Anticipation in Lynch syndrome: Where we are where we go

Current Genomics

Volumn 12, Issue 7, 2011, Pages 451-465

  Bozzao, Cristina ^a   Lastella, Patrizia ^a   Stella, Alessandro ^a  

^a UNIVERSITY OF BARI   (Italy)

Author keywords

Anticipation; Lynch syndrome; Microsatellite instability; MMR genes; Telomere dynamics; Telomere length

Indexed keywords

CANCER DIAGNOSIS; CARCINOGENESIS; FOLLOW UP; GENETIC SUSCEPTIBILITY; GENOTYPE PHENOTYPE CORRELATION; HEREDITARY NONPOLYPOSIS COLORECTAL CANCER; HUMAN; MICROSATELLITE INSTABILITY; MISMATCH REPAIR; REVIEW; TELOMERE;

EID: 80055113946     PISSN: 13892029     EISSN: 18755488     Source Type: Journal    
DOI: 10.2174/138920211797904070     Document Type: Review

References (165)

1. Hampel, H.; Frankel, W.L.; Martin, E.; Arnold, M.; Khanduja, K.; Kuebler, P.; Clendenning, M.; Sotamaa, K.; Prior, T.; Westman, J.A.; Panescu, J.; Fix, D.; Lockman, J.; LaJeunesse, J.; Comeras, I.; de la Chapelle, A. Feasibility of screening for Lynch syndrome among patients with colorectal cancer. J. Clin. Oncol., 2008, 26, 5783-5788.
2. Lynch, H.T.; de la Chapelle, A. Hereditary colorectal cancer. N. Engl. J. Med., 2003, 348, 919-932.
3. Jasperson, K.W.; Tuohy, T.M.; Neklason, D.W.; Burt, R.W. Hereditary and familial colon cancer. Gastroenterology, 2010, 138, 2044-2058.
4. Vasen, H.F.; Stormorken, A.; Menko, F.H.; Nagengast, F.M.; Kleibeuker, J.H.; Griffioen, G.; Taal, B.G.; Moller, P.; Wijnen, J.T. 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, 4074-4080.
5. Fredriksson, H.; Ikonen, T.; Autio, V.; Matikainen, M.P.; Helin, H.J.; Tammela, T.L.; Koivisto, P.A.; Schleutker, J. Identification of germline MLH1 alterations in familial prostate cancer. Eur. J. Cancer., 2006, 42, 2802-2806.
6. Stoffel, E.; Mukherjee, B.; Raymond, V.M.; Tayob, N.; Kastrinos, F.; Sparr, J.; Wang, F.; Bandipalliam, P.; Syngal, S.; Gruber, S.B. Calculation of risk of colorectal and endometrial cancer among patients with Lynch syndrome. Gastroenterology, 2009, 137, 1621-1627.
7. Hampel, H.; Frankel, W.; Panescu, J.; Lockman, J.; Sotamaa, K.; Fix, D.; Comeras, I.; La Jeunesse, J.; Nakagawa, H.; Westman, J.A.; Prior, T.W.; Clendenning, M.; Penzone, P.; Lombardi, J.; Dunn, P.; Cohn, D.E.; Copeland, L.; Eaton, L.; Fowler, J.; Lewan-dowski, G.; Vaccarello, L.; Bell, J.; Reid, G.; de la Chapelle, A. Screening for Lynch syndrome (hereditary nonpolyposis colorectal cancer) among endometrial cancer patients. Cancer Res., 2006, 66, 7810-7817.
8. Vasen, H.F. Clinical description of the Lynch syndrome [hereditary nonpolyposis colorectal cancer (HNPCC)]. Fam. Cancer, 2005, 4, 219-225.
9. Vasen, H.F.; Wijnen, J.T.; Menko, F.H.; Kleibeuker, J.H.; Taal, B.G.; Griffioen, G.; Nagengast, F.M.; Meijers-Heijboer, E.H.; Ber-tario, L.; Varesco, L.; Bisgaard, M.L.; Mohr, J.; Fodde, R; Khan, P.M. Cancer risk in families with hereditary nonpolyposis colorec-tal cancer diagnosed by mutation analysis. Gastroenterology, 1996, 110, 1020-1027.
10. Lin, K.M.; Shashidharan, M.; Thorson, A.G.; Ternent, C.A.; Blatchford, G.J.; Christensen, M.A.; Watson, P.; Lemon, S.J.; Franklin, B.; Karr, B.; Lynch, J.; Lynch, H.T. Cumulative incidence of colorectal and extracolonic cancers in MLH1 and MSH2 mutation carriers of hereditary nonpolyposis colorectal cancer. J. Gastrointest. Surg., 1998, 2, 67-71.
11. Buckowitz, A.; Knaebel, H.P.; Benner, A.; Bläker, H.; Gebert, J.; Kienle, P.; von Knebel Doeberitz, M.; Kloor, M. Microsatellite instability in colorectal cancer is associated with local lymphocyte infiltration and low frequency of distant metastases. B r. J. Can cer, 2005, 92, 1746-1753.
12. Lastella, P.; Patruno, M.; Forte, G.; Montanaro, A.; Di Gregorio, C.; Sabbà, C.; Suppressa, P.; Piepoli, A.; Panza, A.; Andriulli, A.; Resta, N.; Stella, A. Identification and surveillance of 19 Lynch syndrome families in southern Italy: report of six novel germline mutations and a common founder mutation. Fam. Cancer, 2011 Feb 1.
13. Peltomäki, P. Lynch syndrome genes. Fam. Cancer, 2005, 4, 227-232.
14. Boland, C.R.; Koi, M.; Chang, D.K.; Carethers, J.M. The biochemical basis of microsatellite instability and abnormal immuno-histochemistry and clinical behavior in Lynch syndrome: from bench to bedside. Fam. Cancer, 2008, 7, 41-52.
15. Pino, MS.; Chung, DC. Application of molecular diagnostics for the detection of Lynch syndrome. Expert Rev. Mol. Diagn., 2010, 10:651-665.
16. Kovacs, M.E.; Papp, J.; Szentirmay, Z.; Otto, S.; Olah, E. Deletions removing the last exon of TACSTD1 constitute a distinct class of mutations predisposing to Lynch syndrome. Hum. Mutat., 2009, 30, 197-203.
17. Llor, X.; Pons, E.; Xicola, RM.; Castells, A.; Alenda, C; Piñol, V.; Andreu, M.; Castellví-Bel, S.; Payá, A.; Jover, R.; Bessa, X.; Girós, A.; Roca, A.; Gassull, MA.; Gastrointestinal Oncology Group of the Spanish Gastroenterological Association. Differential features of colorectal cancers fulfilling Amsterdam criteria without involvement of the mutator pathway. Clin. Cancer Res., 2005, 11, 7304-7310.
18. Kerber, RA.; Neklason, DW.; Samowitz, WS.; Burt, RW. Frequency of familial colon cancer and hereditary nonpolyposis colorectal cancer (Lynch syndrome) in a large population database. Fam. Cancer, 2005, 4, 239-244.
