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MSH6 syndrome

The MSH6 gene in collaboration with MSH2, MLH1, MSH3, PMS1 and PMS2 genes is involved in one of the systems repairing the errors that arise during DNA replication, called the "methyl directed mismatch repair" system [13]. hMLH1 and hMSH2 mutations give rise most frequently to the classical Lynch syndrome (HNPCC) [46]. hMSH6 mutations often occur in clinically less typical HNPCC families, that do not fulfil the Amsterdam criteria [711]. So far more than 200 families with germline hMSH6 mutation have been described

Characteristic features of families with hMSH6 mutation are:

  • higher risk for colorectal cancer (~70% for men and ~30% for females), endometrial cancer (~70%) and also for ovarian, upper urinary tract, stomach and breast cancer [12],

  • higher incidence of extracolonic cancers, when compared with HNPCC families [13],

  • later age at onset of cancers, e.g. for colorectal cancer the mean age at diagnosis is ~56 years, for endometrial cancer ~54 years and for ovarian cancer ~49 years [12, 13],

  • frequent left-sided localization of colorectal cancer [9].

The prevalence of hMSH6 constitutional mutations in families that fulfil the Amsterdam criteria is about 5-10% [8, 9].

Because the frequency of hMSH6 mutations in other groups is not precisely determined, we recommend the following diagnostic procedure for hMSH6 mutation detection:

  • selection of families with colorectal, endometrial, ovarian, urinary tract and/or stomach, breast cancer aggregation,

  • immunohistochemical analysis (IHC) of hMSH6 protein expression in tumour colorectal or endometrial tissue [1416],

  • in cases of hMSH6-negative tumours, DHPLC/sequencing of the coding regions of the hMSH6 gene.

Among the reported hMSH6 mutations about 30 are recurrent, i.e. they are detected in more than one family [1719]. Probably in the near future diagnostic tests will be described to allow cheap, simple and fast detection of mutations showing a "founder effect" characteristic for particular ethnic groups.

Surveillance protocol

As yet a suitable surveillance programme in hMSH6 families based on prospective family trials is not available. In our centre we offer the following surveillance protocol:

  • colorectal cancer - colonoscopy every 2 to 3 years beginning at least 15 years before the earliest age of onset in the family,

  • endometrial cancer - annual transvaginal ultrasound scan starting at least 15 years before the earliest age of onset in the family,

  • screening for other cancers depending on the tumour spectrum in the family.

Surgical management

Because of the described higher risk of developing multiple (synchronous and metachronous) cancers and also endometrial cancer in females after age of 50 years in hMSH6 mutation carriers [12, 17, 20], it is recommended to take into consideration surgical treatment similar to that for patients with CRC associated with Lynch syndrome, i.e. colectomy with ileorectal anastomosis, extended by prophylactic hysterectomy and oophorectomy for women over 50 years old.


  1. Fleck O, Nielsen O: DNA repair. J Cell Sci 2004, 117: 515–517. 10.1242/jcs.00952

    Article  CAS  PubMed  Google Scholar 

  2. Pinto LA, Regis da Silva CG, Lopes D, Machado-Silva A, Machado CR: Escherichia coli as a model system to study DNA repair genes of eukaryotic organisms. Genetics Mol Res 2003, 2: 77–91.

    Google Scholar 

  3. Marti T, Kunz C, Fleck O: DNA mismatch repair and mutation avoidance pathways. J Cell Physiol 2002, 191: 28–41. 10.1002/jcp.10077

    Article  CAS  PubMed  Google Scholar 

  4. Abdel-Rahman WM, Mecklin JP, Peltomäki P: The genetics of HNPCC: application to diagnosis and screening. Crit Rev Oncol Hematol 2006, 58: 208–220. 10.1016/j.critrevonc.2005.11.001

    Article  PubMed  Google Scholar 

  5. Lagerstedt Robinson K, Liu T, Vandrovcova J, Halvarsson B, Clendenning M, Frebourg T, Papadopoulos N, Kinzler KW, Vogelstein B, Peltomäki P, Kolodner RD, Nilbert M, Lindblom A: Lynch syndrome (hereditary nonpolyposis colorectal cancer) diagnostics. J Natl Cancer Inst 2007, 99: 291–299. 10.1093/jnci/djk051

