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Distinct mutations in MLH1 and MSH2 genes in Hereditary Non-polyposis Colorectal Cancer (HNPCC) families from China

  • Wei, Wenqian (Ministry of Education Key Laboratory for Biodiversity Science and Ecological Engineering, School of Life Sciences, Fudan University) ;
  • Liu, Fangqi (Colorectal Surgery, Shanghai Cancer Hospital of Fudan University) ;
  • Liu, Lei (Ministry of Education Key Laboratory for Biodiversity Science and Ecological Engineering, School of Life Sciences, Fudan University) ;
  • Li, Zuofeng (Shanghai Center for Bioinformation Technology) ;
  • Zhang, Xiaoyan (School of Life Science and Technology, Tongji University) ;
  • Jiang, Fan (Ministry of Education Key Laboratory for Biodiversity Science and Ecological Engineering, School of Life Sciences, Fudan University) ;
  • Shi, Qu (Ministry of Education Key Laboratory for Biodiversity Science and Ecological Engineering, School of Life Sciences, Fudan University) ;
  • Zhou, Xiaoyan (Colorectal Surgery, Shanghai Cancer Hospital of Fudan University) ;
  • Sheng, Weiqi (Colorectal Surgery, Shanghai Cancer Hospital of Fudan University) ;
  • Cai, Sanjun (Colorectal Surgery, Shanghai Cancer Hospital of Fudan University) ;
  • Li, Xuan (Shanghai Center for Bioinformation Technology) ;
  • Xu, Ye (Colorectal Surgery, Shanghai Cancer Hospital of Fudan University) ;
  • Nan, Peng (Ministry of Education Key Laboratory for Biodiversity Science and Ecological Engineering, School of Life Sciences, Fudan University)
  • Received : 2011.01.04
  • Accepted : 2011.02.22
  • Published : 2011.05.31

Abstract

Hereditary non-polyposis Colorectal Cancer (HNPCC) is an autosomal dominant inheritance syndrome. HNPCC is the most common hereditary variant of colorectal cancer (CRC), which accounts for 2-5% CRCs, mainly due to hMLH1 and hMSH2 mutations that impair DNA repair functions. Our study aimed to identify the patterns of hMSH2 and hMLH1 mutations in Chinese HNPCC patients. Ninety-eight unrelated families from China meeting Amsterdam or Bethesda criteria were included in our study. Germline mutations in MLH1 and MSH2 genes, located in the exons and the splice-site junctions, were screened in the 98 probands by direct sequencing. Eleven mutations were found in ten patients (11%), with six in MLH1 (54.5%) and five in MSH2 (45.5%) genes. One patient had mutations in both MLH1 and MSH2 genes. Three novel mutations in MLH1 gene (c.157_160delGAGG, c.2157dupT and c.-64G>T) were found for the first time, and one suspected hotspot in MSH2 (c.1168C>T) was revealed.

