Fax: (011) 91-033-473 0284
Inactivation of human mutL homolog 1 and mutS homolog 2 genes in head and neck squamous cell carcinoma tumors and leukoplakia samples by promoter hypermethylation and its relation with microsatellite instability phenotype
Article first published online: 11 JAN 2007
Copyright © 2006 American Cancer Society
Volume 109, Issue 4, pages 703–712, 15 February 2007
How to Cite
Sengupta, S., Chakrabarti, S., Roy, A., Panda, C. K. and Roychoudhury, S. (2007), Inactivation of human mutL homolog 1 and mutS homolog 2 genes in head and neck squamous cell carcinoma tumors and leukoplakia samples by promoter hypermethylation and its relation with microsatellite instability phenotype. Cancer, 109: 703–712. doi: 10.1002/cncr.22430
- Issue published online: 2 FEB 2007
- Article first published online: 11 JAN 2007
- Manuscript Accepted: 7 NOV 2006
- Manuscript Revised: 6 NOV 2006
- Manuscript Received: 22 SEP 2006
- Department of Biotechnology. Grant Number: BT/PR/5524/Med/14/649/2004
- Council of Scientific & Industrial Research (CSIR). Grant Numbers: CMM 0016, CMM 0003
- DST. Grant Number: SR/SO/BB22/2003
- promoter hypermethylation;
- microsatellite instability;
- head and neck squamous cell carcinoma
A subset of head and neck squamous cell carcinoma (HNSCC) exhibits a microsatellite instability (MIN) phenotype. The authors correlated alterations in the mismatch-repair genes human mutL homolog 1 (hMLH1) and human mutS homolog 2 (hMSH2) in primary head and neck squamous cell carcinoma (HNSCC) tumors and in samples of leukoplakia with the MIN phenotype.
One hundred twenty-three paired HNSCC normal and tumor tissues and 27 leukoplakia samples were examined for hypermethylation of hMLH1 and hMSH2 promoters. The hypermethylation status of the tissues was confirmed by expression studies. Sixty-three of 123 randomly selected tumors and all 27 leukplakia samples were genotyped with 8 microsatellite markers to determine MIN.
Fifty percent of HNSCC tumors and 63% of leukoplakia samples harbored hypermethylation at either or both hMLH1 and hMSH2 promoters. Normal tissues adjacent to methylation-positive tumors also demonstrated hypermethylation of both promoters at a high frequency (25%). A positive correlation between tobacco habit and promoter hypermethylation was observed (P = .001). A correlation was observed between MIN and the frequency of promoter hypermethylation in the leukoplakia samples, but no such trend was observed in the HNSCC tumors. It is noteworthy that patients who had a high frequency of MIN-positive tumors exhibited hypermethylation in both the affected tissues and the adjacent normal tissues (P = .007). Patients with a tobacco habit who had promoter hypermethylation at both the affected tissues and the adjacent normal tissues had tumors that mostly were MIN positive (P = .047).
The current results suggested that tobacco-addicted individuals are more susceptible to promoter hypermethylation of hMLH1 and hMSH2 and that, if such hypermethylation occurs in the normal squamous epithelium of the head and neck region, then those tissues are likely to develop into tumors that involve the MIN pathway. Cancer 2007;109:703–12. © 2007 American Cancer Society.