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New Insights into Lynch Syndrome Diagnosis

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DNA Alterations in Lynch Syndrome

Abstract

Colorectal cancer (CRC) is the third most common cancer worldwide. Lynch syndrome accounts for 1–3 % of patients developing colorectal cancer. This autosomal dominant disorder is caused by germline mutations in the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2. A mutation in one of these genes is characterised by the development of CRC and various other associated cancers at an early age. The diagnosis of Lynch syndrome has evolved over the last two decades to include family history, tumour histopathological characteristics, immunohistochemistry, testing for microsatellite instability as well as germline genetic testing as modalities for making the diagnosis. By identifying families and individuals with Lynch syndrome, individuals can be enrolled in focussed screening programmes that have been shown to decrease mortality from colorectal cancer. In this chapter we define the terms “HNPCC”, “Lynch syndrome” and “Familial colorectal cancer syndrome X” and discuss the different diagnostic modalities. We propose a logical and cost-effective algorithm to diagnose Lynch syndrome, by appropriately using all the diagnostic modalities in the at-risk individual.

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References

  1. Siegel R, Naishadham D, Jemal A (2012) Cancer statistics. CA Cancer J Clin 62:10–29. doi:10.3322/caac.20138; 10.3322/caac.20138

    Article  PubMed  Google Scholar 

  2. Jass JR (2005) What’s new in hereditary colorectal cancer? Arch Pathol Lab Med 129:1380–1384. doi:10.1043/1543-2165(2005)129

    PubMed  Google Scholar 

  3. Hampel H, Frankel WL, Martin E et al (2005) Screening for the lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med 352:1851–1860. doi:10.1056/NEJMoa043146

    Article  PubMed  CAS  Google Scholar 

  4. Lynch HT, de la Chapelle A (2003) Hereditary colorectal cancer. N Engl J Med 348:919–932. doi:10.1056/NEJMra012242

    Article  PubMed  CAS  Google Scholar 

  5. Vasen HF, Moslein G, Alonso A et al (2007) Guidelines for the clinical management of lynch syndrome (hereditary non-polyposis cancer). J Med Genet 4:353–362. doi:10.1136/jmg.2007.048991

    Article  Google Scholar 

  6. Moreira L, Balaguer F, Lindor N et al (2012) Identification of lynch syndrome among patients with colorectal cancer. JAMA 308:1555–1565. doi:10.1001/jama.2012.13088; 10.1001/jama.2012.13088

    Article  PubMed  CAS  Google Scholar 

  7. Stupart DA, Goldberg PA, Algar U, Ramesar R (2009) Surveillance colonoscopy improves survival in a cohort of subjects with a single mismatch repair gene mutation. Colorectal Dis 11:126–130. doi:10.1111/j.1463-1318.2008.01702.x; 10.1111/j.1463-1318.2008.01702.x

    Article  PubMed  CAS  Google Scholar 

  8. Stoffel EM, Chittenden A (2010) Genetic testing for hereditary colorectal cancer: challenges in identifying, counseling, and managing high-risk patients. Gastroenterology 139:1436–1441, 1441.e1. doi:10.1053/j.gastro.2010.09.018

    Article  PubMed  Google Scholar 

  9. Bonadona V, Bonaiti B, Olschwang S et al (2011) Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in lynch syndrome. JAMA 305:2304–2310. doi:10.1001/jama.2011.743

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  11. Wijnen JT, Vasen HF, Khan PM et al (1998) Clinical findings with implications for genetic testing in families with clustering of colorectal cancer. N Engl J Med 339:511–518. doi:10.1056/NEJM199808203390804

    Article  PubMed  CAS  Google Scholar 

  12. Syngal S, Fox EA, Eng C, Kolodner RD, Garber JE (2000) Sensitivity and specificity of clinical criteria for hereditary non-polyposis colorectal cancer associated mutations in MSH2 and MLH1. J Med Genet 37:641–645

