Analysis of human MutS homolog 2 missense mutations in patients with colorectal cancer

Zhang,Xiaomei; Chen,Senqing; Yu,Jun; Zhang,Yuanying; Lv,Min; Zhu,Ming

doi:10.3892/ol.2018.8161

Analysis of human MutS homolog 2 missense mutations in patients with colorectal cancer

Authors:
- Xiaomei Zhang
- Senqing Chen
- Jun Yu
- Yuanying Zhang
- Min Lv
- Ming Zhu
View Affiliations

Affiliations: Department of Molecular Biology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, Jiangsu 210009, P.R. China
Published online on: March 2, 2018 https://doi.org/10.3892/ol.2018.8161
Pages: 6275-6282
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Germline mutations of DNA mismatch repair gene human MutS homolog 2 (hMSH2) are associated with hereditary nonpolyposis colorectal cancer (HNPCC). A total of one‑third of these mutations are missense mutations. Several hMSH2 missense mutations have been identified in patients in East Asia, although their function has not been evaluated. In the present study, the role of ten hMSH2 missense mutations in the pathogenesis of colorectal cancer was examined. The hMSH2/hMSH6 protein interaction system was established using yeast two‑hybrid screening. Next, the missense mutations were analyzed for their ability to affect the protein interaction of hMSH2 with its partner hMSH6. Additionally, the Sorting Intolerant from Tolerant tool was applied to predict the effects of different amino acid substitutions. The results demonstrated that certain hMSH2 mutations (L173R and C199R) caused a significant functional change in the human hMutSα complex and were identified to be pathological mutations. The Y408C, D603Y, P696L and S703Y mutations partially affected interaction and partly affected the function of hMSH2. The remaining four variants, T8M, I169V, A370T and Q419K, may be non‑functional polymorphisms or could affect protein function through other molecular mechanisms. The present study evaluated the functional consequences of previously unknown missense mutations in hMSH2, and may contribute to improved clinical diagnosis and mutation screening of HNPCC.