19. Lindor, NM.; Rabe, K.; Petersen, GM.; Haile, R.; Casey, G.; Baron, J.; Gallinger, S.; Bapat, B.; Aronson, M.; Hopper, J.; Jass, J.; LeMarchand, L.; Grove, J.; Potter, J.; Newcomb, P.; Terdiman, JP; Conrad, P.; Moslein, G.; Goldberg, R.; Ziogas, A.; AntonCulver, H.; de Andrade, M.; Siegmund, K.; Thibodeau, SN.; Boardman, LA.; Seminara, D. Lower cancer incidence in Amster-dam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X. JAMA, 2005, 293, 1979-1985.
20. Boland, C.R.; Thibodeau, S.N.; Hamilton, S.R.; Sidransky, D.; Eshleman, J.R.; Burt, R.W.; Meltzer, S.J.; Rodriguez-Bigas, M.A.; Fodde, R.; Ranzani, G.N.; Srivastava, S. 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., 1998, 58, 5248-5257.
21. Wu, Y.; Berends, MJ.; Mensink, RG.; Kempinga, C; Sijmons, RH.; van Der Zee, AG.; Hollema, H.; Kleibeuker, JH.; Buys, CH.; Hofstra, RM. Association of hereditary nonpolyposis colorectal cancer-related tumors displaying low microsatellite instability with MSH6 germline mutations. Am. J. Hum. Genet., 1999, 65, 1291-1298.
22. Berends, MJ.; Wu, Y.; Sijmons, RH.; Mensink, RG.; van der Sluis, T; Hordijk-Hos, JM.; de Vries, EG.; Hollema, H.; Karrenbeld, A.; Buys, CH.; van der Zee, AG.; Hofstra, RM.; Kleibeuker, JH. Molecular and clinical characteristics of MSH6 variants: an analysis of 25 index carriers of a germline variant. Am. J. Hum. Genet., 2002, 70, 26-37.
23. Murphy, K.M.; Zhang, S.; Geiger, T; Hafez, M.J.; Bacher, J.; Berg, K.D.; Eshleman, J.R. Comparison of the microsatellite instability analysis system and the Bethesda panel for the determination of microsatellite instability in colorectal cancers. J. Mol. Diagn., 2006, 8, 305-311.
24. Poulogiannis, G.; Frayling, I.M.; Arends, M.J. DNA mismatch repair deficiency in sporadic colorectal cancer and Lynch syndrome. Histopathology, 2010, 56, 167-179.
25. You, JF.; Buhard, O.; Ligtenberg, MJ.; Kets, CM.; Niessen, RC; Hofstra, RM.; Wagner, A.; Dinjens, WN.; Colas, C; Lascols, O.; Collura, A.; Flejou, JF.; Duval, A.; Hamelin, R. Tumours with loss of MSH6 expression are MSI-H when screened with a pentaplex of five mononucleotide repeats. Br. J. Cancer, 2010, 103, 1840-1845.
26. Nardon, E.; Glavac, D.; Benhattar, J.; Groenen, PJ.; Höfler, G.; Höfler, H.; Jung, A.; Keller, G.; Kirchner, T; Lessi, F.; Ligtenberg, MJ.; Mazzanti, CM.; Winter, G.; Stanta, G. A multicenter study to validate the reproducibility of MSI testing with a panel of 5 quasi-monomorphic mononucleotide repeats. Diagn. Mol. Pathol, 2010, 19, 236-242.
27. Agostini, M.; Enzo, M.V.; Morandi, L.; Bedin, C; Pizzini, S.; Mason, S.; Bertorelle, R.; Urso, E.; Mescoli, C; Lise, M.; Pucci-arelli, S.; Nitti, D. A ten markers panel provides a more accurate and complete microsatellite instability analysis in mismatch repair-deficient colorectal tumors. Cancer Biomark., 2010, 6, 49-61.
28. Hoang, J.M.; Cottu, P.H.; Thuille, B.; Salmon, R.J.; Thomas, G.; Hamelin, R. BAT-26, an indicator of the replication error phenotype in colorectal cancers and cell lines. Cancer Res., 1997, 57, 300-303.
29. Xicola, R.M.; Llor, X.; Pons, E.; Castells, A.; Alenda, C.; Piñol, V.; Andreu, M.; Castellví-Bel, S.; Payá, A.; Jover, R.; Bessa, X.; Girós, A.; Duque, J.M.; Nicolás-Pérez, D.; Garcia, A.M.; Rigau, J.; Gas-sull, M.A.; Gastrointestinal Oncology Group of the Spanish Gas-troenterological Association. Performance of different microsatel-lite marker panels for detection of mismatch repair-deficient colo-rectal tumors. J. Natl. Cancer Inst., 2007, 99, 244-252.
30. Iacopetta, B.; Grieu, F.; Amanuel, B. Microsatellite instability in colorectal cancer. Asia Pac. J. Clin. Oncol., 2010, 6, 260-269.
31. Loughrey, M.B.; Waring, P.M.; Tan, A.; Trivett, M.; Kovalenko, S.; Beshay, V.; Young, M.A.; McArthur, G.; Boussioutas, A.; Do-brovic, A. Incorporation of somatic BRAF mutation testing into an algorithm for the investigation of hereditary non-polyposis colorec-tal cancer. Fam. Cancer, 2007, 6, 301-310.
32. Johnson, V.; Lipton, L.R.; Cummings, C.; Eftekhar Sadat, A.T.; Izatt, L.; Hodgson, S.V.; Talbot, I.C.; Thomas, H.J.; Silver, A.J.; Tomlinson, I.P. Analysis of somatic molecular changes, clinicopa-thological features, family history, and germline mutations in colo-rectal cancer families: evidence for efficient diagnosis of HNPCC and for the existence of distinct groups of non-HNPCC families. J. Med. Genet., 2005, 42, 756-762.
33. Parsons, R.; Myeroff, L.L.; Liu, B.; Willson, J.K.; Markowitz, S.D.; Kinzler, K.W.; Vogelstein, B. Microsatellite instability and mutations of the transforming growth factor beta type II receptor gene in colorectal cancer. Cancer Res., 1995, 55, 5548-5550.
34. Li, G.M. Mechanisms and functions of DNA mismatch repair. Cell Res., 2008, 18, 85-98.
35. Alhopuro, P.; Sammalkorpi, H.; Niittymäki, I.; Biström, M.; Rait-ila, A.; Saharinen, J.; Nousiainen, K.; Lehtonen, H.J.; Heliövaara, E.; Puhakka, J.; Tuupanen, S.; Sousa, S.; Seruca, R.; Ferreira, A.M.; Hofstra, R.M.; Mecklin, J.P.; Järvinen, H.; Ristimäki, A.; Orntoft, T.F.; Hautaniemi, S.; Arango, D.; Karhu, A.; Aaltonen, L.A. Candidate driver genes in microsatellite-unstable colorectal cancer. Int. J. Cancer, 2011 May 4.
36. Boland, C.R.; Goel, A. Microsatellite instability in colorectal cancer. Gastroenterology, 2010, 6, 2073-2087
37. Hofstra, R.M.; Spurdle, A.B.; Eccles, D.; Foulkes, W.D.; de Wind, N.; Hoogerbrugge, N.; Hogervorst, F.B.; IARC Unclassified Genetic Variants Working Group. Tumor characteristics as an analytic tool for classifying genetic variants of uncertain clinical significance. Hum. Mutat., 2008, 29,1292-1303.