    Article  PubMed  CAS  Google Scholar 

  13. de Leon MP, Pedroni M, Benatti P et al (2011) Hereditary colorectal cancer in the general population: from cancer registration to molecular diagnosis. Gut 45:32–38

    Article  Google Scholar 

  14. Goodenberger M, Lindor NM (2011) Lynch syndrome and MYH-associated polyposis: review and testing strategy. J Clin Gastroenterol 45:488–500. doi:10.1097/MCG.0b013e318206489c; 10.1097/MCG.0b013e318206489c

    Article  PubMed  Google Scholar 

  15. Jass JR (2006) Hereditary non-polyposis colorectal cancer: the rise and fall of a confusing term. World J Gastroenterol 12:4943–4950

    PubMed  CAS  Google Scholar 

  16. Vasen HF, Mecklin JP, Khan PM, Lynch HT (1991) The international collaborative group on hereditary non-polyposis colorectal cancer (ICG-HNPCC). Dis Colon Rectum 34:424–425

    Article  PubMed  CAS  Google Scholar 

  17. Rodriguez-Bigas MA, Boland CR, Hamilton SR et al (1997) A National Cancer Institute workshop on hereditary nonpolyposis colorectal cancer syndrome: meeting highlights and Bethesda guidelines. J Natl Cancer Inst 89:1758–1762

    Article  PubMed  CAS  Google Scholar 

  18. Boland CR, Goel A (2010) Microsatellite instability in colorectal cancer. Gastroenterology 138:2073–2087.e3. doi:10.1053/j.gastro.2009.12.064; 10.1053/j.gastro.2009.12.064

    Article  PubMed  CAS  Google Scholar 

  19. Umar A, Boland CR, Terdiman JP et al (2004) Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (lynch syndrome) and microsatellite instability. J Natl Cancer Inst 96:261–268

    Article  PubMed  CAS  Google Scholar 

  20. Pinol V, Castells A, Andreu M et al (2005) Accuracy of revised Bethesda guidelines, microsatellite instability, and immunohistochemistry for the identification of patients with hereditary nonpolyposis colorectal cancer. JAMA 293:1986–1994. doi:10.1001/jama.293.16.1986

    Article  PubMed  CAS  Google Scholar 

  21. Alexander J, Watanabe T, Wu TT, Rashid A, Li S, Hamilton SR (2001) Histopathological identification of colon cancer with microsatellite instability. Am J Pathol 158:527–535. doi:10.1016/S0002-9440(10)63994-6

    Article  PubMed  CAS  Google Scholar 

  22. Smyrk TC, Watson P, Kaul K, Lynch HT (2001) Tumor-infiltrating lymphocytes are a marker for microsatellite instability in colorectal carcinoma. Cancer 91:2417–2422

    Article  PubMed  CAS  Google Scholar 

  23. Shia J, Ellis NA, Paty PB et al (2003) Value of histopathology in predicting microsatellite instability in hereditary nonpolyposis colorectal cancer and sporadic colorectal cancer. Am J Surg Pathol 27:1407–1417

    Article  PubMed  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  26. Peltomaki P, Vasen HF (1997) Mutations predisposing to hereditary nonpolyposis colorectal cancer: database and results of a collaborative study. The international collaborative group on hereditary nonpolyposis colorectal cancer. Gastroenterology 113:1146–1158

    Article  PubMed  CAS  Google Scholar 

  27. Shia J, Ellis NA, Klimstra DS (2004) The utility of immunohistochemical detection of DNA mismatch repair gene proteins. Virchows Arch 445:431–441. doi:10.1007/s00428-004-1090-5

    Article  PubMed  CAS  Google Scholar 

  28. Salahshor S, Koelble K, Rubio C, Lindblom A (2001) Microsatellite instability and hMLH1 and hMSH2 expression analysis in familial and sporadic colorectal cancer. Lab Invest 81:535–541

    Article  PubMed  CAS  Google Scholar 

  29. Liu T, Tannergard P, Hackman P et al (1999) Missense mutations in hMLH1 associated with colorectal cancer. Hum Genet 105:437–441

