Cellular Oncology

, Volume 36, Issue 3, pp 225–231 | Cite as

Mismatch repair gene mutation analysis and colonoscopy surveillance in Chinese lynch syndrome families

  • Lei Fu
  • Jian-qiu Sheng
  • Xiao-ou Li
  • Peng Jin
  • Hong Mu
  • Min Han
  • Ji-sheng Huang
  • Zi-qin Sun
  • Ai-qin Li
  • Zi-tao Wu
  • Shi-rong Li
Original Paper

Abstract

Background

Lynch syndrome (or HNPCC) is a colorectal cancer syndrome caused by germline mutations in either one of the DNA mismatch repair (MMR) genes hMLH1, hMSH2, hMSH6 or hPMS2. Mutations in hMLH1 and hMSH2 are most prevalent. Here we aimed to determine the cancer risk of MMR gene mutation carriers and, in addition, the efficacy of colonoscopy surveillance in Chinese Lynch syndrome family members with and without MMR gene mutations.

Methods

A Lynch syndrome family registry encompassing 106 families in Northern China was recently established. Detailed pedigree data for each family were collected and hMLH1 and hMSH2 gene mutation analyses were performed. Germ-line mutations were identified in probands from 42 of these families, and additional genetic analyses were performed in each member of these 42 families to identify mutation and non-mutation carriers. Among the family members included, 180 received colonoscopy and the remaining cases were followed without colonoscopy.

Results

Overall 54.8 % of the Lynch syndrome family members carried MMR gene mutations, and these mutation carriers exhibited significantly higher colorectal cancer and other Lynch syndrome-associated cancer risks as compared to non-mutation carriers. The cumulative risk for all Lynch syndrome-related cancers at age 70 was 93.8 % for both hMLH1 and hMSH2 mutation carriers, and 81.7 % and 93.1 % for colorectal cancer at this age, respectively. Whereas 43 of 102 (42.2 %) mutation carriers exhibited significant colonoscopy findings, including 10 colorectal cancers, none of 78 non-mutation carriers exhibited significant findings, and no cancers were detected. In addition, in the mutation carriers, colonoscopy surveillance led to the detection of more early stage cancers than in the non-surveillance group (70.0 % versus 36.5 %, p < 0.01).

Conclusion

In Lynch syndrome family members, we recommend pre-symptomatic MMR gene mutation analysis in order to identify high risk individuals for colonoscopy surveillance.

