Phenotypic and genotypic heterogeneity of Lynch syndrome: a complex diagnostic challenge

  • Henry T. Lynch
  • Stephen Lanspa
  • Trudy Shaw
  • Murray Joseph Casey
  • Marc Rendell
  • Mark Stacey
  • Theresa Townley
  • Carrie Snyder
  • Megan Hitchins
  • Joan Bailey-Wilson
Review

Abstract

Lynch syndrome is the hereditary disorder that most frequently predisposes to colorectal cancer as well as predisposing to a number of extracolonic cancers, most prominently endometrial cancer. It is caused by germline mutations in the mismatch repair genes. Both its phenotype and genotype show marked heterogeneity. This review gives a historical overview of the syndrome, its heterogeneity, its genomic landscape, and its implications for complex diagnosis, genetic counseling and putative implications for immunotherapy.

Keywords

Lynch syndrome Hereditary nonpolyposis colorectal cancer Hereditary cancer Mismatch repair Colorectal cancer Endometrial cancer 

Notes

Acknowledgements

We thank Peter Silberstein, M.D., for technical assistance.

Funding

This work was supported by revenue from Nebraska’s excise tax on cigarettes awarded to Creighton University by the Nebraska Department of Health and Human Services. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the State of Nebraska or the Nebraska Department of Health and Human Services. Funding was also received from the Liz’s Legacy fund through Kicks for a Cure. Dr. Henry Lynch’s work is partially funded through the Charles F. and Mary C. Heider Chair in Cancer Research, which he holds at Creighton University.