    Article  PubMed  CAS  Google Scholar 

  30. Halvarsson B, Lindblom A, Rambech E, Lagerstedt K, Nilbert M (2004) Microsatellite instability analysis and/or immunostaining for the diagnosis of hereditary nonpolyposis colorectal cancer? Virchows Arch 444:135–141. doi:10.1007/s00428-003-0922-z

    Article  PubMed  CAS  Google Scholar 

  31. Acharya S, Wilson T, Gradia S et al (1996) hMSH2 forms specific mispair-binding complexes with hMSH3 and hMSH6. Proc Natl Acad Sci U S A 93:13629–13634

    Article  PubMed  CAS  Google Scholar 

  32. Hampel H (2009) Genetic testing for hereditary colorectal cancer. Surg Oncol Clin N Am 18:687–703. doi:10.1016/j.soc.2009.08.001; 10.1016/j.soc.2009.08.001

    Article  PubMed  Google Scholar 

  33. Young J, Simms LA, Biden KG et al (2001) Features of colorectal cancers with high-level microsatellite instability occurring in familial and sporadic settings: parallel pathways of tumorigenesis. Am J Pathol 159:2107–2116. doi:10.1016/S0002-9440(10)63062-3

    Article  PubMed  CAS  Google Scholar 

  34. Harfe BD, Minesinger BK, Jinks-Robertson S (2000) Discrete in vivo roles for the MutL homologs Mlh2p and Mlh3p in the removal of frameshift intermediates in budding yeast. Curr Bio 10:145–148

    Article  CAS  Google Scholar 

  35. Kadyrov FA, Dzantiev L, Constantin N, Modrich P (2006) Endonucleolytic function of MutLalpha in human mismatch repair. Cell 126:297–308. doi:10.1016/j.cell.2006.05.039

    Article  PubMed  CAS  Google Scholar 

  36. Muller W, Burgart LJ, Krause-Paulus R et al (2001) The reliability of immunohistochemistry as a prescreening method for the diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC) – results of an international collaborative study. Fam Cancer 1:87–92

    Article  PubMed  CAS  Google Scholar 

  37. Chiaravalli AM, Furlan D, Facco C et al (2001) Immunohistochemical pattern of hMSH2/hMLH1 in familial and sporadic colorectal, gastric, endometrial and ovarian carcinomas with instability in microsatellite sequences. Virchows Arch 438:39–48

    Article  PubMed  CAS  Google Scholar 

  38. Chapusot C, Martin L, Bouvier AM et al (2002) Microsatellite instability and intratumoural heterogeneity in 100 right-sided sporadic colon carcinomas. Br J Cancer 87:400–404. doi:10.1038/sj.bjc.6600474

    Article  PubMed  CAS  Google Scholar 

  39. Pritchard CC, Grady WM (2011) Colorectal cancer molecular biology moves into clinical practice. Gut 60:116–129. doi:10.1136/gut.2009.206250; 10.1136/gut.2009.206250

    Article  PubMed  CAS  Google Scholar 

  40. Legolvan MP, Taliano RJ, Resnick MB (2012) Application of molecular techniques in the diagnosis, prognosis and management of patients with colorectal cancer: a practical approach. Hum Pathol 43:1157–1168. doi:10.1016/j.humpath.2012.03.003; 10.1016/j.humpath.2012.03.003

    Article  PubMed  CAS  Google Scholar 

  41. Baudhuin LM, Burgart LJ, Leontovich O, Thibodeau SN (2005) Use of microsatellite instability and immunohistochemistry testing for the identification of individuals at risk for lynch syndrome. Fam Cancer 4:255–265. doi:10.1007/s10689-004-1447-6

    Article  PubMed  Google Scholar 

  42. Boland CR, Thibodeau SN, Hamilton SR et al (1998) 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 58:5248–5257

    PubMed  CAS  Google Scholar 

  43. Lindor NM, Burgart LJ, Leontovich O et al (2002) Immunohistochemistry versus microsatellite instability testing in phenotyping colorectal tumors. J Clin Oncol 20:1043–1048

