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Published in:

01-09-2010

Analysis of mismatch repair gene mutations in Turkish HNPCC patients

Authors: Berrin Tunca, Monica Pedroni, Gulsah Cecener, Unal Egeli, Enrica Borsi, Abdullah Zorluoglu, Carmela Di Gregorio, Tuncay Yilmazlar, Omer Yerci, Maurizio Ponz de Leon

Published in: Familial Cancer | Issue 3/2010

Abstract

Hereditary non-polyposis colorectal cancer (HNPCC or Lynch syndrome) is caused by the inheritance of a mutant allele of a DNA mismatch repair gene. We aimed to investigate types and frequencies of mismatch repair (MMR) gene mutations in Turkish patients with HNPCC and to identify specific biomarkers for early diagnosis of their non-symptomatic kindred’s. The molecular characteristics of 28 Turkish colorectal cancer patients at high-risk for HNPCC were investigated by analysis of microsatellite instability (MSI), immunohistochemistry and methylation-specific PCR in order to select tumors for mutation analysis. Ten cases (35.7%) were classified as MSI (+). Lack of expression of the main MMR proteins was observed in MSI (+) tumors. Hypermethylation of the MLH1 promoter region was observed in one tumor. Nine Lynch syndrome cases showed novel germ-line alterations of the MMR gene: two frame-shifts (MLH1 c.1843dupC and MLH1 c.1743delG) and three missense mutations (MLH1 c.293G>C, MLH1 c.954_955delinsTA and MSH2 c.2210G>A). Unclassified variants were evaluated as likely to be pathogenic by using the in-silico analyses. In addition, the MSH2 c.2210G>A alteration could be considered as a founder mutation for the Turkish population due to its identification in five different Lynch syndrome families and absence in control group. The present study adds new information about MMR gene mutation types and their role in Lynch syndrome. This is the first detailed research on Turkish Lynch syndrome families.

Turkish Ministry of Health (1999) http://www.saglik.gov.tr

Lynch HT, Smyrk T (1996) Hereditary non-polyposis colorectal cancer (Lynch syndrome). An updated review. Cancer 78:1149–1167CrossRefPubMed

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

Vasen HF (2005) Clinical description of the Lynch Syndrome [Hereditary Nonpolyposis Colorectal Cancer (HNPCC)]. Fam Cancer 4:219–225CrossRefPubMed

Ricciardiello L, Boland CR (2005) Lynch syndrome (Hereditary Nonpolyposis Colorectal Cancer): current concepts and approaches to management. Curr Gastroenterol Rep 7:412–420CrossRefPubMed

Lynch HT, Lynch JF, Lynch PM et al (2007) Toward a consensus in molecular diagnosis of hereditary nonpolyposis colorectal cancer (Lynch syndrome). J Natl Cancer Inst 99:261–263CrossRefPubMed

Brian DH, Sue JR (2000) DNA mismatch repair and genetic instability. Annu Rev Genet 34:359–399CrossRef

Kurzawski G, Safranow K, Suchy J et al (2002) Mutation analysis of MLH1 and MSH2 genes performed by denaturing high-performance liquid chromatography. J Biochem Biophys Methods 51:89–100CrossRefPubMed

Wang Q, Lasset C, Desseigne F et al (1999) Prevalence of germline mutations of hMLH1, hMSH2, hPMS1, hPMS2 and hMSH6 genes in 75 French kindreds with nonpolyposis colorectal cancer. Hum Genet 105:79–85CrossRefPubMed

10.

Umar A, Boland CR, Terdiman JP et al (2004) Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch Syndrome) and microsatellite instability. J Nat Cancer Inst 96:261–268CrossRefPubMed

11.

Yan HL, Hao LQ, Jin HY et al (2008) Clinical features and mismatch repair genes analyses of Chinese suspected hereditary non-polyposis colorectal cancer: a cost-effective screening strategy proposal. Cancer Sci 99:770–780CrossRefPubMed

12.

Tunca B, Bekar A, Cecener G et al (2006) Impact of novel PTEN mutations in Turkish patients with glioblastoma multiforme. J Neurooncol 82:263–269CrossRefPubMed

13.

Xicola RM, Llor X, Pons E et al (2007) Gastrointestinal oncology group of the Spanish gastroenterological association. Performance of different microsatellite marker panels for detection of mismatch repair-deficient colorectal tumors. J Natl Cancer Inst 99:244–252CrossRefPubMed

14.

Buhard O, Cattaneo F, Wong YF et al (2006) Multipopulation analysis of polymorphisms in five mononucleotide repeats used to determine the microsatellite instability status of human tumors. J Clin Oncol 24:241–251CrossRefPubMed

15.

