International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
Head of Department of Genetics and Pathology: prof. zw. dr hab. med. Jan Lubiński
1) higher risk for colorectal cancer (~70% for men and ~30% for female), endometrial cancer (~70%) and also for ovarian, upper urinary tract, stomach and breast cancer (25);
2) higher incidence of extracolonic cancers, when compare with HNPCC families (26);
3) later age at onset of cancers e.g. for colorectal cancer the mean age at diagnosis is ~56 yrs, for endometrial cancer ~54 yrs and for ovarian cancer ~49 yrs (25, 26);
4) frequent left-sided localization of colorectal cancer (9).
1) selection of families with colorectal, endometrial, ovarian, urinary tract and/or stomach, breast cancer aggregation,
1. Fleck O, Nielsen O: DNA repair. J Cell Science 2004; 117: 515-517.
2. Pinto LA, Regis da Silva CG, Lopes D et al.: Escherichia coli as a model system to study DNA repair genes of eukaryotic organisms. Genetics Mol Res 2003; 2: 77-91.
3. Marti T, Kunz Ch, Fleck O: DNA Mismatch Repair and Mutation Avoidance Pathways. J Cell Phys 2002; 191: 28-41.
4. Abel-Rahman WM, Mecklin JP, Peltomaki P: The genetics of HNPCC: application to diagnosis and screening. Crit Rev Oncol Hematol 2006; 58: 208-20.
5. Robinson KL, Vandrovcova J, Halvarsson B et al.: Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer) Diagnostics. J Natl Cancer Inst 2007; 99: 291-9.
6. Lynch HT, de la Chapelle A: Genetic susceptibility to non-polyposis colorectal cancer. J Med Genet 1999; 36: 801-818.
7. Wagner A, Hendriks Y, Meijers-Heijboer EJ et al.: Atypical HNPCC owing to MSH6germline mutations: analysis of a large Dutch pedigree. J Med Genet 2001; 38: 318-22.
8. Roncari B, Pedroni M, Maffei S et al.: Frequency of constitutional MSH6mutations in a consecutive series of families with the clinical suspicion of HNPCC. Clin Genet 2007; 72: 230-7.
9. Berends MJW, Wu Y, Sijmons RH et al.: Molecular and clinical characteristics of MSH6variants: an analysis of 25 index carriers of a germline variant. Am J Hum Genet 2002; 70: 26-37.
10. Suchy J, Kurzawski G, Jakubowska A, Lubiński J: Ovarian cancer of endometrioid type as part of the MSH6 gene mutation phenotype. J Hum Genet 2002; 47: 529-531.
11. Suchy J, Kurzawski G, Jakubowska K et al.: Frequency and nature of hMSH6 germline mutations in Polish patients with colorectal, endometrial and ovarian cancers. Clin Genet 2006; 70: 68-70.
12. Peltomaki P: Role of DNA mismatch repair defects in the pathogenesis of human cancer. J Clin Oncol 2003; 21: 1174-1179.
13. Silva FC, Valentin MD, Ferreira Fde O et al.: Mismatch repair genes in Lynch syndrome: a review. Sao Paulo Med J 2009; 127: 46-51.
14. Chadwick RB, Meek JE, Prior TW et al.: Polymorphisms in a pseudogene highly homologous to PMS2. Hum Mutat 2000; 16: 530.
15. Hayward BE, De Vos M, Valleley EM et al.: Extensive gene conversion at the PMS2 DNA mismatch repair locus. Hum Mutat 2007; 28: 424-430.
16. Niessen RC, Kleibeuker JH, Jager PO et al.: Getting rid of the PMS2 pseudogenes: mission impossible? Hum Mutat 2007; 28: 414-415.
17. Lagerstedt Robinson K, Liu T et al.: M, Frebourg T, Papadopoulos N, Kinzler KW, Vogelstein B, Peltomaki P. Lynch syndrome (hereditary nonpolyposis colorectal cancer) diagnostics. J Natl Cancer Inst 2007; 99: 291-299.