    Article  PubMed  CAS  Google Scholar 

  44. Hampel H, Frankel WL, Martin E et al (2008) Feasibility of screening for lynch syndrome among patients with colorectal cancer. J Clin Oncol 26:5783–5788. doi:10.1200/JCO.2008.17.5950

    Article  PubMed  Google Scholar 

  45. Zhang L (2008) Immunohistochemistry versus microsatellite instability testing for screening colorectal cancer patients at risk for hereditary nonpolyposis colorectal cancer syndrome: Part II. The utility of microsatellite instability testing. J Mol Diagn 10:301–307. doi:10.2353/jmoldx.2008.080062; 10.2353/jmoldx.2008.080062

    Article  PubMed  CAS  Google Scholar 

  46. Shia J (2008) 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 10:293–300. doi:10.2353/jmoldx.2008.080031; 10.2353/jmoldx.2008.080031

    Article  PubMed  Google Scholar 

  47. Marcus VA, Madlensky L, Gryfe R et al (1999) Immunohistochemistry for hMLH1 and hMSH2: a practical test for DNA mismatch repair-deficient tumors. Am J Surg Pathol 23:1248–1255

    Article  PubMed  CAS  Google Scholar 

  48. Debniak T, Kurzawski G, Gorski B, Kladny J, Domagala W, Lubinski J (2000) 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 36:49–54

    Article  PubMed  CAS  Google Scholar 

  49. Cunningham JM, Kim CY, Christensen ER et al (2001) The frequency of hereditary defective mismatch repair in a prospective series of unselected colorectal carcinomas. Am J Hum Genet 69:780–790. doi:10.1086/323658

    Article  PubMed  CAS  Google Scholar 

  50. Dieumegard B, Grandjouan S, Sabourin JC et al (2000) Extensive molecular screening for hereditary non-polyposis colorectal cancer. Br J Cancer 82:871–880. doi:10.1054/bjoc.1999.1014

    Article  PubMed  CAS  Google Scholar 

  51. Stone JG, Robertson D, Houlston RS (2001) Immunohistochemistry for MSH2 and MHL1: a method for identifying mismatch repair deficient colorectal cancer. J Clin Pathol 54:484–487

    Article  PubMed  CAS  Google Scholar 

  52. Terdiman JP, Gum JR Jr, Conrad PG et al (2001) Efficient detection of hereditary nonpolyposis colorectal cancer gene carriers by screening for tumor microsatellite instability before germline genetic testing. Gastroenterology 120:21–30

    Article  PubMed  CAS  Google Scholar 

  53. Wahlberg SS, Schmeits J, Thomas G et al (2002) Evaluation of microsatellite instability and immunohistochemistry for the prediction of germ-line MSH2 and MLH1 mutations in hereditary nonpolyposis colon cancer families. Cancer Res 62:3485–3492

    PubMed  CAS  Google Scholar 

  54. Furukawa T, Konishi F, Shitoh K, Kojima M, Nagai H, Tsukamoto T (2002) Evaluation of screening strategy for detecting hereditary nonpolyposis colorectal carcinoma. Cancer 94:911–920

    Article  PubMed  Google Scholar 

  55. Bouzourene H, Hutter P, Losi L, Martin P, Benhattar J (2010) Selection of patients with germline MLH1 mutated lynch syndrome by determination of MLH1 methylation and BRAF mutation. Fam Cancer 9:167–172. doi:10.1007/s10689-009-9302-4; 10.1007/s10689-009-9302-4

    Article  PubMed  CAS  Google Scholar 

  56. Herman JG, Umar A, Polyak K et al (1998) Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci U S A 95:6870–6875

    Article  PubMed  CAS  Google Scholar 

  57. Deng G, Bell I, Crawley S et al (2004) BRAF mutation is frequently present in sporadic colorectal cancer with methylated hMLH1, but not in hereditary nonpolyposis colorectal cancer. Clin Cancer Res 10:191–195

