Vasen HF, Khan PM, et al. Clinical findings with implications for genetic testing in families with clustering of colorectal cancer. N Engl J Med 1998; 339:511.
  41. Green RC, Parfrey PS, Woods MO, Younghusband HB. Prediction of Lynch syndrome in consecutive patients with colorectal cancer. J Natl Cancer Inst 2009; 101:331.
  42. Chen S, Wang W, Lee S, et al. Prediction of germline mutations and cancer risk in the Lynch syndrome. JAMA 2006; 296:1479.
  43. Kastrinos F, Steyerberg EW, Mercado R, et al. The PREMM(1,2,6) model predicts risk of MLH1, MSH2, and MSH6 germline mutations based on cancer history. Gastroenterology 2011; 140:73.
  44. Giardiello FM, Allen JI, Axilbund JE, 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 2014; 57:1025.
  45. Dinh TA, Rosner BI, Atwood JC, et al. Health benefits and cost-effectiveness of primary genetic screening for Lynch syndrome in the general population. Cancer Prev Res (Phila) 2011; 4:9.
  46. Kastrinos F, Steyerberg EW, Balmaña J, et al. Comparison of the clinical prediction model PREMM(1,2,6) and molecular testing for the systematic identification of Lynch syndrome in colorectal cancer. Gut 2013; 62:272.
  47. Balmaña J, Balaguer F, Castellví-Bel S, et al. Comparison of predictive models, clinical criteria and molecular tumour screening for the identification of patients with Lynch syndrome in a population-based cohort of colorectal cancer patients. J Med Genet 2008; 45:557.
  48. Tresallet C, Brouquet A, Julié C, et al. Evaluation of predictive models in daily practice for the identification of patients with Lynch syndrome. Int J Cancer 2012; 130:1367.
  49. Hampel H, Frankel WL, Martin E, et al. Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med 2005; 352:1851.
  50. 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.
  51. Percesepe A, Borghi F, Menigatti M, et al. Molecular screening for hereditary nonpolyposis colorectal cancer: a prospective, population-based study. J Clin Oncol 2001; 19:3944.
  52. Ravnik-Glavac M, Potocnik U, Glavac D. Incidence of germline hMLH1 and hMSH2 mutations (HNPCC patients) among newly diagnosed colorectal cancers in a Slovenian population. J Med Genet 2000; 37:533.
  53. Julié C, Trésallet C, Brouquet A, et al. Identification in daily practice of patients with Lynch syndrome (hereditary nonpolyposis colorectal cancer): revised Bethesda guidelines-based approach versus molecular screening. Am J Gastroenterol 2008; 103:2825.
  54. Moreira L, Balaguer F, Lindor N, et al. Identification of Lynch syndrome among patients with colorectal cancer. JAMA 2012; 308:1555.
  55. Mvundura M, Grosse SD, Hampel H, Palomaki GE. The cost-effectiveness of genetic testing strategies for Lynch syndrome among newly diagnosed patients with colorectal cancer. Genet Med 2010; 12:93.
  56. Ladabaum U, Wang G, Terdiman J, et al. Strategies to identify the Lynch syndrome among patients with colorectal cancer: a cost-effectiveness analysis. Ann Intern Med 2011; 155:69.
  57. Weissman SM, Bellcross C, Bittner CC, et al. Genetic counseling considerations in the evaluation of families for Lynch syndrome--a review. J Genet Couns 2011; 20:5.
  58. Shia J. Immunohistochemistry versus microsatellite instability testing for screening colorectal cancer patients at risk for hereditary nonpolyposis colorectal cancer syndrome. Part I. The utility of immunohistochemistry. J Mol Diagn 2008; 10:293.
  59. Hampel H, Frankel WL, Martin E, et al. Feasibility of screening for Lynch syndrome among patients with colorectal cancer. J Clin Oncol 2008; 26:5783.
  60. Yurgelun MB, Goel A, Hornick JL, et al. Microsatellite instability and DNA mismatch repair protein deficiency in Lynch syndrome colorectal polyps. Cancer Prev Res (Phila) 2012; 5:574.
  61. Walsh MD, Buchanan DD, Pearson SA, et al. Immunohistochemical testing of conventional adenomas for loss of expression of mismatch repair proteins in Lynch syndrome mutation carriers: a case series from the Australasian site of the colon cancer family registry. Mod Pathol 2012; 25:722.
  62. Parsons MT, Buchanan DD, Thompson B, et al. Correlation of tumour BRAF mutations and MLH1 methylation with germline mismatch repair (MMR) gene mutation status: a literature review assessing utility of tumour features for MMR variant classification. J Med Genet 2012; 49:151.
  63. Jin M, Hampel H, Zhou X, et al. BRAF V600E mutation analysis simplifies the testing algorithm for Lynch syndrome. Am J Clin Pathol 2013; 140:177.
  64. Lynch HT, Lynch JF, Lynch PM. Toward a consensus in molecular diagnosis of hereditary nonpolyposis colorectal cancer (Lynch syndrome). J Natl Cancer Inst 2007; 99:261.
  65. Castillejo A, Vargas G, Castillejo MI, et al. Prevalence of germline MUTYH mutations among Lynch-like syndrome patients. Eur J Cancer 2014; 50:2241.
  66. Ricciardone MD, Ozçelik T, Cevher B, et al. Human MLH1 deficiency predisposes to hematological malignancy and neurofibromatosis type 1. Cancer Res 1999; 59:290.
  67. Whiteside D, McLeod R, Graham G, et al. A homozygous germ-line mutation in the human MSH2 gene predisposes to hematological malignancy and multiple café-au-lait spots. Cancer Res 2002; 62:359.
  68. Bougeard G, Charbonnier F, Moerman A, et al. Early onset brain tumor and lymphoma in MSH2-deficient children. Am J Hum Genet 2003; 72:213.
  69. Gallinger S, Aronson M, Shayan K, et al. Gastrointestinal cancers and neurofibromatosis type 1 features in children with a germline homozygous MLH1 mutation. Gastroenterology 2004; 126:576.
  70. Menko FH, Kaspers GL, Meijer GA, et al. A homozygous MSH6 mutation in a child with café-au-lait spots, oligodendroglioma and rectal cancer. Fam Cancer 2004; 3:123.
  71. Nakagawa H, Lockman JC, Frankel WL, 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 2004; 64:4721.
  72. Truninger K, Menigatti M, Luz J, et al. Immunohistochemical analysis reveals high frequency of PMS2 defects in colorectal cancer. Gastroenterology 2005; 128:1160.
  73. Worthley DL, Walsh MD, Barker M, et al. Familial mutations in PMS2 can cause autosomal dominant hereditary nonpolyposis colorectal cancer. Gastroenterology 2005; 128:1431.
  74. Felton KE, Gilchrist DM, Andrew SE. Constitutive deficiency in DNA mismatch repair. Clin Genet 2007; 71:483.
  75. Will O, Carvajal-Carmona LG, Gorman P, et al. Homozygous PMS2 deletion causes a severe colorectal cancer and multiple adenoma phenotype without extraintestinal cancer. Gastroenterology 2007; 132:527.
  76. Lindor NM, Rabe K, Petersen GM, et al. Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X. JAMA 2005; 293:1979.
  77. Mensenkamp AR, Vogelaar IP, van Zelst-Stams WA, et al. Somatic mutations in MLH1 and MSH2 are a frequent cause of mismatch-repair deficiency in Lynch syndrome-like tumors. Gastroenterology 2014; 146:643.