Keywords

Lynch syndrome Mismatch Repair Gene Cumulative Risk Colonoscopy 

References

  1. 1.
    J.R. Jass, Hereditary nonpolyposis colorectal cancer: the rise and fall of a confusing term. World J Gastroenterol 12(31), 4943–4950 (2006). PMID:16937488PubMedGoogle Scholar
  2. 2.
    D.J. Peel, A. Ziogas, E.A. Fox, M. Gildea, B. Laham, E. Clements, R.D. Kolodner, H. Anton-Culver, Characterization of hereditary nonpolyposis colorectal cancer families from a population-based series of cases. J Natl Cancer Inst 92(18), 1517–1522 (2000). http://dx.doi.org/10.1093/jnci/92.18.1517 PMID:10995807PubMedCrossRefGoogle Scholar
  3. 3.
    M.A. Rodriguez-Bigas, C.R. Boland, S.R. Hamilton, D.E. Henson, J.R. Jass, P.M. Khan, H. Lynch, M. Perucho, T. Smyrk, L. Sobin, S. Srivastava, A national cancer institute workshop on hereditary nonpolyposis colorectal cancer syndrome: meeting highlights and Bethesda guidelines. J Natl Cancer Inst 89(23), 1758–1762 (1997). http://dx.doi.org/10.1093/jnci/89.23.1758 PMID: 9392616PubMedCrossRefGoogle Scholar
  4. 4.
    H.T. Lynch, T. Smyrk, Hereditary nonpolyposis colorectal cancer (Lynch syndrome). An updated review. Cancer 78(6), 1149–1167 (1996). http://dx.doi.org/10.1002/(SICI)1097-0142(19960915)78:6<1149::AID-CNCR1>3.0.CO;2-5 PMID: 8826936Google Scholar
  5. 5.
    J.K. Greenson, S.C. Huang, C. Herron, V. Moreno, J.D. Bonner, L.P. Tomsho, O. Ben-Izhak, H.I. Cohen, P. Trougouboff, J. Bejhar, Y. Sova, M. Pinchev, G. Rennert, S.B. Gruber, Pathologic predictors of microsatellite instability in colorectal cancer. Am J Surg Pathol 33(1), 126–133 (2009). http://dx.doi.org/10.1097/PAS.0b013e31817ec2b1 PMID:18830122PubMedCrossRefGoogle Scholar
  6. 6.
    G. Manceau, M. Karoui, A. Charachon, J.C. Delchier, I. Sobhani, HNPCC (hereditary non-polyposis colorectal cancer) or Lynch syndrome: a syndrome related to a failure of DNA repair system. Bull Cancer 98(3), 323–336 (2011)PubMedGoogle Scholar
  7. 7.
    S. Jacob, F. Praz, DNA mismatch repair defects: role in colorectal carcinogenesis. Biochimie 84(1), 27–47 (2002). http://dx.doi.org/10.1016/S0300-9084(01)01362-1 PMID: 11900875PubMedCrossRefGoogle Scholar
  8. 8.
    Y.Z. Zhang, J.Q. Sheng, S.R. Li, H. Zhang, Clinical phenotype and prevalence of hereditary Nonpolyposis colorectal cancer syndrome in Chinese population. World J Gastroenterol 11(10), 1481–1488 (2005)PubMedGoogle Scholar
  9. 9.
    J.Q. Sheng, H. Zhang, M. Ji, L. Fu, H. Mu, M.Z. Zhang, J.S. Huang, M. Han, A.Q. Li, Z. Wei, Z.Q. Sun, Z.T. Wu, C.H. Xia, S.R. Li, Genetic diagnosis strategy of hereditary non-polyposis colorectal cancer. World J Gastroenterol 15(8), 983–989 (2009). http://dx.doi.org/10.3748/wjg.15.983 PMID: 19248199 PMCID: PMC2653409PubMedCrossRefGoogle Scholar
  10. 10.
    J.Q. Sheng, L. Fu, Z.Q. Sun, J.S. Huang, M. Han, H. Mu, H. Zhang, Y.Z. Zhang, M.Z. Zhang, A.Q. Li, Z.T. Wu, Y. Han, S.R. Li, Mismatch repair gene mutations in Chinese HNPCC patients. Cytogenet Genome Res 122(1), 22–27 (2008). http://dx.doi.org/10.1159/000151312 PMID: 18931482PubMedCrossRefGoogle Scholar
  11. 11.
    S.J. Winawer, A.G. Zauber, R.H. Fletcher, J.S. Stillman, M.J. O’Brien, B. Levin, R.A. Smith, D.A. Lieberman, R.W. Burt, T.R. Levin, J.H. Bond, D. Brooks, T. Byers, N. Hyman, L. Kirk, A. Thorson, C. Simmang, D. Johnson, D.K. Rex, US Multi-Society Task Force on Colorectal Cancer, American Cancer Society, Guidelines for colonoscopy surveillance after polypectomy: a consensus update by the US Multi-Society Task Force on Colorectal Cancer and the American Cancer Society. Gastroenterology 130(6), 1872–1885 (2006)PubMedCrossRefGoogle Scholar
  12. 12.
    G. Dionigi, V. Bianchi, F. Rovera, L. Boni, M. Annoni, P. Castano, F. Villa, R. Dionigi, Genetic alteration in hereditary colorectal cancer. Surg Oncol 16(Suppl 1), S11–15 (2007). http://dx.doi.org/10.1016/j.suronc.2007.10.020 PMID:18023570PubMedCrossRefGoogle Scholar
  13. 13.
    H.T. Lynch, C.R. Boland, G. Gong, T.G. Shaw, P.M. Lynch, R. Fodde, J.F. Lynch, A. de la Chapelle, Phenotypic and genotypic heterogeneity in the Lynch syndrome: diagnostic, surveillance and management implications. Eur J Hum Genet 14(4), 390–402 (2006). http://dx.doi.org/10.1038/sj.ejhg.5201584 PMID:16479259PubMedCrossRefGoogle Scholar
  14. 14.
    R.J. Mitchell, S.M. Farrington, M.G. Dunlop, H. Campbell, Mismatch repair genes hMLH1 and hMSH2 and colorectal cancer: a HuGE review. Am J Epidemiol 156(10), 885–902 (2002). http://dx.doi.org/10.1093/aje/kwf139 PMID:12419761PubMedCrossRefGoogle Scholar