38. Edelstein, D.L.; Axilbund, J.; Baxter, M.; Hylind, L.M.; Romans, K.; Griffin, C.A.; Cruz-Correa, M.; Giardiello, F.M. Rapid development of colorectal neoplasia in patients with lynch syndrome. Clin. Gastroenterol. Hepatol., 2011, 9, 340-343.
39. Lynch, H.T.; Boland, C.R.; Gong, G.; Shaw, T.G.; Lynch, P.M.; Fodde, R.; Lynch, J.F.; de la Chapelle, A. Phenotypic and geno-typic heterogeneity in the Lynch syndrome: diagnostic, surveillance and management implications. Eur. J. Hum. Genet., 2006, 14, 390-402.
40. Graham, D.M.; Appelman, H.D. Crohn's-like lymphoid reaction and colorectal carcinoma: a potential histologic prognosticator. Mod. Pathol., 1990, 3, 332-335.
41. Popat, S.; Hubner, R.; Houlston, R.S. Systematic review of micro-satellite instability and colorectal cancer prognosis. J. Clin. Oncol., 2005, 23, 609-618.
42. Järvinen, H.J.; Renkonen-Sinisalo, L.; Aktán-Collán, K.; Pel-tomäki, P.; Aaltonen, L.A.; Mecklin, J.P. Ten years after mutation testing for Lynch syndrome: cancer incidence and outcome in mutation-positive and mutation-negative family members. J. Clin. Oncol., 2009, 27, 4793-4797.
43. Drescher, K.M.; Sharma, P.; Lynch, H.T. Current hypotheses on how microsatellite instability leads to enhanced survival of Lynch Syndrome patients. Clin. Dev. Immunol., 2010 Jun 10.
44. Sinicrope, F.A.; Rego, R.L.; Garrity-Park, M.M.; Foster, N.R.; Sargent, D.J.; Goldberg, R.M.; Wiesenfeld, M.; Witzig, T.E.; Thi-bodeau, S.N.; Burgart, L.J. Alterations in cell proliferation and apoptosis in colon cancers with microsatellite instability. Int. J. Cancer, 2007, 120, 1232-1238.
45. Drescher, K.M.; Sharma, P.; Watson, P.; Gatalica, Z.; Thibodeau, S.N.; Lynch, H.T. Lymphocyte recruitment into the tumor site is altered in patients with MSI-H colon cancer. Fam. Cancer, 2009, 8, 231-239.
46. Dierssen, J.W.; de Miranda, N.F.; Ferrone, S.; van Puijenbroek, M.; Cornelisse, C.J.; Fleuren, G.J.; van Wezel, T.; Morreau, H. HNPCC versus sporadic microsatellite-unstable colon cancers follow different routes toward loss of HLA class I expression. BMC Cancer, 2007, 7, 33.
47. Kloor, M.; Michel, S.; Buckowitz, B.; Rüschoff, J.; Büttner, R.; Holinski-Feder, E.; Dippold, W.; Wagner, R.; Tariverdian, M.; Benner, A.; Schwitalle, Y.; Kuchenbuch, B.; von Knebel Doeberitz, M. Beta2-microglobulin mutations in microsatellite unstable colorectal tumors. Int. J. Cancer, 2007, 121, 454-458.
48. Carethers, J.M.; Chauhan, D.P.; Fink, D.; Nebel, S.; Bresalier, R.S.; Howell, S.B.; Boland, C.R. Mismatch repair proficiency and in vitro response to 5-fluorouracil. Gastroenterology, 1999, 117, 123-131.
49. Arnold, C.N.; Goel, A.; Boland, C.R. Role of hMLH1 promoter hypermethylation in drug resistance to 5-fluorouracil in colorectal cancer cell lines. Int. J. Cancer, 2003, 106, 66-73.
50. Carethers, J.M.; Smith, E.J.; Behling, C.A.; Nguyen, L.; Tajima, A.; Doctolero, R.T.; Cabrera, B.L.; Goel, A.; Arnold, C.A.; Miyai, K.; Boland, C.R. Use of 5-fluorouracil and survival in patients with microsatellite-unstable colorectal cancer. Gastroenterology, 2004, 126, 394-401.
51. De Vos tot Nederveen Cappel, W.H.; Meulenbeld, H.J.; Kleibeuker, J.H.; Nagengast, F.M.; Menko, F.H.; Griffioen, G.; Cats, A.; Mor-reau, H.; Gelderblom, H.; Vasen, H F. Survival after adjuvant 5-FU treatment for stage III colon cancer in hereditary nonpolyposis co-lorectal cancer. Int. J. Cancer, 2004, 109, 468-471.
52. Jover, R.; Zapater, P.; Castells, A.; Llor, X.; Andreu, M.; Cubiella, J.; Piñol, V.; Xicola, R.M.; Bujanda, L.; Reñé, J.M.; Clofent, J.; Bessa, X.; Morillas, J.D.; Nicolás-Pérez, D.; Payá, A.; Alenda, C.; Gastrointestinal Oncology Group of the Spanish Gastroenterologi-cal Association. Mismatch repair status in the prediction of benefit from adjuvant fluorouracil chemotherapy in colorectal cancer. Gut, 2006, 55, 848-855.
53. Lynch, H.T.; Lynch, P.M.; Lanspa, S.J.; Snyder, C.L.; Lynch, J.F.; Boland, C.R. Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medico legal ramifications. Clin. Genet., 2009, 76, 1-18.
54. Vasen, H.F.; Mecklin, J.P.; Khan, P.M.; Lynch, H.T. The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC). Dis. Colon Rectum, 1991, 34, 424-425.
55. Vasen, H.F.; Watson, P.; Mecklin, J.P.; Lynch, H.T. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology, 1999, 116, 1453-1456.
56. Rodriguez-Bigas, M.A.; Boland, C.R.; Hamilton, S.R.; Henson, D.E.; Jass, J.R.; Khan, P.M.; Lynch, H.; Perucho, M.; Smyrk, T.; Sobin, L.; Srivastava, S. A National Cancer Institute Workshop on Hereditary Nonpolyposis Colorectal Cancer Syndrome: meeting highlights and Bethesda guidelines. J. Natl. Cancer. Inst., 1997, 89, 1758-1762.
57. Umar, A.; Boland, C.R.; Terdiman, J.P.; Syngal, S.; de la Chapelle, A.; Rüschoff, J.; Fishel, R.; Lindor, N.M.; Burgart, L.J.; Hamelin, R.; Hamilton, S.R.; Hiatt, R.A.; Jass, J.; Lindblom, A.; Lynch, H.T.; Peltomaki, P.; Ramsey, S.D.; Rodriguez-Bigas, M.A.; Vasen, H.F.; Hawk, E.T.; Barrett, J.C.; Freedman, A.N.; Srivastava, S. Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J. Natl. Cancer Inst., 2004, 96, 261-268.
58. Jass, J.R. Molecular heterogeneity of colorectal cancer: Implications for cancer control. Surg. Oncol., 2007, 16, Suppl 1:S7-9.
59. Manders, P.; Spruijt, L.; Kets, C.M.; Willems, H.W.; Bodmer, D.; Hebeda, K.M.; Nagtegaal, I.D.; van Krieken, J.H.; Ligtenberg, M.J.; Hoogerbrugge, N. Young age and a positive family history of colorectal cancer are complementary selection criteria for the identification of Lynch syndrome. Eur. J. Cancer, 2011 Jan 25.