References

  1. 1.
    Hampel H, Frankel WL, Martin E, Arnold M, Khanduja K, Kuebler P, Clendenning M, Sotamaa K, Prior T, Westman JA, Panescu J, Fix D, Lockman J, LaJeunesse J, Comeras I, de la Chapelle A (2008) Feasibility of screening for Lynch syndrome among patients with colorectal cancer. J Clin Oncol 26:5783–5788PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Blue Ribbon Panel: Cancer Moonshot Blue Ribbon Panel Report (2016) Available at: https://www.cancer.gov/research/key-initiatives/moonshot-cancer-initiative/blue-ribbon-panel/blue-ribbon-panel-report-2016.pdf. Accessed 9 Oct 2017
  3. 3.
    Warthin AS (1913) Heredity with reference to carcinoma as shown by the study of the cases examined in the pathological laboratory of the University of Michigan, 1895–1913. Arch Intern Med 12:546–555CrossRefGoogle Scholar
  4. 4.
    Lynch HT, Shaw MW, Magnuson CW, Larsen AL, Krush AJ (1966) Hereditary factors in cancer: study of two large Midwestern kindreds. Arch Intern Med 117:206–212PubMedCrossRefGoogle Scholar
  5. 5.
    Peltomäki P, Aaltonen L, Sistonen P, Pylkkänen L, Mecklin J-P, Järvinen H, Green JS, Jass JR, Weber JL, Leach FS, Petersen GM, Hamilton SR, de la Chapelle A, Vogelstein B (1993) Genetic mapping of a locus predisposing to human colorectal cancer. Science 260:810–812PubMedCrossRefGoogle Scholar
  6. 6.
    Lindblom A, Tannergard P, Werelius B, Nordenskjold M (1993) Genetic mapping of a second locus predisposing to hereditary nonpolyposis colorectal cancer. Nat Genet 5:279–282PubMedCrossRefGoogle Scholar
  7. 7.
    Leach FS, Nicolaides NC, Papadopoulos N, Liu B, Jen J, Parsons R, Peltomaki P, Sistonen P, Aaltonen LA, Nystrom-Lahti M, Guan X-Y, Zhang J, Metzler PS, Yu J-W, Kao F-T, Chen DJ, Cerosaletti KM, Fournier REK, Todd S, Lewis T, Leach RJ, Naylor SL, Weissenbach J, Mecklin J-P, Jarvinen H, Petersen GM, Hamilton SR, Green J, Jass J, Watson P, Lynch HT, Trent JM, de la Chapelle A, Kinzler KW, Vogelstein B (1993) Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell 75:1215–1225PubMedCrossRefGoogle Scholar
  8. 8.
    Nicolaides NC, Papadopoulos N, Liu B, Wei Y-F, Carter KC, Ruben SM, Rosen CA, Haseltine WA, Fleischmann RD, Fraser CM, Adams MD, Venter JC, Dunlop MG, Hamilton SR, Petersen GM, de la Chapelle A, Vogelstein B, Kinzler KW (1994) Mutations of two PMS homologues in hereditary nonpolyposis colon cancer. Nature 371:75–80PubMedCrossRefGoogle Scholar
  9. 9.
    Miyaki M, Konishi M, Tanaka K, Kikuchi-Yanoshita R, Muraoka M, Yasuno M, Igari T, Koike M, Chiba M, Mori T (1997) Germline mutation of MSH6 as the cause of hereditary nonpolyposis colorectal cancer. Nat Genet 17:271–272PubMedCrossRefGoogle Scholar
  10. 10.
    Ligtenberg MJL, Kuiper RP, Chan TL, Goossens M, Hebeda KM, Voorendt M, Lee TYH, Bodmer D, Hoenselaar E, Hendriks-Cornelissen SJB, Tsui WY, Kong CK, Brunner HG, van Kessel AG, Yuen ST, van Krieken JHJM, Leung SY, Hoogerbrugge N (2009) Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3´ exons of TACSTD1. Nat Genet 41:112–117PubMedCrossRefGoogle Scholar
  11. 11.
    Vasen HFA, Mecklin J-P, Khan PM, Lynch HAT (1991) The International Collaborative Group on hereditary nonpolyposis colorectal cancer (ICG-HNPCC). Dis Colon Rectum 34:424–425PubMedCrossRefGoogle Scholar
  12. 12.
    Vasen HFA, Watson P, Mecklin J-P, Lynch HT, ICG-HNPCC (1999) New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative Group on HNPCC. Gastroenterology 116:1453–1456PubMedCrossRefGoogle Scholar
  13. 13.
    Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW, Meltzer SJ, Rodriguez-Bigas MA, Fodde R, Ranzani GN, Srivastava S (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 58:5248–5257PubMedGoogle Scholar
  14. 14.
    Laghi L, Bianchi P, Roncalli M, Malesci A (2004) Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 96:1402–1403PubMedCrossRefGoogle Scholar
  15. 15.
    Boland CR, Shike M (2010) Report from the Jerusalem workshop on Lynch syndrome-hereditary nonpolyposis colorectal cancer. Gastroenterology 138:2197.e1–2197.e7Google Scholar
  16. 16.
    Lynch HT, Lynch PM, Pester J, Fusaro RM (1981) The cancer family syndrome: rare cutaneous phenotypic linkage of Torre’s syndrome. Arch Intern Med 141:607–611PubMedCrossRefGoogle Scholar
  17. 17.
    Watson P, Lynch HT (1994) The tumor spectrum in HNPCC. Anticancer Res 14:1635–1640PubMedGoogle Scholar
  18. 18.