Pedroni M, Roncari B, Maffei S et al (2007) A mononucleotide markers panel to identify hMLH1/hMSH2 germline mutations. Dis Markers 23:179–187PubMed

16.

Menigatti M, Di Gregorio C, Borghi F et al (2001) Methylation pattern of different regions of the MLH1 promoter and silencing of gene expression in hereditary and sporadic colorectal cancer. Genes Chromosomes Cancer 31:357–361CrossRefPubMed

17.

Deng G, Chen A, Hong J et al (1999) Methylation of CpG in a small region of the hMLH1 promoter in variably correlates with the absence of gene expression. Cancer Res 59:2029–2033PubMed

18.

Losi L, Di Gregorio C, Pedroni M et al (2005) Molecular genetic alterations and clinical features in early-onset colorectal carcinomas and their role for the recognition of hereditary cancer syndromes. Am J Gastroenterol 100(10):2280–2287CrossRefPubMed

19.

Ng PC, Henikoff S (2003) SIFT: predicting amino acid changes that affect protein function. Nucleic Acids Res 31(13):3812–3814CrossRefPubMed

20.

Yue P, Melamud E, Moult J (2006) 1SNPs3D: candidate gene and SNP selection for association studies. BMC Bioinform 7:1–15CrossRef

21.

Capriotti E, Calabrese R, Casadio R (2006) Predicting the insurgence of human genetic diseases associated to single point protein mutations with support vector machines and evolutionary information. Bioinformatics 22:2729–2734CrossRefPubMed

22.

Tavtigian SV, Deffenbaugh AM, Yin L et al (2006) Comprehensive statistical study of 452 BRCA1missense substitutions with classification of eightrecurrent substitutions as neutral. J Med Genet 43:295–305CrossRefPubMed

23.

Desmet FO, Hamroun D, Lalande M et al. (2009) Human Splicing Finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res 1–14 doi:10.1093/nar/gkp215

24.

Dobrovic A, Kristensen LS (2009) DNA methylation, epimutations and cancer predisposition. Intl J Biochem Cell Biol 41:34–39CrossRef

25.

Hitchins MP, Ward RL (2009) Constitutional (germline) MLH1 epimutation as an aetiological mechanism for hereditary non-polyposis colorectal cancer. J Med Genet. doi:10.1136/jmg.2009.068122

26.

Gazzoli I, Loda M, Garber J et al (2002) A hereditary nonpolyposis colorectal carcinoma case associated with hypermethylation of the MLH1 gene in normal tissue and loss of heterozygosity of the unmethylated allele in the resulting microsatellite instability-high tumor. Cancer Res 62:3925–3928PubMed

27.

Miyakura Y, Sugano K, Akasu T et al (2004) Extensive but hemiallelic methylation of the hMLH1 promoter region in early-onset sporadic colon cancers with microsatellite instability. Clin Gastroenterol Hepatol 2:147–156CrossRefPubMed

28.

Suter CM, Martin DI, Ward RL (2004) Germline epimutation of MLH1 in individuals with multiple cancers. Nat Genet 36:497–501CrossRefPubMed

29.

Hitchins MP, Wong JJ, Suthers G et al (2007) Inheritance of a cancer-associated MLH1 germ-line epimutation. N Engl J Med 356:697–705CrossRefPubMed

30.

Valle L, Carbonell P, Fernandez V (2007) MLH1 germline epimutations in selected patients with early-onset non-polyposis colorectal cancer. Clin Genet 71:232–237CrossRefPubMed

31.

Morak M, Schackert HK, Rahner N et al (2008) Further evidence for heritability of an epimutation in one of 12 cases with MLH1 promoter methylation in blood cells clinically displaying HNPCC. Eur J Hum Genet 16:804–811CrossRefPubMed

32.

Niessen RC, Hofstra RMW, Westers H et al (2009) Germline hypermethylation of MLH1 and EPCAM deletions are a frequent cause of Lynch syndrome. Genes Chromosomes Cancer 48:737–744CrossRefPubMed

33.

Flicek P, Aken BL, Beal K et al (2008) Ensembl 2008. Nucleic Acids Res 36:707–714CrossRef

34.

Wang Q, Desseigne F, Lasset C et al (1997) Germline hMSH2 and hMLH1 gene mutations in incomplete HNPCC families. Int J Cancer 73:831–836CrossRefPubMed

35.

Güran S, Ozet A, Dede M et al (2005) Hereditary breast cancer syndromes in a Turkish population. Results of molecular germline analysis. Cancer Genet Cytogenet 160:164–168CrossRefPubMed

36.

Chan PA, Duraisamy S, Miller PJ et al (2007) Interpreting missense variants: comparing computational methods in human disease genes CDKN2A, MLH1, MSH2, MECP2, and tyrosinase (TYR). Hum Mutat 28:683–693CrossRefPubMed

37.