Keywords

HNPCC;MLH1;MSH2;Mutations

References

  1. Lynch, H. T. and Smyrk, T. (1996) Hereditary nonpolyposis colorectal cancer (Lynch syndrome): An updated review. Cancer 78, 1149-1167. https://doi.org/10.1002/(SICI)1097-0142(19960915)78:6<1149::AID-CNCR1>3.0.CO;2-5
  2. Lynch, H. T. and de la Chapelle, A. (1999) Genetic susceptibility to non-polyposis colorectal cancer. J. Med. Genet. 36, 801-818.
  3. Ricciardiello, L. and Boland, C. (2005) Lynch syndrome (hereditary non-polyposis colorectal cancer): Current concepts and approaches to management. Curr. Gastroenterol. Rep. 7, 412-420. https://doi.org/10.1007/s11894-005-0012-2
  4. Lynch, H. T. and de la Chapelle, A. (2003) Hereditary colorectal cancer. New Engl. J. Med. 348, 919-932. https://doi.org/10.1056/NEJMra012242
  5. Peltomaki, P. and Vasen, H. (2004) Mutations associated with HNPCC predisposition - Update of ICG-HNPCC/ INSiGHT mutation database. Dis. Markers 20, 269-276. https://doi.org/10.1155/2004/305058
  6. Wijnen, J. T., Vasen, H. F. A., Khan, P. M., Zwinderman, A. H., van der Klift, H., Mulder, A., Tops, C., Møller, P., Fodde, R., Menko, F., Taal, B., Nagengast, F., Brunner, H., Kleibeuker, J., Sijmons, R., Griffioen, G., Bröcker- Vriends, A., Bakker, E., van Leeuwen-Cornelisse, I., Meijers-Heijboer, A., Lindhout, D., Breuning, M., Post, J., Schaap, C., Apold, J., Heimdal, K., Bertario, L., Bisgaard, M. L. and Goetz, P. (1998) Clinical findings with implications for genetic testing in families with clustering of colorectal cancer. New Engl. J. Med. 339, 511-518. https://doi.org/10.1056/NEJM199808203390804
  7. Wei, W. Q., Liu, L., Chen, J., Jin, K., Jiang, F., Liu, F. Q., Fan, R., Cheng, Z., Shen, M., Xue, C. Y., Cai, S. J., Xu, Y., and Nan, P. (2010) Racial differences in MLH1 and MSH2 mutation: an analysis of yellow race and white race based on the InSiGHT. J. Bioinform. Comp. Biol. 8 (Suppl 1), 111-125.
  8. Sheng, J. Q., Chan, T. L., Chan, Y. W., Huang, J. S., Chen, J. G., Zhang, M. Z., Guo, X. L., Mu, H., Chan, A. S., Li, S. R., Yuen, S. T. and Leung, S. Y. (2006) Microsatellite instability and novel mismatch repair gene mutations in northern Chinese population with Hereditary non-polyposis colorectal cancer. Chinese J. Digest. Dis. 7, 197- 205. https://doi.org/10.1111/j.1443-9573.2006.00269.x
  9. Chew, M. H., Koh, P. K., Ng, K. H., Lim, J. F., Ho, K. S., Ooi, B. S., Tang, C. L. and Eu, K. W. (2008) Phenotypic characteristics of hereditary non-polyposis colorectal cancer by the Amsterdam criteria: an Asian perspective. ANZ J. Surg. 78, 556-560. https://doi.org/10.1111/j.1445-2197.2008.04570.x
  10. Cai, S. J., Xu, Y., Cai, G. X., Lian, P., Guan, Z. Q., Mo, S. J., Sun, M. H., Cai, Q. and Shi, D. R. (2003) Clinical characteristics and diagnosis of patients with hereditary nonpolyposis colorectal cancer. World J. Gastroenterol. 9, 284-287. https://doi.org/10.3748/wjg.v9.i2.284
  11. Kim, Y. M., Choe, C. G., Cho, S. K., Jung, I. H., Chang, W. Y. and Cho, M. (2010) Three novel germline mutations in MLH1 and MSH2 in families with Lynch syndrome living on Jeju island, Korea. BMB Rep. 43, 693- 697. https://doi.org/10.5483/BMBRep.2010.43.10.693