18. Jarvinen HJ, Renkonen-Sinisalo L, Aktan-Collan K et al.: 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.
19. Jensen UB, Sunde L, Timshel S et al.: Mismatch repair defective breast cancer in the hereditary nonpolyposis colorectal cancer syndrome. Breast Cancer Res Treat 2010; 120 (3): 777-82.
20. Ramsoekh D, Wagner A, van Leerdam ME et al.: A high incidence of MSH6 mutations in Amsterdam criteria II-negative families tested in a diagnostic setting. Gut 2008; 57: 1539-1544.
21. Al-Sukhni W, Aronson M, Gallinger S: Hereditary colorectal cancer syndromes: familial adenomatous polyposis and lynch syndrome. Surg Clin North Am 2008; 88: 819-844.
22. Boland CR, Koi M, Chang DK, Carethers JM: The biochemical basis of microsatellite instability and abnormal immunohistochemistry and clinical behavior in Lynch syndrome: from bench to bedside. Fam Cancer 2008; 7: 41-52.
23. Plaschke J, Engel C, Kruger S et al.: 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.
24. Kastrinos F, Syngal S: Recently identified colon cancer predispositions: MYH and MSH6 mutations. Semin Oncol 2007; 34: 418-424.
25. Hendriks YMC, Wagner A, Morreau H et al.: Cancer Risk in Hereditary Nonpolyposis Colorectal Cancer Due to MSH6Mutations: Impact on Counseling and Surveillance. Gastroent 2004; 127: 17-25.
26. Plaschke J, Engel Ch, Kruger S et al.: Lower Incidence of Colorectal Cancer and Later Age of Disease Onset in 27 Families With Pathogenic MSH6Germline Mutations Compared With Families With MLH1or MSH2Mutations: The German Hereditary Nonpolyposis Colorectal Cancer Consortium. J Clin Oncol 2004; 22: 4486-94.
27. Rigau V, Sebbagh N, Olschwang S et al.: Microsatellite Instability in Colorectal Carcinoma. The Comparison of Immunohistochemistry and Molecular Biology Suggests a Role for hMSH6 Immunostaining. Arch Pathol Lab Med 2003; 127: 694-700.
28. Plaschke J, Kruger S, Pistorius S et al.: Involvement of hMSH6 in the development of hereditary and sporadic colorectal cancer revealed by immunostaining is based on germline mutations, but rarely on somatic inactivation. Int J Cancer 2002; 97: 643-648.
29. Plaschke J, Kruger S, Dietmaier W et al.: Eight Novel MSH6 Germline Mutations in Patients With Familial and Nonfamilial Colorectal Cancer Selected By Loss of Protein Expression in Tumor Tissue. Hum Mut 2004; Online.
30. Cederquist K, Emanuelsson M, Goransson I et al.: Mutation analysis of the MLH1, MSH2 and MSH6 genes in patients with double primary cancers of the colorectum and the endometrium: a population-based study in Northern Sweden. Int J Cancer 2004; 109: 370-376.
31. Wu Y, Berends M, Mensink R, Kempinga C: Association of Hereditary Nonpolyposis Colorectal Cancer-Related Tumors Displaying Low Microsatellite Instability with MSH6 Germline Mutations. Am J Hum Genet 1999; 65: 1291-1298.
32. Shin K-H, Ku J-L, Park J-G: Germline mutations in a polycytosine repeat of the hMSH6 gene in Korean hereditary nonpolyposis colorectal cancer. J Hum Genet 1999; 44: 18-21.
33. Charames G, Millar A, Pal T et al.: Do MSH6 mutations contribute to double primary cancers of the colorectum and endometrium? Hum Genet 2000; 107: 623-629.
34. Talseth-Palmer BA, McPhillips M, Groombridge C et al.: MSH6 and PMS2 mutation positive Australian Lynch syndrome families: novel mutations, cancer risk and age of diagnosis of colorectal cancer. Hered Cancer Clin Pract 2010 May 21; 8 (1): 5.