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Clinical features and diagnosis of Lynch syndrome (hereditary nonpolyposis colorectal cancer)

INTRODUCTION

Lynch syndrome, also called hereditary nonpolyposis colorectal cancer (HNPCC), is the most common of the inherited colon cancer susceptibility syndromes. The use of the name HNPCC can be misleading in that this disorder predisposes to colon cancer and a variety of other cancers. As a result, the previously used name Lynch syndrome (after Dr. Henry Lynch, who did much to characterize and emphasize the importance of this familial syndrome) is being used more commonly.

Lynch syndrome is an autosomal dominant disorder that is caused by a germline mutation in one of several DNA mismatch repair (MMR) genes. It accounts for 2 to 3 percent of all colon cancer cases and similarly is responsible for about 2 percent of endometrial cancers. Lynch syndrome is characterized by significantly increased risk for colon cancer and endometrial cancer as well as a smaller risk of several other associated cancers.

The clinical manifestations, diagnostic criteria, and genetics of Lynch syndrome will be reviewed here. Surveillance and screening strategies for Lynch syndrome are discussed separately. (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Screening and management of patients and families".)

The American Gastroenterological Association (AGA) guideline for hereditary colorectal cancer and genetic testing [1], as well as other AGA guidelines, can be accessed through the AGA web site at www.gastro.org/practice/medical-position-statements.

CLINICAL MANIFESTATIONS

Patients with Lynch syndrome have a markedly increased risk of colorectal cancer (picture 1), endometrial cancer, and several other cancers including ovarian, upper urologic tract, gastric, small bowel, biliary/pancreatic, skin (sebaceous adenomas and carcinomas and keratoacanthomas), and brain cancers. The cancer risk in Lynch syndrome varies depending on geographic/environmental factors (for example, gastric cancer is a more common Lynch-associated cancer in countries such as China and Korea with a high sporadic prevalence of that disease). Similarly, the age-incidence and spectrum of cancers in Lynch syndrome vary significantly based upon the mismatch repair (MMR) gene mutated; this will be described in more detail after the genetics of the syndrome is presented.

                          

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Literature review current through: Oct 2014. | This topic last updated: Nov 5, 2013.
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References
Top
  1. American Gastroenterological Association. American Gastroenterological Association medical position statement: hereditary colorectal cancer and genetic testing. Gastroenterology 2001; 121:195.
  2. Hampel H, Stephens JA, Pukkala E, et al. Cancer risk in hereditary nonpolyposis colorectal cancer syndrome: later age of onset. Gastroenterology 2005; 129:415.
  3. 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.
  4. 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.
  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. 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.
  7. 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.
  8. 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.
  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. 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.
  16. Mecklin JP, Järvinen HJ. Tumor spectrum in cancer family syndrome (hereditary nonpolyposis colorectal cancer). Cancer 1991; 68:1109.
  17. 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.
  18. 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.
  19. 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.
  20. 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.
  21. Raymond VM, Mukherjee B, Wang F, et al. Elevated risk of prostate cancer among men with Lynch syndrome. J Clin Oncol 2013.
  22. 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.
  23. Raymond VM, Everett JN, Furtado LV, et al. Adrenocortical carcinoma is a lynch syndrome-associated cancer. J Clin Oncol 2013; 31:3012.
  24. 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.
  25. 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.
  26. Ponti G, Ponz de Leon M. Muir-Torre syndrome. Lancet Oncol 2005; 6:980.
  27. Wu Y, Berends MJ, Sijmons RH, et al. A role for MLH3 in hereditary nonpolyposis colorectal cancer. Nat Genet 2001; 29:137.
  28. 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.
  29. Koessler T, Oestergaard MZ, Song H, et al. Common variants in mismatch repair genes and risk of colorectal cancer. Gut 2008; 57:1097.
  30. 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.
  31. 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.
  32. 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.
  33. Lin-Hurtubise KM, Yheulon CG, Gagliano RA Jr, Lynch HT. Excess of extracolonic non-endometrial multiple primary cancers in MSH2 germline mutation carriers over MLH1. J Surg Oncol 2013; 108:433.
  34. Ricciardone MD, Ozçelik T, Cevher B, et al. Human MLH1 deficiency predisposes to hematological malignancy and neurofibromatosis type 1. Cancer Res 1999; 59:290.
  35. 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.
  36. 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.
  37. 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.
  38. 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.
  39. 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.
  40. Truninger K, Menigatti M, Luz J, et al. Immunohistochemical analysis reveals high frequency of PMS2 defects in colorectal cancer. Gastroenterology 2005; 128:1160.
  41. Worthley DL, Walsh MD, Barker M, et al. Familial mutations in PMS2 can cause autosomal dominant hereditary nonpolyposis colorectal cancer. Gastroenterology 2005; 128:1431.
  42. Felton KE, Gilchrist DM, Andrew SE. Constitutive deficiency in DNA mismatch repair. Clin Genet 2007; 71:483.
  43. 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.
  44. 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.
  45. 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.
  46. 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.
  47. 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.
  48. 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.
  49. 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.
  50. 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.
  51. 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.
  52. Rumilla K, Schowalter KV, Lindor NM, et al. Frequency of deletions of EPCAM (TACSTD1) in MSH2-associated Lynch syndrome cases. J Mol Diagn 2011; 13:93.
  53. 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.
  54. 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.
  55. 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.
  56. Hampel H, Frankel WL, Martin E, et al. Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med 2005; 352:1851.
  57. 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.
  58. 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.
  59. 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.
  60. 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.
  61. Beamer LC, Grant ML, Espenschied CR, et al. Reflex immunohistochemistry and microsatellite instability testing of colorectal tumors for Lynch syndrome among US cancer programs and follow-up of abnormal results. J Clin Oncol 2012; 30:1058.
  62. Moreira L, Balaguer F, Lindor N, et al. Identification of Lynch syndrome among patients with colorectal cancer. JAMA 2012; 308:1555.
  63. 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.
  64. 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.
  65. Lindor NM, Petersen GM, Hadley DW, et al. Recommendations for the care of individuals with an inherited predisposition to Lynch syndrome: a systematic review. JAMA 2006; 296:1507.
  66. 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.
  67. Balmaña J, Stockwell DH, Steyerberg EW, et al. Prediction of MLH1 and MSH2 mutations in Lynch syndrome. JAMA 2006; 296:1469.
  68. 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.
  69. 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.
  70. 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.
  71. 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.
  72. Chen S, Wang W, Lee S, et al. Prediction of germline mutations and cancer risk in the Lynch syndrome. JAMA 2006; 296:1479.
  73. Balaguer F, Balmaña J, Castellví-Bel S, et al. Validation and extension of the PREMM1,2 model in a population-based cohort of colorectal cancer patients. Gastroenterology 2008; 134:39.
  74. 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.
  75. 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.
  76. 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.
  77. Lagerstedt Robinson K, Liu T, Vandrovcova J, et al. Lynch syndrome (hereditary nonpolyposis colorectal cancer) diagnostics. J Natl Cancer Inst 2007; 99:291.
  78. Goel A, Nagasaka T, Spiegel J, et al. Low frequency of Lynch syndrome among young patients with non-familial colorectal cancer. Clin Gastroenterol Hepatol 2010; 8:966.
  79. Statement of the American Society of Clinical Oncology: genetic testing for cancer susceptibility, Adopted on February 20, 1996. J Clin Oncol 1996; 14:1730.
  80. Leib JR, Hoddfar E, Larsen Haidle J, et al. The new genetic privacy law. Community Oncology 2008; 5:351.