  12. Mangold, E., Pagenstecher, C., Friedl, W., Mathiak, M., Buettner, R., Engel, C., Loeffler, M., Holinski-Feder, E., Muller-Koch, Y., Keller, G., Schackert, H. K., Kruger, S., Goecke, T., Moeslein, G., Kloor, M., Gebert, J., Kunstmann, E., Schulmann, K., Ruschoff, J. and Propping, P. (2005) Spectrum and frequencies of mutations in MSH2 and MLH1 identified in 1,721 German families suspected of hereditary nonpolyposis colorectal cancer. Int. J. Cancer 116, 692-702. https://doi.org/10.1002/ijc.20863
  13. Konishi, M., Kikuchi-Yanoshita, R., Tanaka, K., Muraoka, M., Onda, A., Okumura, Y., Kishi, N., Iwama, T., Mori, T., Koike, M., Ushio, K., Chiba, M., Nomizu, S., Konishi, F., Utsunomiya, J. and Miyaki, M. (1996) Molecular nature of colon tumors in hereditary nonpolyposis colon cancer, familial polyposis, and sporadic colon cancer. Gastroenterology 111, 307-317. https://doi.org/10.1053/gast.1996.v111.pm8690195
  14. Banno, K., Susumu, N., Nozawa, S. and Sugano, K. (2004) Met688Ile and Leu390Phe of the MSH2 gene are not functional mutations, but polymorphisms in Japanese individuals. Cancer Genet. Cytogenet. 155, 92.
  15. Kim, J. C., Roh, S. A., Koo, K. H., Ka, I. H., Kim, H. C., Yu, C. S., Lee, K. H., Kim, J. S., Lee, H. I. and Bodmer, W. F. (2004) Genotyping possible polymorphic variants of human mismatch repair genes in healthy Korean individuals and sporadic colorectal cancer patients. Fam. Cancer 3, 129-137.
  16. Chen, C. H., Huang, R. L., Yu, M. S., Wong, L. J., Chao, T. F. and Chu, T. Y. (2001) Hereditary nonpolyposis colorectal cancer with gynecologic malignancies: report of two families in Taiwan. J. Formos. Med. Assoc. 100, 269-273.
  17. Fan, Y., Liu, X., Zhang, H., Dai, J., Zhang, X., Zhu, M., Gao, X. and Wang, Y. (2006) Variations in exon 7 of the MSH2 gene and susceptibility to gastrointestinal cancer in a Chinese population. Cancer Genet. Cytogenet. 170, 121-128. https://doi.org/10.1016/j.cancergencyto.2006.05.010
  18. Zhang, Y., Liu, X., Fan, Y., Ding, J., Xu, A., Zhou, X., Hu, X., Zhu, M., Zhang, X., Li, S., Wu, J., Cao, H., Li, J. and Wang, Y. (2006) Germline mutations and polymorphic variants in MMR, E-cadherin and MYH genes associated with familial gastric cancer in Jiangsu of China. Int. J. Cancer 119, 2592-2596. https://doi.org/10.1002/ijc.22206
  19. 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. and Nyström, M. (2005) Functional significance and clinical phenotype of nontruncating mismatch repair variants of MLH1. Gastroenterology 129, 537-549.
  20. Trojan, J., Zeuzem, S., Randolph, A., Hemmerle, C., Brieger, A., Raedle, J., Plotz, G., Jiricny, J. and Marra, G. (2002) Functional analysis of hMLH1 variants and HNPCC-related mutations using a human expression system. Gastroenterology 122, 211-219. https://doi.org/10.1053/gast.2002.30296
  21. Kondo, E., Suzuki, H., Horii, A. and Fukushige, S. (2003) A yeast two-hybrid assay provides a simple way to evaluate the vast majority of hMLH1 germ-line mutations. Cancer Res. 63, 3302-3308.
  22. Marais, G. and Duret, L. (2001) Synonymous codon usage, accuracy of translation, and gene length in caenorhabditis elegans. J. Mol. Evol. 52, 275-280. https://doi.org/10.1007/s002390010155
  23. Takahashi, M., Shimodaira, H., Andreutti-Zaugg, C., Iggo, R., Kolodner, R. D. and Ishioka, C. (2007) Functional analysis of human MLH1 variants using yeast and in vitro mismatch repair assays. Cancer Res. 67, 4595-4604. https://doi.org/10.1158/0008-5472.CAN-06-3509
