Molecular and clinical characteristics of MSH6 germline variants detected in colorectal cancer patients

Terui,Hiroko; Tachikawa,Tetsuhiko; Kakuta,Miho; Nishimura,Yoji; Yatsuoka,Toshimasa; Yamaguchi,Kensei; Yura,Kei; Akagi,Kiwamu

doi:10.3892/or.2013.2781

Molecular and clinical characteristics of MSH6 germline variants detected in colorectal cancer patients

Authors:
- Hiroko Terui
- Tetsuhiko Tachikawa
- Miho Kakuta
- Yoji Nishimura
- Toshimasa Yatsuoka
- Kensei Yamaguchi
- Kei Yura
- Kiwamu Akagi
View Affiliations

Affiliations: Division of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, Saitama 362-0806, Japan, Gastroenterological Surgery, Saitama Cancer Center, Saitama 362-0806, Japan, Gastroenterology, Saitama Cancer Center, Saitama 362-0806, Japan, The Graduate School of Humanities and Sciences, Ochanomizu University, Tokyo 112-8610, Japan
Published online on: October 2, 2013 https://doi.org/10.3892/or.2013.2781
Pages: 2909-2916

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

The MSH6 gene is one of the mismatch repair genes involved in Lynch syndrome and its mutations account for 10-20% of Lynch syndrome. Although previous studies suggested that the difference of the geographical region affects the clinical phenotype of Lynch syndrome, there has been no report on the detailed features of Japanese Lynch syndrome patients carrying an MSH6 mutation. The aim of the present study was to investigate the clinical and molecular features of MSH6 mutation carriers in Japan. Surgically resected 1720 colorectal carcinoma specimens were screened by microsatellite instability (MSI) testing and the MSI-high cases were subjected to a germline mutation analysis of the mismatch repair genes MLH1, MSH2 and MSH6. We investigated the clinical and molecular features of the MSH6 variants, such as the family cancer history, pathological findings, immunohistochemistry, methylation status of the MLH1 promoter and BRAF mutation in the colorectal tumor. Furthermore, the impact of the missense variants on MSH6 protein was predicted by using in silico tools. We identified nine novel pathogenic mutations and eight unclassified missense variants. Among the eight missense variants, three were suspected pathogenic by in silico analysis. We also found that most colorectal cancers in the MSH6 mutation carrier were diagnosed after the age of 50 and were localized distally. Furthermore, the mean age at diagnosis of endometrial cancer in Japanese MSH6 mutation carriers (49.2 years) was earlier than previous reports from Western countries (56.5 years). These results may improve the surveillance program for Japanese MSH6 mutation carriers.