    Article  PubMed  Google Scholar 

  6. Lynch HT, de la Chapelle A: Genetic susceptibility to non-polyposis colorectal cancer. J Med Genet 1999, 36: 801–818.

    PubMed Central  CAS  PubMed  Google Scholar 

  7. Wagner A, Hendriks Y, Meijers-Heijboer EJ, de Leeuw WJ, Morreau H, Hofstra R, Tops C, Bik E, Bröcker-Vriends AH, Meer C, Lindhout D, Vasen HF, Breuning MH, Cornelisse CJ, van Krimpen C, Niermeijer MF, Zwinderman AH, Wijnen J, Fodde R: Atypical HNPCC owing to MSH6 germline mutations: analysis of a large Dutch pedigree. J Med Genet 2001, 38: 318–332. 10.1136/jmg.38.5.318

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Roncari B, Pedroni M, Maffei S, Di Gregorio C, Ponti G, Scarselli A, Losi L, Benatti P, Roncucci L, De Gaetani C, Camellini L, Lucci-Cordisco E, Tricarico R, Genuardi M, Ponz de Leon M: Frequency of constitutional MSH6 mutations in a consecutive series of families with the clinical suspicion of HNPCC. Clin Genet 2007, 72: 230–237. 10.1111/j.1399-0004.2007.00856.x

    Article  CAS  PubMed  Google Scholar 

  9. Berends MJ, Wu Y, Sijmons RH, Mensink RG, Sluis T, Hordijk-Hos JM, de Vries EG, Hollema H, Karrenbeld A, Buys CH, 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. 10.1086/337944

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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. 10.1007/s100380200079

    Article  CAS  PubMed  Google Scholar 

  11. Suchy J, Kurzawski G, Jakubowska K, Rać ME, Safranow K, Kładny J, Rzepka-Górska I, Chosia M, Czeszyńska B, Oszurek O, Scott RJ, Lubiński J: Frequency and nature of hMSH6 germline mutations in Polish patients with colorectal, endometrial and ovarian cancers. Clin Genet 2006, 70: 68–70. 10.1111/j.1399-0004.2006.00630.x

    Article  CAS  PubMed  Google Scholar 

  12. Hendriks YM, 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 GB, Breuning MH, Fodde R, Wijnen JT, Bröcker-Vriends AH, Vasen H: Cancer risk in hereditary nonpolyposis colorectal cancer due to MSH6 mutations: impact on counseling and surveillance. Gastroenterology 2004, 127: 17–25. 10.1053/j.gastro.2004.03.068

    Article  CAS  PubMed  Google Scholar 

  13. Plaschke J, Engel C, Krüger S, Holinski-Feder E, Pagenstecher 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. 10.1200/JCO.2004.02.033

    Article  CAS  PubMed  Google Scholar 

  14. Rigau V, Sebbagh N, Olschwang S, Paraf F, Mourra N, Parc Y, Flejou JF: Microsatellite instability in colorectal carcinoma. The comparison of immunohistochemistry and molecular biology suggests a role for hMSH6 [correction of hMLH6] immunostaining. Arch Pathol Lab Med 2003, 127: 694–700.

    CAS  PubMed  Google Scholar 

  15. Plaschke J, Krüger S, Pistorius S, Theissig F, Saeger H, Schackert H: 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. 10.1002/ijc.10097

    Article  CAS  PubMed  Google Scholar 

  16. Plaschke J, Krüger S, Dietmaier W, Gebert J, Sutter C, Mangold E, Pagenstecher C, Holinski-Feder E, Schulmann K, Möslein G, Rüschoff J, Engel C, Evans G, Schackert HK, German HNPCC Consortium: 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, 23: 285. 10.1002/humu.9217

    Article  PubMed  Google Scholar 

  17. Cederquist K, Emanuelsson M, Göransson I, Holinski-Feder E, Müller-Koch Y, Golovleva I, Grönberg H: 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. 10.1002/ijc.11718

    Article  CAS  PubMed  Google Scholar 

  18. Wu Y, Berends MJ, Mensink RG, Kempinga C, Sijmons RH, 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. 10.1086/302612

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Shin KH, Ku JL, Park JG: Germline mutations in a polycytosine repeat of the hMSH6 gene in Korean hereditary nonpolyposis colorectal cancer. J Hum Genet 1999, 44: 18–21. 10.1007/s100380050099

    Article  CAS  PubMed  Google Scholar 

  20. Charames GS, Millar AL, Pal T, Narod S, Bapat B: Do MSH6 mutations contribute to double primary cancers of the colorectum and endometrium? Hum Genet 2000, 107: 623–629. 10.1007/s004390000417

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Janina Suchy.

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Suchy, J., Lubiński, J. MSH6 syndrome. Hered Cancer Clin Pract 6, 103 (2008).

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