60. Boland, C.R. The molecular biology of gastrointestinal cancer: implications for diagnosis and therapy. Gastrointest. Endosc. Clin. N. Am., 2008, 18, 401-413.
61. Müller, A.; Giuffre, G.; Edmonston, T.B.; Mathiak, M.; Roggen-dorf, B.; Heinmöller, E.; Brodegger, T.; Tuccari, G.; Mangold, E.; Buettner, R.; Rüschoff, J.; German HNPCC Consortium German Cancer Aid (Deutsche Krebshilfe). Challenges and pitfalls in HNPCC screening by microsatellite analysis and immunohisto-chemistry. J. Mol. Diagn., 2004, 6, 308-315.
62. Raevaara, T.E.; Korhonen, M.K.; Lohi, H.; Hampel, H.; Lynch, E.; Lönnqvist, K.E.; Holinski-Feder, E.; Sutter, C.; McKinnon, W.; Duraisamy, S.; Gerdes, A.M.; Peltomäki, P.; Kohonen-Ccorish, M.; Mangold, E.; Macrae, F.; Greenblatt, M.; de la Chapelle, A.; Nyström, M. Functional significance and clinical phenotype of nontruncating mismatch repair variants of MLH1. Gastroenterol-ogy, 2005, 129, 537-549.
63. Blasi, M.F.; Ventura, I.; Aquilina, G.; Degan, P.; Bertario, L.; Bassi, C.; Radice, P.; Bignami, M. A human cell-based assay to evaluate the effects of alterations in the MLH1 mismatch repair gene. Cancer Res., 2006, 66, 9036-9044.
64. Stupart, D.A.; Goldberg, P.A.; Algar, U.; Ramesar, R. Surveillance colonoscopy improves survival in a cohort of subjects with a single mismatch repair gene mutation. Colorectal Dis., 2009, 11, 126-130.
65. Hüneburg, R.; Lammert, F.; Rabe, C.; Rahner, N.; Kahl, P.; Büttner, R.; Propping, P.; Sauerbruch, T.; Lamberti, C. Chro-mocolonoscopy detects more adenomas than white light colono-scopy or narrow band imaging colonoscopy in hereditary nonpoly-posis colorectal cancer screening. Endoscopy, 2009, 41, 316-322.
66. Lindor, N.M.; Petersen, G.M.; Hadley, D.W.; Kinney, A.Y.; Mies-feldt, S.; Lu, K.H.; Lynch, P.; Burke, W.; Press, N. Recommendations for the care of individuals with an inherited predisposition to Lynch syndrome: a systematic review. JAMA, 2006, 296, 1507-1517.
67. Auranen, A.; Joutsiniemi, T. A systematic review of gynecological cancer surveillance in women belonging to hereditary nonpolyposis colorectal cancer (Lynch syndrome) families. Acta Obstet. Gyne-col. Scand., 2011, 90, 437-444.
68. Palomaki, G.E.; McClain, M.R.; Melillo, S.; Hampel, H.L.; Thi-bodeau, S.N. EGAPP supplementary evidence review: DNA testing strategies aimed at reducing morbidity and mortality from Lynch syndrome. Genet. Med., 2009, 11, 42-65.
69. Jasperson, K.W.; Tuohy, T.M.; Neklason, D.W.; Burt, R.W. Hereditary and familial colon cancer. Gastroenterology, 2010, 138, 2044-2058.
70. Vasen, H.F.; Wijnen, J.T.; Menko, F.H.; Kleibeuker, J.H.; Taal, B.G.; Griffioen, G.; Nagengast, F.M.; Meijers-Heijboer, E.H.; Ber-tario, L.; Varesco, L.; Bisgaard, M.L.; Mohr, J.; Fodde, R.; Khan, P.M. Cancer risk in families with hereditary nonpolyposis colorec-tal cancer diagnosed by mutation analysis. Gastroenterology, 1996, 110, 1020-1027.
71. Barrow, E.; Robinson, L.; Alduaij, W.; Shenton, A.; Clancy, T.; Lalloo, F.; Hill, J.; Evans, D.G. Cumulative lifetime incidence of extracolonic cancers in Lynch syndrome: a report of 121 families with proven mutations. Clin. Genet., 2009, 75, 141-149.
72. Vasen, H.F.; Sanders, E.A.; Taal, B.G.; Nagengast, F.M.; Grif-fioen, G.; Menko, F.H.; Kleibeuker, J.H.; Houwing-Duistermaat, J.J.; Meera Khan, P. The risk of brain tumours in hereditary non-polyposis colorectal cancer (HNPCC). Int. J. Cancer, 1996, 65, 422-425.
73. Vasen, H.F.; Stormorken, A.; Menko, F.H.; Nagengast, F.M.; Klei-beuker, J.H.; Griffioen, G.; Taal, B.G.; Moller, P.; Wijnen, J.T. 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, 4074-4080.
74. Pineda, M.; González, S.; Lázaro, C.; Blanco, I.; Capellá, G. Detection of genetic alterations in hereditary colorectal cancer screening. Mutat. Res., 2010, 693, 19-31.
75. Jäger, A.C.; Bisgaard, M.L.; Myrhøj, T.; Bernstein, I.; Rehfeld, J.F.; Nielsen, F.C. Reduced frequency of extracolonic cancers in hereditary nonpolyposis colorectal cancer families with monoallelic hMLH1 expression. Am. J. Hum. Genet., 1997, 61, 129-138.
76. Mukherjee, B.; Rennert, G.; Ahn, J.; Dishon, S.; Lejbkowicz, F.; Rennert, H.; Shiovitz, S.; Moreno, V.; Gruber, S.B. High risk of colorectal and endometrial cancer in ashkenazi families with the MSH2 A636P founder mutation. Gastroenterology, 2011 Mar 16.
77. Liu, B.; Parsons, R.E.; Hamilton, S.R.; Petersen, G.M.; Lynch, H.T.; Watson, P.; Markowitz, S.; Willson, J.K.; Green, J.; de la Chapelle, A.; Kinzler, K.W.; Vogelstein B. hMSH2 mutations in hereditary nonpolyposis colorectal cancer kindreds. Cancer Res., 1994, 54, 4590-4594.
78. Froggatt, N.J.; Joyce, J.A.; Davies, R.; Gareth, D.; Evans, R.; Ponder, B.A.; Barton, D.E.; Maher, E.R. A frequent hMSH2 mutation in hereditary non-polyposis colon cancer syndrome. Lancet, 1995, 345, 727.
79. Froggatt, N.J.; Green, J.; Brassett, C.; Evans, D.G.; Bishop, D.T.; Kolodner, R.; Maher, E.R. A common MSH2 mutation in English and North American HNPCC families: origin, phenotypic expression and sex specific differences in colorectal cancer. J. Med. Genet., 1999, 36, 97-102.
80. Stuckless, S.; Parfrey, P.S.; Woods, M.O.; Cox, J.; Fitzgerald, G.W.; Green, J.S.; Green, R.C. The phenotypic expression of three MSH2 mutations in large Newfoundland families with Lynch syndrome. Fam. Cancer, 2007, 6, 1-12.