  15. 15.
    P. Watson, B. Riley, The tumor spectrum in the Lynch syndrome. Fam Cancer 4(3), 245–248 (2005). http://dx.doi.org/10.1007/s10689-004-7994-z PMID:16136385PubMedCrossRefGoogle Scholar
  16. 16.
    Y.M. Hendriks, A.E. de Jong, H. Morreau, C.M. Tops, H.F. Vasen, J.T. Wijnen, M.H. Breuning, A.H. Bröcker-Vriends, Diagnostic approach and management of Lynch syndrome (hereditary nonpolyposis colorectal carcinoma): a guide for clinicians. CA Cancer J Clin 56(4), 213–225 (2006). http://dx.doi.org/10.3322/canjclin.56.4.213 PMID: 16870997PubMedCrossRefGoogle Scholar
  17. 17.
    S. Syngal, E.A. Fox, C. Eng, R.D. Kolodner, J.E. Garber, Sensitivity and specificity of clinical criteria for hereditary non-polyposis colorectal cancer associated mutations in MSH2 and MLH1. J Med Genet 37(9), 641–645 (2000). http://dx.doi.org/10.1136/jmg.37.9.641 PMID:10978352 PMCID:1734690PubMedCrossRefGoogle Scholar
  18. 18.
    D.A. Stupart, P.A. Goldberg, U. Algar, R. Ramesar, Surveillance colonoscopy improves survival in a cohort of subjects with a single mismatch repair gene mutation. Colorectal Dis 11(2), 126–130 (2009). http://dx.doi.org/10.1111/j.1463-1318.2008.01702.x PMID: 19143775PubMedCrossRefGoogle Scholar
  19. 19.
    D.G. Evans, S. Walsh, J. Hill, R.T. McMahon, Strategies for identifying hereditary nonpolyposis colon cancer. Semin Oncol 34(5), 411–417 (2007). http://dx.doi.org/10.1053/j.seminoncol.2007.07.001 PMID: 17920896PubMedCrossRefGoogle Scholar
  20. 20.
    P. Watson, H.T. Lynch, Cancer risk in mismatch repair gene mutation carriers. Fam Cancer 1(1), 57–60 (2001). http://dx.doi.org/10.1023/A:1011590617833 PMID: 14574017PubMedCrossRefGoogle Scholar
  21. 21.
    D. Ramsoekh, A. Wagner, M.E. van Leerdam, D. Dooijes, C.M. Tops, E.W. Steyerberg, E.J. Kuipers, Cancer risk in MLH1, MSH2 and MSH6 mutation carriers; different risk profiles may influence clinical management. Hered Cancer Clin Pract 7(1), 17 (2009). http://dx.doi.org/10.1186/1897-4287-7-17 PMID: 20028567 PMCID: PMC2804564PubMedCrossRefGoogle Scholar
  22. 22.
    E.M. Stoffel, R.C. Mercado, W. Kohlmann, B. Ford, S. Grover, P. Conrad, A. Blanco, K.M. Shannon, M. Powell, D.C. Chung, J. Terdiman, S.B. Gruber, S. Syngal, Prevalence and predictors of appropriate colorectal cancer surveillance in Lynch syndrome. Am J Gastroenterol 105(8), 1851–1860 (2010). http://dx.doi.org/10.1038/ajg.2010.120 PMID: 20354509 PMCID: PMC3091484PubMedCrossRefGoogle Scholar
  23. 23.
    C. Engel, N. Rahner, K. Schulmann, E. Holinski-Feder, T.O. Goecke, H.K. Schackert, M. Kloor, V. Steinke, H. Vogelsang, G. Möslein, H. Görgens, S. Dechant, M. von Knebel Doeberitz, J. Rüschoff, N. Friedrichs, R. Büttner, M. Loeffler, P. Propping, W. Schmiegel, German HNPCC Consortium, Efficacy of annual colonoscopic surveillance in individuals with hereditary nonpolyposis colorectal cancer. Clin Gastroenterol Hepatol 8(2), 174–182 (2010). http://dx.doi.org/10.1016/j.cgh.2009.10.003 PMID: 19835992PubMedCrossRefGoogle Scholar
  24. 24.
    H.F. Vasen, M. Abdirahman, R. Brohet, A.M. Langers, J.H. Kleibeuker, M. van Kouwen, J.J. Koornstra, H. Boot, A. Cats, E. Dekker, S. Sanduleanu, J.W. Poley, J.C. Hardwick, de Vos Tot Nederveen Cappel WH, van der Meulen-de Jong AE, Tan TG, Jacobs MA, Mohamed FL, de Boer SY, van de Meeberg PC, Verhulst ML, Salemans JM, van Bentem N, Westerveld BD, Vecht J, Nagengast FM. One to 2-year surveillance intervals reduce risk of colorectal cancer in families with Lynch syndrome. Gastroenterology 138(7), 2300–2306 (2010). http://dx.doi.org/10.1053/j.gastro.2010.02.053 PMID: 20206180PubMedCrossRefGoogle Scholar

Copyright information

© International Society for Cellular Oncology 2013

Authors and Affiliations

  • Lei Fu
    • 1
  • Jian-qiu Sheng
    • 2
  • Xiao-ou Li
    • 3
  • Peng Jin
    • 2
  • Hong Mu
    • 4
  • Min Han
    • 5
  • Ji-sheng Huang
    • 5
  • Zi-qin Sun
    • 6
  • Ai-qin Li
    • 2
  • Zi-tao Wu
    • 2
  • Shi-rong Li
    • 2
  1. 1.Department of GastroenterologyThird Military Medical University and General Hospital of Beijing Military RegionChongqingChina
  2. 2.Department of GastroenterologyGeneral Hospital of Beijing Military RegionBeijingChina
  3. 3.Department of General Surgery306 Hospital of PLABeijingChina
  4. 4.Department of Gastroenterology253 Hospital of PLAHohhotChina
  5. 5.Shangqiu People’s HospitalShangqiuChina
  6. 6.Department of GastroenterologyGeneral Hospital of Jinan Military RegionJinanChina

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