View Figures

View References

1	Brosens LA, Offerhaus GJ and Giardiello FM: Hereditary colorectal cancer: Genetics and screening. Surg Clin North Am. 95:1067–1080. 2015. View Article : Google Scholar : PubMed/NCBI
2	Lynch HT and de la Chapelle A: Genetic susceptibility to non-polyposis colorectal cancer. J Med Genet. 36:801–818. 1999.PubMed/NCBI
3	In SiGHT: InSiGHT variant databases. https://www.insight-group.org/variants/databases/June 29–2017
4	Woods MO, Williams P, Careen A, Edwards L, Bartlett S, McLaughlin JR and Younghusband HB: A new variant database for mismatch repair genes associated with Lynch syndrome. Hum Mutat. 28:669–673. 2007. View Article : Google Scholar : PubMed/NCBI
5	Peltomaki P and Vasen HF: Mutations predisposing to hereditary nonpolyposis colorectal cancer: Database and results of a collaborative study. The International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer. Gastroenterology. 113:1146–1158. 1997. View Article : Google Scholar : PubMed/NCBI
6	Obmolova G, Ban C, Hsieh P and Yang W: Crystal structures of mismatch repair protein MutS and its complex with a substrate DNA. Nature. 407:703–710. 2000. View Article : Google Scholar : PubMed/NCBI
7	Lamers MH, Perrakis A, Enzlin JH, Winterwerp HH, de Wind N and Sixma TK: The crystal structure of DNA mismatch repair protein MutS binding to a GxT mismatch. Nature. 407:711–717. 2000. View Article : Google Scholar : PubMed/NCBI
8	Jiricny J: The multifaceted mismatch-repair system. Nat Rev Mol Cell Biol. 7:335–346. 2006. View Article : Google Scholar : PubMed/NCBI
9	Geng H, Sakato M, DeRocco V, Yamane K, Du C, Erie DA, Hingorani M and Hsieh P: Biochemical analysis of the human mismatch repair proteins hMutSα MSH2(G674A)-MSH6 and MSH2-MSH6(T1219D). J Biol Chem. 287:9777–9791. 2012. View Article : Google Scholar : PubMed/NCBI
10	Fan Y, Wang W, Zhu M, Zhou J, Peng J, Xu L, Hua Z, Gao X and Wang Y: Analysis of hMLH1 missense mutations in East Asian patients with suspected hereditary nonpolyposis colorectal cancer. Clin Cancer Res. 13:7515–7521. 2007. View Article : Google Scholar : PubMed/NCBI
11	Wang XL, Yuan Y, Zhang SZ, Cai SR, Huang YQ, Jiang Q and Zheng S: Clinical and genetic characteristics of Chinese hereditary nonpolyposis colorectal cancer families. World J Gastroenterol. 12:4074–4077. 2006. View Article : Google Scholar : PubMed/NCBI
12	Nomura S, Sugano K, Kashiwabara H, Taniguchi T, Fukayama N, Fujita S, Akasu T, Moriya Y, Ohhigashi S, Kakizoe T and Sekiya T: Enhanced detection of deleterious and other germline mutations of hMSH2 and hMLH1 in Japanese hereditary nonpolyposis colorectal cancer kindreds. Biochem Biophys Res Commun. 271:120–129. 2000. View Article : Google Scholar : PubMed/NCBI
13	Fan Y, Liu X, Zhang H, Dai J, Zhang X, Zhu M, Gao X and Wang Y: Variations in exon 7 of the MSH2 gene and susceptibility to gastrointestinal cancer in a Chinese population. Cancer Genet Cytogenet. 170:121–128. 2006. View Article : Google Scholar : PubMed/NCBI
14	Leung SY, Chan TL, Chung LP, Chan AS, Fan YW, Hung KN, Kwong WK, Ho JW and Yuen ST: Microsatellite instability and mutation of DNA mismatch repair genes in gliomas. Am J Pathol. 153:1181–1188. 1998. View Article : Google Scholar : PubMed/NCBI
15	Tang R, Hsiung C, Wang JY, Lai CH, Chien HT, Chiu LL, Liu CT, Chen HH, Wang HM, Chen SX, et al: Germ line MLH1 and MSH2 mutations in Taiwanese Lynch syndrome families: Characterization of a founder genomic mutation in the MLH1 gene. Clin Genet. 75:334–345. 2009. View Article : Google Scholar : PubMed/NCBI
16	Zhang Y, Liu X, Fan Y, Ding J, Xu A, Zhou X, Hu X, Zhu M, Zhang X, Li S, et al: 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. 2006. View Article : Google Scholar : PubMed/NCBI
17	Yuen ST, Chan TL, Ho JW, Chan AS, Chung LP, Lam PW, Tse CW, Wyllie AH and Leung SY: Germline, somatic and epigenetic events underlying mismatch repair deficiency in colorectal and HNPCC-related cancers. Oncogene. 21:7585–7592. 2002. View Article : Google Scholar : PubMed/NCBI
18	Jin HY, Yan HL, Song LH, Cui L, Ding YJ and Sun SH: Identification and functional analysis of a novel germ-line mutation in hMSH2 from a Chinese hereditary nonpolyposis colorectal cancer family. Acad J Sec Mil Med Univ. 26:888–891. 2005.(In Chinese).
19	Ng PC and Henikoff S: Predicting deleterious amino acid substitutions. Genome Res. 11:863–874. 2001. View Article : Google Scholar : PubMed/NCBI
20	Kumar P, Henikoff S and Ng PC: Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc. 4:1073–1081. 2009. View Article : Google Scholar : PubMed/NCBI
21	Vander Molen J, Frisse LM, Fullerton SM, Qian Y, Del Bosque-Plata L, Hudson RR and Di Rienzo A: Population genetics of CAPN10 and GPR35: Implications for the evolution of type 2 diabetes variants. Am J Hum Genet. 76:548–560. 2005. View Article : Google Scholar : PubMed/NCBI
22	Nystrom-Lahti M, Perrera C, Raschle M, Panyushkina-Seiler E, Marra G, Curci A, Quaresima B, Costanzo F, D'Urso M, Venuta S and Jiricny J: Functional analysis of MLH1 mutations linked to hereditary nonpolyposis colon cancer. Genes Chromosomes Cancer. 33:160–167. 2002. View Article : Google Scholar : PubMed/NCBI
23	Clark AB, Cook ME, Tran HT, Gordenin DA, Resnick MA and Kunkel TA: Functional analysis of human MutSalpha and MutSbeta complexes in yeast. Nucleic Acids Res. 27:736–742. 1999. View Article : Google Scholar : PubMed/NCBI
24	Rodríguez-Negrete E, Bejarano ER and Castillo AG: Using the yeast two-hybrid system to identify protein-protein interactions. Methods Mol Biol. 1072:241–258. 2014. View Article : Google Scholar : PubMed/NCBI
25	Zhu M, Fan YM, Zhu YB and Wang YP: Establishment of a hMSH2/hMSH6 protein interaction system and functional evaluation of hMSH2 gene missense mutations. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 30:559–564. 2013.(In Chinese). PubMed/NCBI
26	Duraturo F, Liccardo R, Cavallo A, De Rosa M, Grosso M and Izzo P: Association of low-risk MSH3 and MSH2 variant alleles with Lynch syndrome: Probability of synergistic effects. Int J Cancer. 129:1643–1650. 2011. View Article : Google Scholar : PubMed/NCBI