81. Plaschke, J.; Engel, C.; Krüger, S.; Holinski-Feder, E.; Pagen-stecher, C.; Mangold, E.; Moeslein, G.; Schulmann, K.; Gebert, J.; von Knebel Doeberitz, M.; Rüschoff, J.; Loeffler, M.; Schackert, HK. Lower incidence of colorectal cancer and later age of disease onset in 27 families with pathogenic MSH6 germline mutations compared with families with MLH1 or MSH2 mutations: the German Hereditary Nonpolyposis Colorectal Cancer Consortium. J. Clin. Oncol., 2004, 22, 4486-4494.
82. Hendriks, Y.M.; Wagner, A.; Morreau, H.; Menko, F.; Stormorken, A.; Quehenberger, F.; Sandkuijl, L.; Møller, P.; Genuardi, M.; Van Houwelingen, H.; Tops, C.; Van Puijenbroek, M.; Verkuijlen, P.; Kenter, G.; Van Mil, A.; Meijers-Heijboer, H.; Tan, G.B.; Breun-ing, M.H.; Fodde, R.; Wijnen, J.T.; Bröcker-Vriends, A.H.; Vasen, H. Cancer risk in hereditary nonpolyposis colorectal cancer due to MSH6 mutations: impact on counseling and surveillance. Gastro-enterology, 2004, 127, 17-25.
83. Ramsoekh, D.; Wagner, A.; van Leerdam, M.E.; Dooijes, D.; Tops, C.M.; Steyerberg, E.W.; Kuipers, E.J. Cancer risk in MLH1; MSH2 and MSH6 mutation carriers, different risk profiles may influence clinical management. Hered. Cancer Clin. Pract., 2009, 7, 17.
84. Lucci-Cordisco, E.; Rovella, V.; Carrara, S.; Percesepe, A.; Pedroni, M.; Bellacosa, A.; Caluseriu, O.; Forasarig, M.; Anti, M.; Neri, G.; Ponz de Leon, M.; Viel, A.; Genuardi, M. Mutations of the 'minor' mismatch repair gene MSH6 in typical and atypical hereditary nonpolyposis colorectal cancer. Fam. Cancer, 2001, 1, 93-99.
85. Worthley, D.L.; Walsh, M.D.; Barker, M.; Ruszkiewicz, A.; Bennett, G.; Phillips, K.; Suthers, G. Familial mutations in PMS2 can cause autosomal dominant hereditary nonpolyposis colorectal cancer. Gastroenterology, 2005, 128, 1431-1436.
86. Clendenning, M.; Hampel, H.; LaJeunesse, J.; Lindblom, A.; Lockman, J.; Nilbert, M.; Senter, L.; Sotamaa, K.; de la Chapelle, A. Long-range PCR facilitates the identification of PMS2-specific mutations. Hum. Mutat., 2006, 27, 490-495.
87. Vaughn, C.P.; Robles, J.; Swensen, J.J.; Miller, C.E.; Lyon, E.; Mao, R.; Bayrak-Toydemir, P.; Samowitz, W.S. Clinical analysis of PMS2: mutation detection and avoidance of pseudogenes. Hum. Mutat., 2010, 31, 588-593.
88. Senter, L.; Clendenning, M.; Sotamaa, K.; Hampel, H.; Green, J.; Potter, J.D.; Lindblom, A.; Lagerstedt, K.; Thibodeau, S.N.; Lin-dor, N.M.; Young, J.; Winship, I.; Dowty, J.G.; White, D.M.; Hopper, J.L.; Baglietto, L.; Jenkins, M.A.; de la Chapelle, A. The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations. Gastroenterology, 2008, 135, 419-428.
89. Poley, J.W.; Wagner, A.; Hoogmans, M.M.; Menko, F.H.; Tops, C.; Kros, J.M.; Reddingius, R.E.; Meijers-Heijboer, H.; Kuipers, E.J.; Dinjens, W.N.; Rotterdam Initiative on Gastrointestinal Hereditary Tumors. Biallelic germline mutations of mismatch-repair genes: a possible cause for multiple pediatric malignancies. Cancer, 2007, 109, 2349-2356.
90. Bandipalliam, P. Syndrome of early onset colon cancers, hema-tologic malignancies & features of neurofibromatosis in HNPCC families with homozygous mismatch repair gene mutations. Fam. Cancer, 2005, 4, 323-333.
91. Lipkin, S.M.; Wang, V.; Jacoby, R.; Banerjee-Basu, S.; Baxevanis, A.D.; Lynch, H.T.; Elliott, R.M.; Collins, F.S. MLH3: a DNA mismatch repair gene associated with mammalian microsatellite instability. Nat. Genet., 2000, 24, 27-35.
92. Wu, Y.; Berends, M.J.; Post, J.G.; Mensink, R.G.; Verlind, E.; Van Der Sluis, T.; Kempinga, C.; Sijmons, R.H.; van der Zee, A.G.; Hollema, H.; Kleibeuker, J.H.; Buys, C.H.; Hofstra, R.M. Germline mutations of EXO1 gene in patients with hereditary nonpolyposis colorectal cancer (HNPCC) and atypical HNPCC forms. Gastroen-terology, 2001, 120, 1580-1587.
93. Hitchins, M.; Williams, R.; Cheong, K.; Halani, N.; Lin, V.A.; Packham, D.; Ku, S.; Buckle, A.; Hawkins, N.; Burn, J.; Gallinger, S.; Goldblatt, J.; Kirk, J.; Tomlinson, I.; Scott, R.; Spigelman, A.; Suter, C.; Martin, D.; Suthers, G.; Ward, R. MLH1 germline epimutations as a factor in hereditary nonpoly-posis colorectal cancer. Gastroenterology, 2005, 129, 1392-1399.
94. Niessen, R.C.; Hofstra, R.M.; Westers, H.; Ligtenberg, M.J.; Kooi, K.; Jager, P.O.; de Groote, M.L.; Dijkhuizen, T.; Olderode-Berends, M.J.; Hollema, H.; Kleibeuker, J.H.; Sijmons, R.H. Germ-line hypermethylation of MLH1 and EPCAM deletions are a frequent cause of Lynch syndrome. Genes Chromosomes Cancer, 2009, 48, 737-744.
95. Goel, A.; Nguyen, T.P.; Leung, H.C.; Nagasaka, T.; Rhees, J.; Hotchkiss, E.; Arnold, M.; Banerji, P.; Koi, M.; Kwok, C.T.; Packham, D.; Lipton, L.; Boland, C.R.; Ward, R.L.; Hitchins, M.P. De novo constitutional MLH1 epimutations confer early-onset colorectal cancer in two new sporadic Lynch syndrome cases; with derivation of the epimutation on the paternal allele in one. Int. J. Cancer, 2011, 128, 869-878.
96. Suter, C.M.; Martin, D.I.; Ward, R.L. Germline epimutation of MLH1 in individuals with multiple cancers. Nat. Genet., 2004, 36, 497-501.
97. Valle, L.; Carbonell, P.; Fernandez, V.; Dotor, A.M.; Sanz, M.; Benitez, J.; Urioste, M. MLH1 germline epimutations in selected patients with early-onset non-polyposis colorectal cancer. Clin. Genet., 2007, 71, 232-237.