    Article  PubMed  CAS  Google Scholar 

  58. Domingo E, Niessen RC, Oliveira C et al (1998) BRAF-V600E is not involved in the colorectal tumorigenesis of HNPCC in patients with functional MLH1 and MSH2 genes. Oncogene 24:3995–3998. doi:10.1038/sj.onc.1208569

    Article  Google Scholar 

  59. Kambara T, Simms LA, Whitehall VL et al (2003) BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum. Gut 53:1137–1144. doi:10.1136/gut.2003.037671

    Article  Google Scholar 

  60. Domingo E, Laiho P, Ollikainen M et al (2004) BRAF screening as a low-cost effective strategy for simplifying HNPCC genetic testing. J Med Genet 41:664–668. doi:10.1136/jmg.2004.020651

    Article  PubMed  CAS  Google Scholar 

  61. Petersen GM, Brensinger JD, Johnson KA, Giardiello FM (1999) Genetic testing and counseling for hereditary forms of colorectal cancer. Cancer 86:2540–2550

    Article  PubMed  CAS  Google Scholar 

  62. Peltomaki P, Vasen H (2004) Mutations associated with HNPCC predisposition – update of ICG-HNPCC/INSiGHT mutation database. Dis Markers 20:269–276

    Article  PubMed  Google Scholar 

  63. Senter L, Clendenning M, Sotamaa K et al (2008) The clinical phenotype of lynch syndrome due to germ-line PMS2 mutations. Gastroenterology 135:419–428. doi:10.1053/j.gastro.2008.04.026; 10.1053/j.gastro.2008.04.026

    Article  PubMed  CAS  Google Scholar 

  64. Ligtenberg MJ, Kuiper RP, Chan TL et al (2009) Heritable somatic methylation and inactivation of MSH2 in families with lynch syndrome due to deletion of the 3′ exons of TACSTD1. Nat Genet 41:112–117. doi:10.1038/ng.283; 10.1038/ng.283

    Article  PubMed  CAS  Google Scholar 

  65. Niessen RC, Hofstra RM, Westers H et al (2009) Germline hypermethylation of MLH1 and EPCAM deletions are a frequent cause of lynch syndrome. Genes Chromosomes Cancer 48:737–744. doi:10.1002/gcc.20678; 10.1002/gcc.20678

    Article  PubMed  CAS  Google Scholar 

  66. Grover S, Syngal S (2009) Genetic testing in gastroenterology: Lynch syndrome. Best Pract Res Clin Gastroenterol 23:185–196. doi:10.1016/j.bpg.2009.02.006; 10.1016/j.bpg.2009.02.006

    Article  PubMed  CAS  Google Scholar 

  67. Dove-Edwin I, de Jong AE, Adams J et al (2006) Prospective results of surveillance colonoscopy in dominant familial colorectal cancer with and without lynch syndrome. Gastroenterology 130:1995–2000. doi:10.1053/j.gastro.2006.03.018

    Article  PubMed  Google Scholar 

  68. Lindor NM, Rabe K, Petersen GM et al (2005) Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X. JAMA 293:1979–1985. doi:10.1001/jama.293.16.1979

    Article  PubMed  CAS  Google Scholar 

  69. Torrance N, Mollison J, Wordsworth S et al (2006) Genetic nurse counsellors can be an acceptable and cost-effective alternative to clinical geneticists for breast cancer risk genetic counselling. Evidence from two parallel randomised controlled equivalence trials. Br J Cancer 95:435–444. doi:10.1038/sj.bjc.6603248

    Article  PubMed  CAS  Google Scholar 

  70. Geiersbach KB, Samowitz WS (2011) Microsatellite instability and colorectal cancer. Arch Pathol Lab Med 135:1269–1277. doi:10.5858/arpa.2011-0035-RA; 10.5858/arpa.2011-0035-RA

    Article  PubMed  CAS  Google Scholar 

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Coetzee, E., Algar, U., Goldberg, P. (2013). New Insights into Lynch Syndrome Diagnosis. In: Vogelsang, M. (eds) DNA Alterations in Lynch Syndrome. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-6597-9_3

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