    Watson P, Vasen HFA, Mecklin J-P, Bernstein I, Aarnio M, Järvinen HJ, Myrhøj T, Sunde L, Wijnen JT, Lynch HT (2008) The risk of extra-colonic, extra-endometrial cancer in the Lynch syndrome. Int J Cancer 123:444–449PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Kastrinos F, Mukherjee B, Tayob N, Wang F, Sparr J, Raymond VM, Bandipalliam P, Stoffel EM, Gruber SB, Syngal S (2009) Risk of pancreatic cancer in families with Lynch syndrome. JAMA 302:1790–1795PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Win AK, Young JP, Lindor NM, Tucker KM, Ahnen DJ, Young GP, Buchanan DD, Clendenning M, Giles GG, Winshiip I, Macrae FA, Goldblatt J, Southey MC, Arnold J, Thibodeau SN, Gunawardena SR, Bapat B, Baron JA, Casey G, Gallinger S, Le Marchand L, Newcomb PA, Haile RW, Hopper JL, Jenkins MA (2012) 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 30:958–964PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Bauer CM, Ray AM, Halstead-Nussloch BA, Dekker RG, Raymond VM, Gruber SB, Cooney KA (2011) Hereditary prostate cancer as a feature of Lynch syndrome. Fam Cancer 10:37–42PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Raymond VM, Everett JN, Furtado LV, Gustafson SL, Jungbluth CR, Gruber SB, Hammer GD, Stoffel EM, Greenson JK, Giordano TJ, Else T (2013) Adrenocortical carcinoma is a Lynch syndrome-associated cancer. J Clin Oncol 31:3012–3018PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    National Comprehensive Cancer Network (2017) NCCN guidelines version 1.2017, Lynch syndrome. Available at: http://www.nccn.org. Accessed 9 Oct 2017
  24. 24.
    Peltomäki P (2005) Lynch syndrome genes. Fam Cancer 4:227–232PubMedCrossRefGoogle Scholar
  25. 25.
    Bronner CE, Baker SM, Morrison PT, Warren G, Smith LG, Lescoe MK, Kane M, Earabino C, Lipford J, Lindblom A, Tannergard P, Bollag RJ, Godwin AR, Ward DC, Nordenskjold M, Fishel R, Kolodner R, Liskay RM (1994) Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary nonpolyposis colon cancer. Nature 368:258–261PubMedCrossRefGoogle Scholar
  26. 26.
    Fishel R, Lescoe MK, Rao MRS, Copeland NG, Jenkins NA, Garber J, Kane M, Kolodner R (1993) The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 75:1027–1038PubMedCrossRefGoogle Scholar
  27. 27.
    Carneiro da Silva F, Wernhoff P, Dominguez-Barrera C, Dominguez-Valentin M (2016) Update on hereditary colorectal cancer. Anticancer Res 36:4399–4406CrossRefGoogle Scholar
  28. 28.
    Kovacs ME, Papp J, Szentirmay Z, Otto S, Olah E (2009) Deletions removing the last exon of TACSTD1 constitute a distinct class of mutations predisposing to Lynch syndrome. Hum Mutat 30:197–203PubMedCrossRefGoogle Scholar
  29. 29.
    Hitchins MP (2013) The role of epigenetics in Lynch syndrome. Fam Cancer 12:189–205PubMedCrossRefGoogle Scholar
  30. 30.
    Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group (2009) Recommendations from the EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives. Genet Med 11:35–41CrossRefGoogle Scholar
  31. 31.
    Hampel H, Frankel W, Panescu J, Lockman J, Sotamaa K, Fix D, Comeras I, La Jeunesse J, Nakagawa H, Westman JA, Prior TW, Clendenning M, Penzone P, Lombardi J, Dunn P, Cohn DE, Copeland L, Eaton L, Fowler J, Lewandowski G, Vaccarello L, Bell J, Reid G, de la Chapelle A (2006) Screening for Lynch syndrome (hereditary nonpolyposis colorectal cancer) among endometrial cancer patients. Cancer Res 66:7810–7817PubMedCrossRefGoogle Scholar
  32. 32.
    Win AK, Jenkins MA, Dowty JG, Antoniou AC, Lee A, Giles GG, Buchanan DD, Clendenning M, Rosty C, Ahnen DJ, Thibodeau SN, Casey G, Gallinger S, Le Marchand L, Haile RW, Potter JD, Zheng Y, Lindor NM, Newcomb PA, Hopper JL, Macinnis RJ (2017) Prevalence and penetrance of major genes and polygenes for colorectal cancer. Cancer Epidemiol Biomarkers Prev 26:404–412PubMedCrossRefGoogle Scholar
  33. 33.
    Espenschied CR, LaDuca H, Li S, McFarland R, Gau C-L, Hampel H (2017) Multigene panel testing provides a new perspective on Lynch syndrome. J Clin Oncol 35:2568–2575PubMedCrossRefGoogle Scholar
  34. 34.
    Yamano T, Hamanaka M, Babaya A, Kimura K, Kobayashi M, Fukumoto M, Tsukamoto K et al (2017) Management strategies in Lynch syndrome and familial adenomatous polyposis: a national healthcare survey in Japan. Cancer Sci 108:243–249PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Soares BL, Brant AC, Gomes R, Pastor T, Schneider NB, Ribeiro-dos-Santos Â, Pimentel de Assumpção P, Achatz MIW, Ashton-Prolla P, Moreira MAM (2017) Screening for germline mutations in mismatch repair genes in patients with Lynch syndrome by next generation sequencing. Fam Cancer. doi: 10.1007/s10689-017-0043-5 (in press)PubMedGoogle Scholar