98. Ligtenberg, M.J.; Kuiper, R.P.; Chan, T.L.; Goossens, M.; Hebeda, K.M.; Voorendt, M.; Lee, T.Y.; Bodmer, D.; Hoenselaar, E.; Hen-driks-Cornelissen, S.J.; Tsui, W.Y.; Kong, C.K.; Brunner, H.G.; van Kessel, A.G.; Yuen, S.T.; van Krieken, J.H.; Leung, S.Y.; Hoogerbrugge, N. Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3' exons of TACSTD1. Nat. Genet., 2009, 41, 112-117.
99. Kempers, M.J.; Kuiper, R.P.; Ockeloen, C.W.; Chappuis, P.O.; Hutter, P.; Rahner, N.; Schackert, H.K.; Steinke, V.; Holinski-Feder, E.; Morak, M.; Kloor, M.; Büttner, R.; Verwiel, E.T.; van Krieken, J.H.; Nagtegaal, I.D.; Goossens, M.; van der Post, R.S.; Niessen, R.C.; Sijmons, R.H.; Kluijt, I.; Hogervorst, F.B.; Leter, E.M.; Gille, J.J.; Aalfs, C.M.; Redeker, E.J.; Hes, F.J.; Tops, C.M.; van Nesselrooij, B.P.; van Gijn, M.E.; Gómez García, E.B.; Eccles, D.M.; Bunyan, D.J.; Syngal, S.; Stoffel, E.M.; Culver, J.O.; Palomares, M.R.; Graham, T.; Velsher, L.; Papp, J.; Oláh, E.; Chan, T.L.; Leung, S.Y.; van Kessel, A.G.; Kiemeney, L.A.; Hoogerbrugge, N.; Ligtenberg, M.J. Risk of colorectal and endometrial cancers in EPCAM deletion-positive Lynch syndrome: a cohort study. Lancet Oncol., 2011, 12, 49-55.
100. Woods, M.O.; Williams, P.; Careen, A.; Edwards, L.; Bartlett, S.; McLaughlin, J.R.; Younghusband, H.B. A new variant database for mismatch repair genes associated with Lynch syndrome. Hum. Mu-tat., 2007, 28, 669-673.
101. Peltomäki, P.; Vasen, H. Mutations associated with HNPCC predisposition -- Update of ICG-HNPCC/INSiGHT mutation database. Dis. Markers, 2004, 20, 269-276.
102. Wijnen, J.; van der Klift, H.; Vasen, H.; Khan, P.M.; Menko, F.; Tops, C.; Meijers Heijboer, H.; Lindhout, D.; Møller, P.; Fodde, R. MSH2 genomic deletions are a frequent cause of HNPCC. Nat. Genet., 1998, 20, 326-328.
103. Zhang, J.; Lindroos, A.; Ollila, S.; Russell, A.; Marra, G.; Mueller, H.; Peltomaki, P.; Plasilova, M.; Heinimann, K. Gene conversion is a frequent mechanism of inactivation of the wild-type allele in cancers from MLH1/MSH2 deletion carriers. Cancer Res., 2006, 66, 659-664.
104. Grabowski, M.; Mueller-Koch, Y.; Grasbon-Frodl, E.; Koehler, U.; Keller, G.; Vogelsang, H.; Dietmaier, W.; Kopp, R.; Siebers, U.; Schmitt, W.; Neitzel, B.; Gruber, M.; Doerner, C.; Kerker, B.; Ruemmele, P.; Henke, G.; Holinski-Feder, E. Deletions account for 17% of pathogenic germline alterations in MLH1 and MSH2 in hereditary nonpolyposis colorectal cancer (HNPCC) families. Genet. Test., 2005, 9, 138-146.
105. Van der Klift, H.; Wijnen, J.; Wagner, A.; Verkuilen, P.; Tops, C.; Otway, R.; Kohonen-Corish, M.; Vasen, H.; Oliani, C.; Barana, D.; Moller, P.; Delozier-Blanchet, C.; Hutter, P.; Foulkes, W.; Lynch, H.; Burn, J.; Möslein, G.; Fodde, R. Molecular characterization of the spectrum of genomic deletions in the mismatch repair genes MSH2, MLH1, MSH6, and PMS2 responsible for hereditary non-polyposis colorectal cancer (HNPCC). Genes Chromosomes Cancer, 2005, 44, 123-138.
106. Peltomäki, P.; Vasen, H.F. Mutations predisposing to hereditary nonpolyposis colorectal cancer: database and results of a collaborative study. The International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer. Gastroenterology, 1997, 113, 1146-1158.
107. Spurdle, A.B. Clinical relevance of rare germline sequence variants in cancer genes: evolution and application of classification models. Curr. Opin. Genet. Dev., 2010, 20, 315-323.
108. Couch, F.J.; Rasmussen, L.J.; Hofstra, R.; Monteiro, A.N.; Green-blatt, M.S.; de Wind, N.; IARC Unclassified Genetic Variants Working Group. Assessment of functional effects of unclassified genetic variants. Hum. Mutat., 2008, 29, 1314-1326.
109. Kansikas, M.; Kariola, R.; Nyström, M. Verification of the three-step model in assessing the pathogenicity of mismatch repair gene variants. Hum. Mutat., 2011, 32, 107-115.
110. Chao, E.C.; Velasquez, J.L.; Witherspoon, M.S.; Rozek, L.S.; Peel, D.; Ng, P.; Gruber, S.B.; Watson, P.; Rennert, G.; Anton-Culver, H.; Lynch, H.; Lipkin, S.M. Accurate classification of MLH1/MSH2 missense variants with multivariate analysis of protein polymorphisms-mismatch repair (MAPP-MMR). Hum. Mutat., 2008, 29, 852-860.
111. Heinen, C.D. Genotype to phenotype: analyzing the effects of inherited mutations in colorectal cancer families. Mutat. Res., 2010, 693, 32-45.
112. Ou, J.; Niessen, R.C.; Lützen, A.; Sijmons, R.H.; Kleibeuker, J.H.; de Wind, N.; Rasmussen, L.J.; Hofstra, R.M. Functional analysis helps to clarify the clinical importance of unclassified variants in DNA mismatch repair genes. Hum. Mutat., 2007, 28, 1047-1054.
113. Zecevic, M.; Amos, C.I.; Gu, X.; Campos, I.M.; Jones, J.S.; Lynch, P.M.; Rodriguez-Bigas, M.A.; Frazier, M.L. IGF1 gene polymorphism and risk for hereditary nonpolyposis colorectal cancer. J. Natl. Cancer Inst., 2006, 98, 139-143.
114. Talseth, B.A.; Meldrum, C.; Suchy, J.; Kurzawski, G.; Lubinski, J.; Scott, R.J. Genetic polymorphisms in xenobiotic clearance genes and their influence on disease expression in hereditary nonpoly-posis colorectal cancer patients. Cancer Epidemiol. Biomarkers Prev., 2006, 15, 2307-2310.
115. Felix, R.; Bodmer, W.; Fearnhead, N.S.; van der Merwe, L.; Goldberg, P.; Ramesar, R.S. 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, 175-181.