View References

1	Lynch HT and de la Chapelle A: Hereditary colorectal cancer. N Engl J Med. 348:919–932. 2003. View Article : Google Scholar : PubMed/NCBI
2	Grover S and Syngal S: Genetic testing in gastroenterology: Lynch syndrome. Best Pract Res Clin Gastroenterol. 23:185–196. 2009. View Article : Google Scholar : PubMed/NCBI
3	Hampel H, Frankel WL, Martin E, et al: Feasibility of screening for Lynch syndrome among patients with colorectal cancer. J Clin Oncol. 26:5783–5788. 2008. View Article : Google Scholar : PubMed/NCBI
4	Aaltonen LA, Salovaara R, Kristo P, et al: Incidence of hereditary nonpolyposis colorectal cancer and the feasibility of molecular screening for the disease. N Engl J Med. 338:1481–1487. 1998. View Article : Google Scholar : PubMed/NCBI
5	Wijnen J, de Leeuw W, Vasen H, et al: Familial endometrial cancer in female carriers of MSH6 germline mutations. Nat Genet. 23:142–144. 1999. View Article : Google Scholar : PubMed/NCBI
6	Vasen HF, Mecklin JP, Khan PM and Lynch HT: The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC). Dis Colon Rectum. 34:424–425. 1991. View Article : Google Scholar : PubMed/NCBI
7	Baglietto L, Lindor NM, Dowty JG, et al: Risks of Lynch syndrome cancers for MSH6 mutation carriers. J Natl Cancer Inst. 102:193–201. 2010. View Article : Google Scholar : PubMed/NCBI
8	Berends MJW, Wu Y, Sijmons RH, et al: Molecular and clinical characteristics of MSH6 variants: an analysis of 25 index carriers of a germline variant. Am J Hum Genet. 70:26–37. 2002.
9	Hendriks YMC, Wagner A, Morreau H, et al: Cancer risk in hereditary nonpolyposis colorectal cancer due to MSH6 mutations: impact on counseling and surveillance. Gastroenterology. 127:17–25. 2004. View Article : Google Scholar : PubMed/NCBI
10	Wijnen JT, Vasen HF, Khan PM, et al: Clinical findings with implications for genetic testing in families with clustering of colorectal cancer. N Engl J Med. 339:511–518. 1998. View Article : Google Scholar : PubMed/NCBI
11	Cunningham JM, Christensen ER, Tester DJ, et al: Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability. Cancer Res. 58:3455–3460. 1998.PubMed/NCBI
12	Herman JG, Umar A, Polyak K, et al: Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci USA. 95:6870–6875. 1998. View Article : Google Scholar : PubMed/NCBI
13	Kane MF, Loda M, Gaida GM, et al: Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. Cancer Res. 57:808–811. 1997.PubMed/NCBI
14	Bessa X, Ballesté B, Andreu M, et al: A prospective, multicenter, population-based study of BRAF mutational analysis for Lynch syndrome screening. Clin Gastroenterol Hepatol. 6:206–214. 2008. View Article : Google Scholar : PubMed/NCBI
15	Akagi K, Uchibori R, Yamaguchi K, Kurosawa K, Tanaka Y and Kozu T: Characterization of a novel oncogenic K-ras mutation in colon cancer. Biochem Biophys Res Commun. 352:728–732. 2007. View Article : Google Scholar : PubMed/NCBI
16	Vasen HF, Watson P, Mecklin JP and Lynch HT: New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology. 116:1453–1456. 1999. View Article : Google Scholar
17	Umar A, Boland CR, Terdiman JP, et al: Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst. 96:261–268. 2004. View Article : Google Scholar
18	Ohsawa T, Sahara T, Muramatsu S, et al: Colorectal cancer susceptibility associated with the hMLH1 V384D variant. Mol Med Rep. 2:887–891. 2009.
19	Asaka S, Arai Y, Nishimura Y, et al: Microsatellite instability-low colorectal cancer acquires a KRAS mutation during the progression from Dukes' A to Dukes' B. Carcinogenesis. 30:494–499. 2009. View Article : Google Scholar : PubMed/NCBI
20	Campbell PT, Curtin K, Ulrich CM, et al: Mismatch repair polymorphisms and risk of colon cancer, tumour microsatellite instability and interactions with lifestyle factors. Gut. 58:661–667. 2009. View Article : Google Scholar : PubMed/NCBI
21	Jass JR: Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology. 50:113–130. 2007. View Article : Google Scholar : PubMed/NCBI
22	Terui H, Akagi K, Kawame H and Yura K: CoDP: predicting the impact of unclassified genetic variants in MSH6 by the combination of different properties of the protein. J Biomed Sci. 20:252013. View Article : Google Scholar : PubMed/NCBI
23	Ng PC and Henikoff S: Predicting deleterious amino acid substitutions. Genome Res. 11:863–874. 2001. View Article : Google Scholar : PubMed/NCBI
24	Adzhubei IA, Schmidt S, Peshkin L, et al: A method and server for predicting damaging missense mutations. Nat Methods. 7:248–249. 2010. View Article : Google Scholar : PubMed/NCBI
25	Ali H, Olatubosun A and Vihinen M: Classification of mismatch repair gene missense variants with PON-MMR. Hum Mutat. 33:642–650. 2012. View Article : Google Scholar : PubMed/NCBI
26	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
27	Stenson PD, Ball EV, Mort M, Phillips AD, Shaw K and Cooper DN: The Human Gene Mutation Database (HGMD) and its exploitation in the fields of personalized genomics and molecular evolution. Curr Protoc Bioinformatics. 39:1.132012.PubMed/NCBI
28	Sherry ST, Ward MH, Kholodov M, Baker J, Phan L, Smigielski EM and Sirotkin K: dbSNP: the NCBI database of genetic variation. Nucleic Acids Res. 29:308–311. 2001. View Article : Google Scholar : PubMed/NCBI
29	Engel C, Loeffler M, Steinke V, et al: Risks of less common cancers in proven mutation carriers with lynch syndrome. J Clin Oncol. 30:4409–4415. 2012. View Article : Google Scholar : PubMed/NCBI
30	Peltomäki P: Lynch syndrome genes. Fam Cancer. 4:227–232. 2005.
31	Vasen HFA: Review article: The Lynch syndrome (hereditary nonpolyposis colorectal cancer). Aliment Pharmacol Ther. 26:113–126. 2007. View Article : Google Scholar : PubMed/NCBI
32	Zhao Y, Hu F, Wang F, Han B, Li D, Li X and Zhu S: Meta-analysis of MSH6 gene mutation frequency in colorectal and endometrial cancers. J Toxicol Environ Health A. 72:690–697. 2009.
33	Okkels H, Lindorff-Larsen K, Thorlasius-Ussing O, et al: MSH6 mutations are frequent in hereditary nonpolyposis colorectal cancer families with normal pMSH6 expression as detected by immunohistochemistry. Appl Immunohistochem Mol Morphol. 20:470–477. 2012. View Article : Google Scholar : PubMed/NCBI
34	Plon SE, Eccles DM, Easton D, et al: Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results. Hum Mutat. 29:1282–1291. 2008. View Article : Google Scholar : PubMed/NCBI
35	Ellison AR, Lofing J and Bitter GA: Functional analysis of human MLH1 and MSH2 missense variants and hybrid human-yeast MLH1 proteins in Saccharomyces cerevisiae. Hum Mol Genet. 10:1889–1900. 2001.PubMed/NCBI
36	Gammie AE, Erdeniz N, Beaver J, Devlin B, Nanji A and Rose MD: Functional characterization of pathogenic human MSH2 missense mutations in Saccharomyces cerevisiae. Genetics. 177:707–721. 2007. View Article : Google Scholar : PubMed/NCBI
37	Polaczek P, Putzke AP, Leong K and Bitter GA: Functional genetic tests of DNA mismatch repair protein activity in Saccharomyces cerevisiae. Gene. 213:159–167. 1998. View Article : Google Scholar : PubMed/NCBI
38	Furihata M, Shuin T, Takeuchi T, Sonobe H, Ohtsuki Y, Akiyama Y and Yuasa Y: Missense mutation of the hMSH6 and p53 genes in sporadic urothelial transitional cell carcinoma. Int J Oncol. 16:491–496. 2000.PubMed/NCBI