  36. 36.
    Carethers JM, Stoffel EM (2015) Lynch syndrome and Lynch syndrome mimics: the growing complex landscape of hereditary colon cancer. World J Gastroenterol 21:9253–9261PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Wimmer K, Etzler J (2008) Constitutional mismatch repair-deficiency syndrome: have we so far seen only the tip of the iceberg? Hum Genet 124:105–122PubMedCrossRefGoogle Scholar
  38. 38.
    Mensenkamp AR, Vogelaar IP, van Zelst-Stams WAG, Goossens M, Ouchene H, Hendriks-Cornelissen SJB, Kwint MP, Hoogerbrugge N, Nagtegaal ID, Ligtenberg MJL (2014) Somatic mutations in MLH1 and MSH2 are a frequent cause of mismatch-repair deficiency in Lynch syndrome-like tumors. Gastroenterology 146:643–646PubMedCrossRefGoogle Scholar
  39. 39.
    Bettstetter M, Dechant S, Ruemmele P, Grabowski M, Keller G, Holinski-Feder E, Hartmann A, Hofstaedter F, Dietmaier W (2007) Distinction of hereditary nonpolyposis colorectal cancer and sporadic microsatellite-unstable colorectal cancer through quantification of MLH1 methylation by real-time PCR. Clin Cancer Res 13:3221–3228PubMedCrossRefGoogle Scholar
  40. 40.
    Sánchez-Tomé E, Rivera B, Perea J, Pita G, Rueda D, Mercadillo F, Canal A, Gonzalez-Neira A, Benitez J, Urioste M (2015) Genome-wide linkage analysis and tumoral characterization reveal heterogeneity in familial colorectal cancer type X. J Gastroenterol 50:657–666PubMedCrossRefGoogle Scholar
  41. 41.
    Garre P, Martín L, Bando I, Tosar A, Llovet P, Sanz J, Romero A, de la Hoya M, Díaz-Rubio E, Caldés T (2014) Cancer risk and overall survival in mismatch repair proficient hereditary non-polyposis colorectal cancer, Lynch syndrome and sporadic colorectal cancer. Fam Cancer 13:109–119PubMedCrossRefGoogle Scholar
  42. 42.
    Adar T, Rodgers LH, Shannon KM, Yoshida M, Ma T, Mattia A, Lauwers GY, Iafrate AJ, Chung DC (2017) A tailored approach to BRAF and MLH1 methylation testing in a universal screening program for Lynch syndrome. Mod Pathol 30:440–447PubMedCrossRefGoogle Scholar
  43. 43.
    Boulagnon C, Dudez O, Beaudoux O, Dalstein V, Kianmanesh R, Bouché O, Diebold M-D (2016) BRAFV600E gene mutation in colonic adenocarcinomas. Immunohistochemical detection using tissue microarray and clinicopathologic characteristics: an 86 case series. Appl Immunohistochem Mol Morphol 24:88–96PubMedCrossRefGoogle Scholar
  44. 44.
    Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr, Kinzler KW (2013) Cancer genome landscapes. Science 339:1546–1558PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Kempers MJE, Kuiper RP, Ockeloen CW, Chappuis PO, Hutter P, Rahner N, Schackert HK, Steinke V, Holinski-Feder E, Morak M, Kloor M, Büttner R, Verwiel ETP, van Krieken JH, Nagtegaal ID, Goossens M, van der Post RS, Niessen RC, Sijmons RH, Kluijt I, Hogervorst FBL, Leter EM, Gille JJP, Aalfs CM, Redeker EJW, Hes FJ, Tops CMJ, van Nesselrooij BPM, van Gijn ME, Gómez Garcia EBG, Eccles DM, Bunyan DJ, Syngal S, Stoffel EM, Culver JO, Palomares MR, Graham T, Velsher L, Papp J, Oláh E, Chan TL, Leung SY, van Kessel AG, Kiemeney LALM, Hoogerbrugge N, Ligtenberg MJL (2011) Risk of colorectal and endometrial cancers in EPCAM deletion-positive Lynch syndrome: a cohort study. Lancet Oncol 12:49–55PubMedCrossRefGoogle Scholar
  46. 46.
    Lynch H, Riegert-Johnson D, Snyder C, Lynch J, Hagenkord J, Boland CR, Rhees J, Thibodeau S, Boardman L, Davies J, Kuiper RP, Hoogerbrugge N, Ligtenberg M (2011) Lynch syndrome associated extracolonic tumors are rare in two extended families with the same EPCAM deletion. Am J Gastroenterol 106:1829–1836PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Vasen HF, Tomlinson I, Castells A (2015) Clinical management of hereditary colorectal cancer syndromes. Nat Rev Gastroenterol Hepatol 12:88–97PubMedCrossRefGoogle Scholar
  48. 48.