116. Heinimann, K.; Scott, R.J.; Chappuis, P.; Weber, W.; Muller, H.; Dobbie, Z.; Hutter, P. N-acetyltransferase 2 influences cancer prevalence in hMLH1/hMSH2 mutation carriers. Cancer Res., 1999, 59, 3038-3040.
117. Talseth, B.A.; Ashton, K.A.; Meldrum, C.; Suchy, J.; Kurzawski, G.; Lubinski, J.; Scott, R.J. Aurora-A and Cyclin D1 polymorphisms and the age of onset of colorectal cancer in hereditary non-polyposis colorectal cancer. Int. J. Cancer, 2008, 122, 1273-1277.
118. Shi, Z.; Johnstone, D.; Talseth-Palmer, B.A.; Evans, T.J.; Spigelman, A.D.; Groombridge, C.; Milward, E.A.; Olynyk, J.K.; Suchy, J.; Kurzawski, G.; Lubinski, J.; Scott, R.J. Haemo-chromatosis HFE gene polymorphisms as potential modifiers of hereditary nonpolyposis colorectal cancer risk and onset age. Int. J. Cancer, 2009, 125, 78-83.
119. Curia, M.C.; Palmirotta, R.; Aceto, G.; Messerini, L.; Verì, M.C.; Crognale, S.; Valanzano, R.; Ficari, F.; Fracasso, P.; Stigliano, V.; Tonelli, F.; Casale, V.; Guadagni, F.; Battista, P.; Mariani-Costantini, R.; Cama, A. Unbalanced germ-line expression of hMLH1 and hMSH2 alleles in hereditary nonpolyposis colorectal cancer. Cancer Res., 1999, 59, 3570-3575.
120. Tournier, I.; Raux, G.; Di Fiore, F.; Maréchal, I.; Leclerc, C.; Martin, C.; Wang, Q.; Buisine, M.P.; Stoppa-Lyonnet, D.; Olschwang, S.; Frébourg, T.; Tosi, M. Analysis of the allele-specific expression of the mismatch repair gene MLH1 using a simple DHPLC-Based Method. Hum. Mutat., 2004, 23, 379-384.
121. Santibanez Koref, M.; Wilson, V.; Cartwright, N.; Cunnington, M.S.; Mathers, J.C.; Bishop, D.T.; Curtis, A.; Dunlop, M.G.; Burn, J. MLH1 Differential allelic expression in mutation carriers and controls. Ann. Hum. Genet., 2010, 74, 479-488.
122. Wijnen, J.T.; Brohet, R.M.; van Eijk, R.; Jagmohan-Changur, S.; Middeldorp, A.; Tops, C.M.; van Puijenbroek, M.; Ausems, M.G.; Gómez García, E.; Hes, F.J.; Hoogerbrugge, N.; Menko, F.H.; van Os, T.A.; Sijmons, R.H.; Verhoef, S.; Wagner, A.; Nagengast, F.M.; Kleibeuker, J.H.; Devilee, P.; Morreau, H.; Goldgar, D.; Tomlinson, I.P.; Houlston, R.S.; van Wezel, T.; Vasen, H.F. Chromosome 8q23.3 and 11q23.1 variants modify colorectal cancer risk in Lynch syndrome. Gastroenterology, 2009, 136, 131-137.
123. Houlle, S.; Charbonnier, F.; Houivet, E.; Tinat, J.; Buisine, M.P.; Caron, O.; Benichou, J.; Baert-Desurmont, S.; Frebourg, T. Evaluation of Lynch syndrome modifier genes in 748 MMR mutation carriers. Eur. J. Hum. Genet., 2011, Mar 16.
124. Talseth-Palmer, B.A.; Brenne, I.S.; Ashton, K.A.; Evans, T.J.; McPhillips, M.; Groombridge, C.; Suchy, J.; Kurzawski, G.;Spigelman, A.; Lubinski, J.; Scott, R.J. Colorectal cancer susceptibility loci on chromosome 8q23.3 and 11q23.1 as modifiers for disease expression in lynch syndrome. J. Med. Genet., 2011, 48, 279-284.
125. Strachan, T.; Read, A.P. Human Molecular Genetics. 2nd ed.; New York: Wiley-Liss; 1999.
126. McInnis, M.G. Anticipation: an old idea in new genes. Am. J. Hum. Genet., 1996, 59, 973-979.
127. Nussbaum, R.L.; Mclnnes, R.R.; Willard, H.F. The molecular and biochemical basis of genetic disease. Thompson & Thompson Genetics in Medicine; W.B. Saunders Co.: Philadelphia, 2001, pp 203-254.
128. Hsu, L.; Zhao, L.P.; Malone, K.E.; Daling, J.R. Assessing changes in ages at onset over successive generation: an application to breast cancer. Genet. Epidemiol., 2000, 18, 17-32.
129. McFaul, C.D.; Greenhalf, W.; Earl, J.; Howes, N.; Neoptolemos, J.P.; Kress, R.; Sina-Frey, M.; Rieder, H.; Hahn, S.; Bartsch, D.K.; European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer (EUROPAC). German National Case Collection for Familial Pancreatic Cancer (FaPaCa). Anticipation in familial pancreatic cancer. Gut, 2006, 55, 252-258.
130. Goldberg, J.M.; Piver, M.S.; Jishi, M.F.; Blumenson, L. Age at onset of ovarian cancer in women with a strong family history of ovarian cancer. Gynecol. Oncol., 1997, 66, 3-9.
131. Horwitz, M.; Goode, E.L.; Jarvik, G.P. Anticipation in familial leukemia. Am. J. Hum. Genet., 1996, 59, 990-998.
132. Wiernik, P.H.; Wang, S.Q.; Hu, X.P.; Marino, P.; Paietta, E. Age of onset evidence for anticipation in familial non-Hodgkin's lym-phoma. Br. J. Haematol., 2000, 108, 72-79.
133. Goldstein, A.M.; Clark, W.H. Jr.; Fraser, M.C.; Tucker, M.A. Apparent anticipation in familial melanoma. Melanome Res., 1996, 6, 441-446.
134. Warthin, A.S. The further study of a cancer family. J. Cancer Res., 1925, 9, 279-286.
135. Menko, F.H.; te Meerman, G.J.; Sampson, J.R. Variable age of onset in hereditary nonpolyposis colorectal cancer: clinical implications. Gastroenterology, 1993, 104, 946-947.
136. Vasen, H.F.; Taal, B.G.; Griffioen, G.; Nagengast, F.M.; Cats, A.; Menko, F.H.; Oskam, W.; Kleibeuker, J.H.; Offerhaus, G.J.; Khan, P.M. Clinical heterogeneity of familial colorectal cancer and its influence on screening protocols. Gut, 1994, 35, 1262-1266.
137. Rodríguez-Bigas, M.A.; Lee, P.H.; O'Malley, L.; Weber, T.K.; Suh, O.; Anderson, G.R.; Petrelli, N.J. Establishment of a hereditary nonpolyposis colorectal cancer registry. Dis. Colon Rectum, 1996, 39, 649-653.
138. Voskuil, D.W.; Vasen, H.F.; Kampman, E.; van't Veer, P. Colorec-tal cancer risk in HNPCC families: development during lifetime and in successive generations. National Collaborative Group on HNPCC. Int. J. Cancer, 1997, 72, 205-209.