Thusberg J, Vihinen M (2009) Pathogenic or not? And ıf so, then how? Studying the effects of missense mutations using bioinformatics methods. Hum Mutat 30:703–714CrossRefPubMed

38.

Hastings ML, Krainer AR (2001) Pre-mRNA splicing in the new millennium. Curr Opin Cell Biol 13:302–309CrossRefPubMed

39.

Jacob M, Gallinaro H (1989) The 50 splice site: phylogenetic evolution and variable geometry of association with U1RNA. Nucleic Acids Res 17:2159–2180CrossRefPubMed

40.

Krawczak M, Thomas NST, Hundrieser B et al (2007) Single base-pair substitutions in exon–intron junctions of human genes: nature, distribution, and consequences for mRNA splicing. Hum Mutat 28:150–158CrossRefPubMed

41.

Faustino NA, Cooper TA (2003) Pre-mRNA splicing and human disease. Genes Dev 17:419–437CrossRefPubMed

42.

Baralle D, Baralle M (2005) Splicing in action: assessing disease causing sequence changes. J Med Genet 42:737–748CrossRefPubMed

43.

Blencowe BJ (2000) Exonic splicing enhancers: mechanism of action, diversity and role in human genetic diseases. Trends Biochem Sci 25:106–110CrossRefPubMed

44.

Zhu J, Mayeda A, Krainer AR (2001) Exon identity established through differential antagonism between exonic splicing silencer-bound hnRNP A1 and enhancer-bound SR proteins. Mol Cell 8:1351–1361CrossRefPubMed

45.

Vreeswijk MPG, Kraan JN, Klift HM et al (2009) Intronic variants in BRCA1 and BRCA2 that affect RNA splicing can be reliably selected by splice-site prediction programs. Hum Mutat 30:107–114CrossRefPubMed

46.

Reese MG, Eeckman FH, Kulp D, Haussler D (1997) Improved splice site detection in Genie. J Comput Biol 4:311–323CrossRefPubMed

47.

Hebsgaard SM, Korning PG, Tolstrup N et al (1996) Splice site prediction in Arabidopsis thaliana pre-mRNA by combining local and global sequence information. Nucleic Acids Res 24:3439–3452CrossRefPubMed

48.

Shapiro MB, Senapathy P (1987) RNA splice junctions of different classes of eukaryotes: sequence statistics and functional implications in gene expression. Nucleic Acids Res 15:7155–7174CrossRefPubMed

49.

Nalla VK, Rogan PK (2005) Automated splicing mutation analysis by information theory. Hum Mutat 25:334–342CrossRefPubMed

50.

Yeo G, Burge CB (2004) Maximum entropy modeling of short sequence motifs with applications to RNA splicing signals. J Comput Biol 11:377–394CrossRefPubMed

51.

Beroud C, Hamroun D, Collod-Beroud G et al (2005) UMD (Universal Mutation Database): 2005 update. Hum Mutat 26:184–191CrossRefPubMed

52.

Fairbrother WG, Yeo GW, Yeh R et al (2004) RESCUE-ESE identifies candidate exonic splicing enhancers in vertebrate exons. Nucleic Acids Res 32:187–190CrossRef

53.

Cartegni L, Wang J, Zhu Z (2003) ESEfinder: a web resource to identify exonic splicing enhancers. Nucleic Acids Res 31:3568–3571CrossRefPubMed

54.

Zhang XH, Chasin LA (2004) Computational definition of sequence motifs governing constitutive exon splicing. Genes Dev 18:1241–1250CrossRefPubMed

55.

Sironi M, Menozzi G, Riva L et al (2004) Silencer elements as possible inhibitors of pseudoexon splicing. Nucleic Acids Res 32:1783–1791CrossRefPubMed

56.

Zhang C, Li WH, Krainer AR, Zhang MQ (2008) RNA landscape of evolution for optimal exon and intron discrimination. Proc Natl Acad Sci USA 105:5797–5802CrossRefPubMed

57.

Salovaara R, Loukola A, Kristo P et al (2000) Population-based molecular detection of hereditary nonpolyposis colorectal cancer. J Clin Oncol 18:2193–2200PubMed

Title: Analysis of mismatch repair gene mutations in Turkish HNPCC patients
Authors: Berrin Tunca
Monica Pedroni
Gulsah Cecener
Unal Egeli
Enrica Borsi
Abdullah Zorluoglu
Carmela Di Gregorio
Tuncay Yilmazlar
Omer Yerci
Maurizio Ponz de Leon
Publication date: 01-09-2010
Publisher: Springer Netherlands
Published in: Familial Cancer / Issue 3/2010
Print ISSN: 1389-9600
Electronic ISSN: 1573-7292
DOI: https://doi.org/10.1007/s10689-010-9336-7

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