  24. Campbell, P. T., Curtin, K., Ulrich, C. M., Samowitz, W. S., Bigler, J., Velicer, C. M., Caan, B., Potter, J. D. and Slattery, M. L. (2009) Mismatch repair polymorphisms and risk of colon cancer, tumour microsatellite instability and interactions with lifestyle factors. Gut 58, 661-667. https://doi.org/10.1136/gut.2007.144220
  25. Nejda, N., Iglesias, D., Moreno Azcoita, M., Medina Arana, V., González-Aguilera, J. J. and Fernández-Peralta, A. M. (2009) A MLH1 polymorphism that increases cancer risk is associated with better outcome in sporadic colorectal cancer. Cancer Genet. Cytogenet. 193, 71-77. https://doi.org/10.1016/j.cancergencyto.2009.04.011
  26. Bagnoli, S., Putignano, A. L., Melean, G., Baglioni, S., Sestini, R., Milla, M., d'Albasio, G., Genuardi, M., Pacini, F., Trallori, G. and Papi, L. (2004) Susceptibility to refractory ulcerative colitis is associated with polymorphism in the hMLH1 mismatch repair gene. Inflamm. Bowel Dis. 10, 705-708. https://doi.org/10.1097/00054725-200411000-00001
  27. Mathonnet, G., Krajinovic, M., Labuda, D. and Sinnett, D. (2003) Role of DNA mismatch repair genetic polymorphisms in the risk of childhood acute lymphoblastic leukaemia. Br. J. Haematol. 123, 45-48. https://doi.org/10.1046/j.1365-2141.2003.04551.x
  28. An, Y., Jin, G., Wang, H., Wang, Y., Liu, H., Li, R., Wang, H., Qian, J., Sun, W., Ma, H., Miao, R., Hu, Z., Jin, L., Wei, Q., Shen, H., Huang, W. and Lu, D. (2008) Polymorphisms in hMLH1 and risk of early-onset lung cancer in a southeast Chinese population. Lung Cancer 59, 164-170. https://doi.org/10.1016/j.lungcan.2007.08.003
  29. Fredriksson, H., Ikonen, T., Autio, V., Matikainen, M. P., Helin, H. J., Tammela, T. L. J., Koivisto, P. A. and Schleutker, J. (2006) Identification of germline MLH1 alterations in familial prostate cancer. Eur. J. Cancer 42, 2802-2806. https://doi.org/10.1016/j.ejca.2006.04.024
  30. Raptis, S., Mrkonjic, M., Green, R. C., Pethe, V. V., Monga, N., Chan, Y. M., Daftary, D., Dicks, E., Younghusband, B. H., Parfrey, P. S., Gallinger, S. S., McLaughlin, J. R., Knight, J. A. and Bapat, B. (2007) MLH1 -93G>A promoter polymorphism and the risk of microsatellite- unstable colorectal cancer. J. Natl. Cancer I. 99, 463-474. https://doi.org/10.1093/jnci/djk095
  31. Allan, J. M., Shorto, J., Adlard, J., Bury, J., Coggins, R., George, R., Katory, M., Quirke, P., Richman, S., Scott, D., Scott, K., Seymour, M., Travis, L. B., Worrillow, L. J., Bishop, D. T. and Cox, A. (2008) MLH1 −93G>A promoter polymorphism and risk of mismatch repair deficient colorectal cancer. Intl. J. Cancer 123, 2456-2459. https://doi.org/10.1002/ijc.23770
  32. Zhong, X., Arita, M., Yamada, K., Sugiyama, H., Tan, K., Kanazawa, S., Koike, J., Teramoto, T. and Hemmi, H. (2007) A single nucleotide substitution (−107C$\rightarrow$G) in the hMLH1 promoter found in colorectal cancer population reduces transcriptional activity. Biochem. Genet. 45, 671-681. https://doi.org/10.1007/s10528-007-9104-z
  33. Green, R., Green, A., Simms, M., Pater, A., Robb, J. and Green, J. (2003) Germline hMLH1 promoter mutation in a Newfoundland HNPCC kindred. Clin. Genet. 64, 220- 227. https://doi.org/10.1034/j.1399-0004.2003.t01-1-00110.x
  34. Lee, S. C., Guo, J. Y., Lim, R., Soo, R., Koay, E., Salto- Tellez, M., Leong, A. and Goh, B.-C. (2005) Clinical and molecular characteristics of hereditary non-polyposis colorectal cancer families in Southeast Asia. Clin. Genet. 68, 137-145. https://doi.org/10.1111/j.1399-0004.2005.00469.x

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