    Moller P, Seppala TT, Bernstein I, Holinski-Feder E, Sala P, Gareth ED, Lindblom A, Macrae F, Blanco I, Sijmons RH, Jeffries J, Vasen HFA, Burn J, Nakken S, Hovig E, Rodland EA, Tharmaratnam K, de Vos Tot Nederveen Cappel WH, Hill J, Wijnen JT, Jenkins MA, Green K, Lalloo F, Sunde L, Mints M, Bertario L, Pineda M, Navarro M, Morak M, Renkonen-Sinisalo L, Valentin MD, Frayling IM, Plazzer JP, Pylvanainen K, Genuardi M, Mecklin JP, Moeslein G, Sampson JR, Capella G. (2017) Cancer risk and survival in path_MMR carriers by gene and gender up to 75 years of age: a report from the prospective Lynch syndrome database. Gut. doi: 10.1136/gutjni-2017-314057 (in press)Google Scholar
  49. 49.
    Watson P, Ashwathnarayan R, Lynch HT, Roy HK (2004) Tobacco use and increased colorectal cancer risk in patients with hereditary nonpolyposis colorectal cancer (Lynch syndrome). Arch Intern Med 164:2429–2431PubMedCrossRefGoogle Scholar
  50. 50.
    Burn J, Gerdes A-M, Macrae F, Mecklin J-P, Moeslein G, Olschwang S, Eccles D, Evans G, Maher ER, Bertario L, Bisgaard M-L, Dunlop MG, Ho JWC, Hodgson SV, Lindblom A, Lubinski J, Morrison PJ, Murday V, Ramesar R, Side L, Scott RJ, Thomas HJW, Vasen HF, Barker G, Crawford G, Elliott F, Movahedi M, Pylvanainen K, Wijnen JT, Fodde R, Lynch HT, Mathers JC, Bishop T, on behalf of the CAPP2 investigators (2011) Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. The Lancet 378:2081–2087CrossRefGoogle Scholar
  51. 51.
    Donald N, Malik S, McGuire JL, Monahan KJ. (2017) The association of low penetrance genetic risk modifiers with colorectal cancer in lynch syndrome patients: a systematic review and meta-analysis. Fam Cancer. doi: 10.1007/s10689-017-9995-8. (in press)PubMedGoogle Scholar
  52. 52.
    ten Broeke SW, Brohet RM, Tops CM, van der Klift HM, Velthuizen ME, Bernstein I, Munar GC, Garcia EG, Hoogerbrugge N, Letteboer TGW, Menko FH, Lindblom A, Mensenkamp AR, Moller P, van Os TA, Rahner N, Redeker BJW, Sijmons RH, Spruijt L, Suerink M, Vos YJ, Wagner A, Hes FJ, Vasen HF, Nielsen M, Wijnen JT (2015) Lynch syndrome caused by germline PMS2 mutations: delineating the cancer risk. J Clin Oncol 33:319–325PubMedCrossRefGoogle Scholar
  53. 53.
    Senter L, Clendenning M, Sotamaa K, Hampel H, Green J, Potter JD, Lindblom A, Lagerstedt K, Thibodeau SN, Lindor NM, Young J, Winship I, Dowty JG, White DM, Hopper JL, Baglietto L, Jenkins MA, de la Chapelle A (2008) The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations. Gastroenterology 135:419–428PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Kloor M, Staffa L, Ahadova A, von Knebel Doeberitz M (2014) Clinical significance of microsatellite instability in colorectal cancer. Langenbecks Arch Surg 399:23–31PubMedCrossRefGoogle Scholar
  55. 55.
    Järvinen HJ, Aarnio M, Mustonen H, Aktan-Collan K, Aaltonen LA, Peltomäki P, de la Chapelle A, Mecklin J-P (2000) Controlled 15-year trial on screening for colorectal cancer in families with hereditary nonpolyposis colorectal cancer. Gastroenterology 118:829–834PubMedCrossRefGoogle Scholar
  56. 56.
    Dove-Edwin I, Sasieni P, Adams J, Thomas HJW (2005) Prevention of colorectal cancer by colonoscopic surveillance in individuals with a family history of colorectal cancer: 16 year, prospective, follow-up study. BMJ 331:1047PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Ladabaum U, Wang G, Terdiman J, Blanco A, Kuppermann M, Boland CR, Ford J, Elkin E, Phillips KA (2011) Strategies to identify the Lynch syndrome among patients with colorectal cancer: a cost-effectiveness analysis. Ann Intern Med 155:69–79PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Lynch HT, Smyrk T, Jass JR (1995) Hereditary nonpolyposis colorectal cancer and colonic adenomas: aggressive adenomas? Semin Surg Oncol 11:406–410PubMedCrossRefGoogle Scholar
  59. 59.
    Kravochuck SE, Church JM (2017) Colonoscopy in patients with Lynch syndrome: no room for error. ANZ J Surg 87:204–205PubMedCrossRefGoogle Scholar
  60. 60.
    Haanstra JF, Kleibeuker JH, Koornstra JJ (2013) Role of new endoscopic techniques in Lynch syndrome. Fam Cancer 12:267–272PubMedCrossRefGoogle Scholar
  61. 61.
    East JE, Suzuki N, Stavrinidis M, Guenther T, Thomas HJW, Saunders BP (2008) Narrow band imaging for colonoscopic surveillance in hereditary non-polyposis colorectal cancer. Gut 57:65–70PubMedCrossRefGoogle Scholar
  62. 62.
    Stoffel EM, Turgeon DK, Stockwell DH, Zhao L, Normolle DP, Tuck MK, Bresalier RS, Marcon NE, Baron JA, Ruffin MT, Brenner DE, Syngal S, for Great Lakes-New England Clinical Epidemiology and Validation Center of the Early Detection Research Network (2008) Missed adenomas during colonoscopic surveillance in individuals with Lynch syndrome (hereditary nonpolyposis colorectal cancer). Cancer Prev Res 1:470–475CrossRefGoogle Scholar
