A novel c. 204 Ile68Met germline variant in exon 2 of the mutL homolog 1 gene in a colorectal cancer patient

Vodicka,Pavel; Caja,Fabian; Vymetalkova,Veronika; Prochazk,Pavel; Vodickova,Ludmila; Schwarzova,Lucie; Slyskova,Jana; Kumar,Rajiv; Schneiderova,Michaela

doi:10.3892/ol.2014.2666

January-2015 Volume 9 Issue 1

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January-2015 Volume 9 Issue 1

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Article

A novel c. 204 Ile68Met germline variant in exon 2 of the mutL homolog 1 gene in a colorectal cancer patient

Authors:
- Pavel Vodicka
- Fabian Caja
- Veronika Vymetalkova
- Pavel Prochazk
- Ludmila Vodickova
- Lucie Schwarzova
- Jana Slyskova
- Rajiv Kumar
- Michaela Schneiderova
View Affiliations / Copyright

Affiliations: Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague 14220, Czech Republic, Department of Immunology and Gnotobiology, Institute of Microbiology, Academy of Sciences of the Czech Republic, Prague 14220, Czech Republic, Department of Molecular Genetics, Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University in Prague, Prague 12800, Czech Republic, Division of Molecular Genetic Epidemiology, German Cancer Research Center, Im Neuenheimer Feld, Heidelberg 69121, Germany, Department of Surgery, General University Hospital in Prague, Prague 12800, Czech Republic
Pages: 183-186
|
Published online on: November 4, 2014

https://doi.org/10.3892/ol.2014.2666
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Abstract

Mutations in the mutL homolog 1 (MLH1) gene are frequent in patients with hereditary non‑polyposis colorectal cancer (CRC). The MLH1 gene was screened for mutations in patients with sporadic CRC. The nucleotide sequences for all 19 exons of MLH1 were analyzed by high resolution melting and sequenced in a group of 104 sporadic CRC patients, and the results were verified in a replication group of 1,095 patients and 1,469 controls. Different melting profiles for exon 2 of the MLH1 gene were observed in the germline DNA of one patient. Sequencing of the patient's DNA resulted in the identification of a heterozygous C>G variant at c.204, which resulted in an Ile68Met change in the amino acid. A detailed search of the National Center for Biotechnology Information and the 1000 Genomes databases indicated that the detected variant was unique. According to the SIFT and PolyPhen‑2 algorithms, the substitution of Ile to Met was predicted to decrease the activity of the MLH1 protein. The newly identified, functional germline variant was not present in any other CRC patient or control. Thus, a novel germline variant in the MLH1 gene was identified, representing a rare event in sporadic CRC. The occurrence and relevance of this mutation in other types of cancer requires additional investigation.

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1	Pritchard CC and Grady WM: Colorectal cancer molecular biology moves into clinical practice. Gut. 60:116–129. 2011. View Article : Google Scholar
2	Cannavo E, Gerrits B, Marra G, Schlapbach R and Jiricny J: Characterization of the interactome of the human MutL homologues MLH1, PMS1, and PMS2. J Biol Chem. 282:2976–2986. 2007. View Article : Google Scholar
3	Nystrom-Lahti M, Wu Y, Moisio AL, et al: DNA mismatch repair gene mutations in 55 kindreds with verified or putative hereditary non-polyposis colorectal cancer. Hum Mol Genet. 5:763–769. 1996. View Article : Google Scholar : PubMed/NCBI
4	Bianchi F, Raponi M, Piva F, et al: An intronic mutation in MLH1 associated with familial colon and breast cancer. Fam Cancer. 10:27–35. 2011. View Article : Google Scholar :
5	Kolodner RD, Tytell JD, Schmeits JL, et al: Germ-line msh6 mutations in colorectal cancer families. Cancer Res. 59:5068–5074. 1999.PubMed/NCBI
6	Naccarati A, Pardini B, Stefano L, et al: Polymorphisms in miRNA-binding sites of nucleotide excision repair genes and colorectal cancer risk. Carcinogenesis. 33:1346–1351. 2012. View Article : Google Scholar : PubMed/NCBI
7	Pardini B, Rosa F, Barone E, et al: Variation within 3′-UTRs of base excision repair genes and response to therapy in colorectal cancer patients: A potential modulation of microRNAs binding. Clin Cancer Res. 19:6044–6056. 2013. View Article : Google Scholar : PubMed/NCBI
8	Rouleau E, Lefol C, Bourdon V, et al: Quantitative PCR high-resolution melting (qPCR-HRM) curve analysis, a new approach to simultaneously screen point mutations and large rearrangements: application to MLH1 germline mutations in Lynch syndrome. Hum Mutat. 30:867–875. 2009. View Article : Google Scholar : PubMed/NCBI
9	Ng PC and Henikoff S: SIFT: Predicting amino acid changes that affect protein function. Nucleic Acids Res. 31:3812–3814. 2003. View Article : Google Scholar : PubMed/NCBI
10	annergard P, Lipford JR, Kolodner R, Frodin JE, Nordenskjold M and Lindblom A: Mutation screening in the hMLH1 gene in Swedish hereditary nonpolyposis colon cancer families. Cancer Res. 55:6092–6096. 1995.
11	Ellison AR, Lofing J and Bitter GA: Human MutL homolog (MLH1) function in DNA mismatch repair: a prospective screen for missense mutations in the ATPase domain. Nucleic Acid Res. 32:5321–5338. 2004. View Article : Google Scholar : PubMed/NCBI
12	Boland CR and Goel A: Microsatellite instability in colorectal cancer. Gastroenterology. 138:2073–2087 e2073. PubMed/NCBI
13	Kantartzis A, Williams GM, Balakrishnan L, Roberts RL, Surtees JA and Bambara RA: Msh2–Msh3 interferes with Okazaki fragment processing to promote trinucleotide repeat expansions. Cell Rep. 2:216–222. 2012. View Article : Google Scholar : PubMed/NCBI

Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

A novel c. 204 Ile68Met germline variant in exon 2 of the mutL homolog 1 gene in a colorectal cancer patient

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