139. Tsai, Y.Y.; Petersen, G.M.; Booker, S.V.; Bacon, J.A.; Hamilton, S.R.; Giardiello, F.M. Evidence against genetic anticipation in familial colorectal cancer. Genet. Epidemiol., 1997, 14, 435-446.
140. Westphalen, A.A.; Russell, A.M.; Buser, M.; Berthod, C.R.; Hutter, P.; Plasilova, M.; Mueller, H.; Heinimann, K. Evidence for genetic anticipation in hereditary non-polyposis colorectal cancer. Hum. Genet., 2005, 116, 461-465.
141. Stella, A.; Surdo, N.C.; Lastella, P.; Barana, D.; Oliani, C.; Tibiletti, M.G.; Viel, A.; Natale, C.; Piepoli, A.; Marra, G.; Guanti, G. Germline novel MSH2 deletions and a founder MSH2 deletion associated with anticipation effects in HNPCC. Clin. Genet., 2007, 71, 130-139.
142. Nilbert, M.; Timshel, S.; Bernstein, I.; Larsen, K. Role for genetic anticipation in Lynch syndrome. J. Clin. Oncol., 2009, 27, 360-364
143. Huang, J.; Vieland, V. A new statistical test for age-of-onset anticipation: application to bipolar disorder. Genet. Epidemiol., 1997, 14, 1091-1096.
144. Larsen, K.; Petersen, J.; Bernstein, I.; Nilbert, M. A parametric model for analyzing anticipation in genetically predisposed families. Stat. Appl. Genet. Mol. Biol., 2009, 8, Article 26.
145. Boonstra, P.S.; Gruber, S.B.; Raymond, V.M.; Huang, S.C.; Tim-shel, S.; Nilbert, M.; Mukherjee, B. A review of statistical methods for testing genetic anticipation: looking for an answer in Lynch syndrome. Genet. Epidemiol., 2010, 34, 756-768.
146. Shibata, D.; Peinado, M.A.; Ionov, Y.; Malkhosyan, S.; Perucho, M. Genomic instability in repeated sequences is an early somatic event in colorectal tumorigenesis that persists after transformation. Nat. Genet., 1994, 6, 273-281.
147. Li, Z.H.; Aaltonen, L.A.; Shu, Q.; Srivastava, S.; Grizzle, W.E.; Shibata, D. Effects of mutation and growth rates on patterns of microsatellite instability. Am. J. Pathol., 1996, 148, 1757-1761.
148. Vilkki, S.; Tsao, J.L.; Loukola, A.; Pöyhönen, M.; Vierimaa, O.; Herva, R.; Aaltonen, L.A.; Shibata, D. Extensive somatic microsa-tellite mutations in normal human tissue. Cancer Res., 2001, 61, 4541-4544.
149. Alazzouzi, H.; Domingo, E.; González, S.; Blanco, I.; Armengol, M.; Espín, E.; Plaja, A.; Schwartz, S.; Capella, G.; Schwartz, S. Jr. Low levels of microsatellite instability characterize MLH1 and MSH2 HNPCC carriers before tumor diagnosis. Hum. Mol. Genet., 2005, 14, 235-239.
150. Coolbaugh-Murphy, M.I.; Xu, J.; Ramagli, L.S.; Brown, B.W.; Siciliano, M.J. Microsatellite instability (MSI) increases with age in normal somatic cells. Mech. Ageing. Dev., 2005, 126, 1051-1059.
151. Coolbaugh-Murphy, M.I.; Xu, J.P.; Ramagli, L.S.; Ramagli, B.C.; Brown, B.W.; Lynch, P.M.; Hamilton, S.R.; Frazier, M.L.; Siciliano, M.J. Microsatellite instability in the peripheral blood leukocytes of HNPCC patients. Hum. Mutat., 2010, 31, 317-324.
152. Grady, W.M.; Carethers, J.M. Genomic and epigenetic instability in colorectal cancer pathogenesis. Gastroenterology, 2008, 135, 1079-1099.
153. Marrone, A.; Walne, A.; Dokal, I. Dyskeratosis congenita: telom-erase, telomeres and anticipation. Curr. Opin. Genet. Dev., 2005, 15, 249-257.
154. Trkova, M.; Hladikova, M.; Kasal, P.; Goetz, P.; Sedlacek, Z. Is there anticipation in the age at onset of cancer in families with Li-Fraumeni syndrome? J. Hum. Genet., 2002, 47, 381-386.
155. Tabori, U.; Nanda, S.; Druker, H.; Lees, J.; Malkin, D. Younger age of cancer initiation is associated with shorter telomere length in Li-Fraumeni syndrome. Cancer. Res., 2007, 67, 1415-1418.
156. Armanios, M.; Chen, J.L.; Chang, Y.P.; Brodsky, R.A.; Hawkins, A.; Griffin, C.A.; Eshleman, J.R.; Cohen, A.R.; Chakravarti, A.; Hamosh, A.; Greider, C.W. Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita. Proc. Natl. Acad. Sci. U S A, 2005, 102, 15960-15964.
157. Trkova, M.; Prochazkova, K.; Krutilkova, V.; Sumerauer, D.; Sed-lacek, Z. Telomere length in peripheral blood cells of germline TP53 mutation carriers is shorter than that of normal individuals of corresponding age. Cancer, 2007, 110, 694-702.
158. Capezzone, M.; Cantara, S.; Marchisotta, S.; Filetti, S.; De Santi, M.M.; Rossi, B.; Ronga, G.; Durante, C.; Pacini, F. Short te-lomeres; telomerase reverse transcriptase gene amplification; and increased telomerase activity in the blood of familial papillary thyroid cancer patients. J. Clin. Endocrinol. Metab., 2008, 93, 3950-3957.
159. Dagan, E.; Gershoni-Baruch, R. Anticipation in hereditary breast cancer. Clin. Genet., 2002, 62, 147-150.
160. Gramatges, M.M.; Telli, M.L.; Balise, R.; Ford, J.M. Longer relative telomere length in blood from women with sporadic and familial breast cancer compared with healthy controls. Cancer Epidemiol. Biomarkers Prev., 2010, 19, 605-613.
161. Bozzao, C.; Lastella, P.; Ponz de Leon, M.; Pedroni, M.; Di Grego-rio, C.; D'Ovidio, F.D.; Resta, N.; Prete, F.; Guanti, G.; Stella, A. Analysis of telomere dynamics in peripheral blood cells from patients with Lynch syndrome. Cancer, 2011, Mar 8.
162. Mendez-Bermudez, A.; Royle, N.J. Deficiency in DNA mismatch repair increases the rate of telomere shortening in normal human cells. Hum. Mutat., 2011 Apr 28.
163. Martinez, P.; Siegl-Cachedenier, I.; Flores, J.M.; Blasco, MA. MSH2 deficiency abolishes the anticancer and pro-aging effect of short telomeres. Aging Cell. 2009, 8, 2-17.
164. Siehler, S.Y.; Schrauder, M.; Gerisher, U.; Cantor, S.; Marra, G.; Wiesmuller, L. Human MutL-complexes monitor homologous recombination independently of mismatch repair. DNA Repair, 2009, 8, 242-252.
165. Cesare, A.J.; Reddel, R.R. Alternative lengthening of telomeres: models, mechanisms and implications. Nat. Rev. Genetics, 2010, 11, 319-330.