  63. 63.
    Lecomte T, Cellier C, Meatchi T, Barbier JP, Cugnenc PH, Jian R, Laurent-Puig P, Landi B (2005) Chromoendoscopic colonoscopy for detecting preneoplastic lesions in hereditary nonpolyposis colorectal cancer syndrome. Clin Gastroenterol Hepatol 3:897–902PubMedCrossRefGoogle Scholar
  64. 64.
    Hurlstone DP, Karajeh M, Cross SS, McAlindon ME, Brown S, Hunter MD, Sanders DS (2005) The role of high-magnification-chromoscopic colonoscopy in hereditary nonpolyposis colorectal cancer screening: a prospective “back-to-back” endoscopic study. Am J Gastroenterol 100:2167–2173PubMedCrossRefGoogle Scholar
  65. 65.
    Hüneburg R, Lammert F, Rabe C, Rahner N, Kahl P, Büttner R, Propping P, Sauerbruch T, Lamberti C (2009) Chromocolonoscopy detects more adenomas than white light colonoscopy or narrow band imaging colonoscopy in hereditary nonpolyposis colorectal cancer screening. Endoscopy 41:316–322PubMedCrossRefGoogle Scholar
  66. 66.
    Ramsoekh D, Haringsma J, Poley JW, van Putten P, van Dekken H, Steyerberg EW, van Leerdam ME, Kuipers EJ (2010) A back-to-back comparison of white light video endoscopy with autofluorescence endoscopy for adenoma detection in high-risk subjects. Gut 59:785–793PubMedCrossRefGoogle Scholar
  67. 67.
    Rahmi G, Lecomte T, Malka D, Maniere T, Le Rhun M, Guimbaud R, Lapalus M-G, Le Sidaner A, Moussata D, Caron O, Barbieux J-P, Gaudric M, Coron E, Barange K, Ponchon T, Sautereau D, Samaha E, Saurin J-C, Chaussade S, Laurent-Piug P, Chatellier G, Cellier C (2015) Impact of chromoendoscopy on adenoma detection in patients with Lynch syndrome: a prospective, multicenter, blinded, tandem colonoscopy study. Am J Gastroenterol 110:288–298PubMedCrossRefGoogle Scholar
  68. 68.
    Bisschops R, Tejpar S, Willekens H, De Hertogh G, Van Cutsem E (2017) Virtual chromoendoscopy (I-SCAN) detects more polyps in patients with Lynch syndrome: a randomized controlled crossover trial. Endoscopy 49:342–350PubMedCrossRefGoogle Scholar
  69. 69.
    Anele CC, Adegbola SO, Askari A, Rajendran A, Clark SK (2017) Risk of metachronous colorectal cancer following colectomy in Lynch syndrome: a systematic review and meta-analysis. Colorectal Dis 19:528–536PubMedCrossRefGoogle Scholar
  70. 70.
    Natarajan N, Watson P, Silva-Lopez E, Lynch HT (2010) Comparison of extended colectomy and limited resection in patients with Lynch syndrome. Dis Colon Rectum 53:77–82PubMedCrossRefGoogle Scholar
  71. 71.
    Lynch HT, Lynch JF, Fitzgibbons R (2003) Role of prophylactic colectomy in Lynch syndrome. Clin Colorectal Cancer 3:99–101PubMedCrossRefGoogle Scholar
  72. 72.
    Parry S, Win AK, Parry B, Macrae FA, Gurrin LC, Church JM, Baron JA, Giles GG, Leggett BA, Winship I, Lipton L, Young GP, Young JP, Lodge CJ, Southey MC, Newcomb PA, Le ML, Haile RW, Lindor NM, Gallinger S, Hopper JL, Jenkins MA (2011) Metachronous colorectal cancer risk for mismatch repair gene mutation carriers: the advantage of more extensive colon surgery. Gut 60:950–957PubMedCrossRefGoogle Scholar
  73. 73.
    Syngal S, Weeks JC, Schrag D, Garber JE, Kuntz KM (1998) Benefits of colonoscopic surveillance and prophylactic colectomy in patients with hereditary nonpolyposis colorectal cancer mutations. Ann Intern Med 129:787–796PubMedCrossRefGoogle Scholar
  74. 74.
    Church JM (1996) Prophylactic colectomy in patients with hereditary nonpolyposis colorectal cancer. Ann Med 28:479–482PubMedCrossRefGoogle Scholar
  75. 75.
    Lynch HT (1996) Is there a role for prophylactic subtotal colectomy among hereditary nonpolyposis colorectal cancer germline mutation carriers? Dis Colon Rectum 39:109–110PubMedCrossRefGoogle Scholar
  76. 76.
    Liska D, Kalady MF (2015) Colorectal surgery in Lynch syndrome patients: when and how? Curr Colorectal Cancer Rep 11:45–53CrossRefGoogle Scholar
  77. 77.
    Herzig DO, Buie WD, Weiser MR, You YN, Rafferty JF, Feingold D, Steele SR (2017) Clinical practice guidelines for the surgical treatment of patients with Lynch syndrome. Dis Colon Rectum 60:137–143PubMedCrossRefGoogle Scholar
  78. 78.
    Church JM (2016) Controversies in the surgery of patients with familial adenomatous polyposis and Lynch syndrome. Fam Cancer 15:447–451PubMedCrossRefGoogle Scholar
  79. 79.
    Lu KH, Daniels M (2013) Endometrial and ovarian cancer in women with Lynch syndrome: update in screening and prevention. Fam Cancer 12:273–277PubMedCrossRefGoogle Scholar
  80. 80.
    Ryan NAJ, Evans DG, Green K, Crosbie EJ (2017) Pathological features and clinical behavior of Lynch syndrome-associated ovarian cancer. Gynecol Oncol 144:491–495PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Schmeler KM, Lynch HT, Chen L-M, Munsell MF, Soliman PT, Clark MB, Daniels MS, White KG, Boyd-Rogers SG, Conrad PG, Yang KY, Rubin MM, Sun CC, Slomovitz BM, Gershenson DM, Lu KH (2006) Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch syndrome. N Engl J Med 354:261–269PubMedCrossRefGoogle Scholar
  82. 82.
    Moller P, Seppala T, Bernstein I, Holinski-Feder E, Sala P, Evans DG, Lindblom A, Macrae F, Blanco I, Sijmons R, Jeffries J, Vasen H, Burn J, Nakken S, Hovig E, Rodland EA, de Tharmaratnam K, Hill J, Wijnen J, Green K, Lalloo F, Sunde L, Mints M, Bertario L, Pineda M, Navarro M, Morak M, Renkonen-Sinisalo L, Frayling IM, Plazzer JP, Pylvanainen K, Sampson JR, Capella G, Mecklin JP, Moslein G, Vos Tot Nederveen Cappel WH (2017). Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance: first report from the prospective Lynch syndrome database. Gut 66:464–472PubMedCrossRefGoogle Scholar
  83. 83.
    Moller P, Seppala T, Bernstein I, Holinski-Feder E, Sala P, Evans DG, Lindblom A, Macrae F, Blanco I, Sijmons R, Jeffries J, Vasen H, Burn J, Nakken S, Hovig E, Rodland EA, de Tharmaratnam K, Hill J, Wijnen J, Jenkins M, Green K, Lalloo F, Sunde L, Mints M, Bertario L, Pineda M, Navarro M, Morak M, Renkonen-Sinisalo L, Frayling IM, Plazzer JP, Pylvanainen K, Genuardi M, Mecklin JP, Moslein G, Sampson JR, Capella G, Vos Tot Nederveen Cappel WH (2017) Incidence of and survival after subsequent cancers in carriers of pathogenic MMR variants with previous cancer: a report from the prospective Lynch syndrome database. Gut 66:1657–1664PubMedCrossRefGoogle Scholar
  84. 84.
    Llosa NJ, Cruise M, Tam A, Wicks EC, Hechenbleikner EM, Taube JM, Blosser RL, Fan H, Wang H, Luber BS, Zhang M, Papadopoulos N, Kinzler KW, Vogelstein B, Sears CL, Anders RA, Pardoll DM, Housseau F (2015) The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov 5:43–51PubMedCrossRefGoogle Scholar
  85. 85.
    Sweis RF, Luke JJ (2017) Mechanistic and pharmacologic insights on immune checkpoint inhibitors. Pharmacol Res 120:1–9PubMedCrossRefGoogle Scholar
  86. 86.
    Phan GQ, Yang JC, Sherry RM, Hwu P, Topalian SL, Schwartzentruber DJ, Restifo NP, Haworth LR, Seipp CA, Freezer LJ, Morton KE, Mavroukakis SA, Duray PH, Steinberg SM, Allison JP, Davis TA, Rosenberg SA (2003) Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci USA 100:8372–8377PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, Skora AD, Luber BS, Azad NS, Laheru D, Biedrzycki B, Donehower RC, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Duffy SM, Goldberg RM, de la Chapelle A, Koshiji M, Bhaijee F, Huebner T, Hruban RH, Wood LD, Cuka N, Pardoll DM, Papadopoulos N, Kinzler KW, Zhou S, Cornish TC, Taube JM, Anders RA, Eshleman JR, Vogelstein B, Diaz LA, (2015) PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 372:2509–2520PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Sloan EA, Ring KL, Willis BC, Modesitt SC, Mills AM (2017) PD-L1 expression in mismatch repair-deficient endometrial carcinomas, incuding Lynch syndrome-associated and MLH1 promoter hypermethylated tumors. Am J Surg Pathol 41:326–333PubMedCrossRefGoogle Scholar
  89. 89.
    Ribic CM, Sargent DJ, Moore MJ, Thibodeau SN, French AJ, Goldberg RM, Hamilton SR, Laurent-Puig P, Gryfe R, Shepherd LE, Tu D, Redston M, Gallinger S (2003) Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med 349:247–257PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Bertagnolli MM, Niedzwiecki D, Compton CC, Hahn HP, Hall M, Damas B, Jewell SD, Mayer RJ, Goldberg RM, Saltz LB, Warren RS, Redston M (2009) Microsatellite instability predicts improved response to adjuvant therapy with irinotecan, fluorouracil, and leucovorin in stage III colon cancer: Cancer and Leukemia Group Protocol 89803. J Clin Oncol 27:1814–1821PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Boland CR (2016) Recent discoveries in the molecular genetics of Lynch syndrome. Fam Cancer 15:395–403PubMedCrossRefGoogle Scholar
  92. 92.
    Schwitalle Y, Kloor M, Eiermann S, Linnebacher M, Kienle P, Knaebel HP, Taraverdian M, Benner A, von Knebel Doeberitz M (2008) Immune response against frameshift-induced neopeptides in HNPCC patients and healthy HNPCC mutation carriers. Gastroenterology 134:988–997PubMedCrossRefGoogle Scholar
  93. 93.
    Reuschenbach M, Kloor M, Morak M, Wentzensen N, Germann A, Garbe Y, Tariverdian M, Findelsen P, Neumaier M, Holinski-Feder E, von Knebel-Doeberitz M (2010) Serum antibodies against frameshift peptides in microsatellite unstable colorectal cancer patients with Lynch syndrome. Fam Cancer 9:173–179PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Bauer K, Michel S, Reuschenbach M, Nelius N, von Knebel Doeberitz M, Kloor M (2011) Dendritic cell and macrophage infiltration in microsatellite-unstable and microsatellite-stable colorectal cancer. Fam Cancer 10:557–565PubMedCrossRefGoogle Scholar
  95. 95.
    de Miranda NF, Goudkade D, Jordanova ES, Tops CM, Hes FJ, Vasen HF, van Wezel T, Morreau H (2012) Infiltration of Lynch syndrome colorectal cancers by activated immune cells associates with early staging of the primary tumor and absence of lymph node metastases. Clin Cancer Res 18:1237–1245PubMedCrossRefGoogle Scholar
  96. 96.
    von Knebel Doeberitz M, Kloor M (2013) Towards a vaccine to prevent cancer in Lynch syndrome patients. Fam Cancer 12:307–312CrossRefGoogle Scholar
  97. 97.
    Westdorp H, Fennemann FL, Weren RD, Bisseling TM, Ligtenberg MJ, Figdor CG, Schreibelt G, Hoogerbrugge N, Wimmers F, de Vries IJ (2016) Opportunities for immunotherapy in microsatellite instable colorectal cancer. Cancer Immunol Immunother 65:1249–1259PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Lee J-M, Ledermann JA, Kohn EC (2014) PARP inhibitors for BRCA1/2 mutation-associated and BRCA-like malignancies. Ann Oncol 25:32–40PubMedCrossRefGoogle Scholar
  99. 99.
    Link JT, Overman MJ (2016) Immunotherapy progress in mismatch repair-deficient colorectal cancer and future therapeutic challenges. Cancer J 22:190–195PubMedCrossRefGoogle Scholar
  100. 100.
    Ginsburg GS, Willard HF (2009) Genomic and personalized medicine: foundations and applications. Transl Res 154:277–287PubMedCrossRefGoogle Scholar
  101. 101.
    Kravochuck SE, Kalady MF, Burke CA, Heald B, Church JM (2014) Defining HNPCC and Lynch syndrome: what’s in a name? Gut 63:1525–1526PubMedCrossRefGoogle Scholar
  102. 102.
    Fusaro RM, Lemon SJ, Lynch HT (1996) The Muir-Torre syndrome: a variant of hereditary nonpolyposis colorectal cancer syndrome. J Tumor Marker Oncol 11:19–31Google Scholar
  103. 103.
    Shiovitz S, Copeland WK, Passarelli MN, Burnett-Hartman AN, Grady WM, Potter JD, Gallinger S, Buchanan DD, Rosty C, Win AK, Jenkins M, Thibodeau SN, Haile R, Baron JA, Marchand LL, Newcomb PA, Lindor NM, Colon Cancer Family Registry (2014) Characterisation of familial colorectal cancer type X, Lynch syndrome, and non-familial colorectal cancer. Br J Cancer 111:598–602PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    MedicineNet (2017) Familial colorectal cancer. Available at: http://www.medicinenet.com/script/main/art.asp?articlekey=38753. Accessed 9 Oct 2017
  105. 105.
    Westdorp H, Kolders S, Hoogerbrugge N, de Vries IJM, Jongmans MCJ, Schreibelt G (2017) Immunotherapy holds the key to cancer treatment and prevention in constitutional mismatch repair deficiency (CMMRD) syndrome. Cancer Lett 403:159–164PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2017

Authors and Affiliations

  • Henry T. Lynch
    • 1
  • Stephen Lanspa
    • 1
    • 2
  • Trudy Shaw
    • 1
  • Murray Joseph Casey
    • 1
    • 3
  • Marc Rendell
    • 4
  • Mark Stacey
    • 1
  • Theresa Townley
    • 5
  • Carrie Snyder
    • 1
  • Megan Hitchins
    • 6
  • Joan Bailey-Wilson
    • 7
  1. 1.Hereditary Cancer CenterCreighton UniversityOmahaUSA
  2. 2.Gastrointestinal Division, Internal Medicine DepartmentCreighton UniversityOmahaUSA
  3. 3.Department of Obstetrics and GynecologyCreighton UniversityOmahaUSA
  4. 4.The Rose Salter Medical Research FoundationNewport CoastUSA
  5. 5.Internal Medicine DepartmentCreighton UniversityOmahaUSA
  6. 6.Department of Biomedical SciencesCedars-Sinai Medical CenterLos AngelesUSA
  7. 7.Computational and Statistical Genomics Branch, National Human Genome Research InstituteNational Institutes of HealthBaltimoreUSA

Personalised recommendations