Differential alterations of the genes in the CDKN2A-CCND1-CDK4-RB1 pathway are associated with the development of head and neck squamous cell carcinoma in Indian patients
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The aim of this study was to analyse the alterations of the genes in the CDKN2A/CCND1/CDK4/RB1 pathway in the G1-S phase of the cell cycle during development of head and neck squamous cell carcinoma (HNSCC).
The alterations of these genes were analysed in 22 dysplastic lesions, 26 stage-I/II and 33 stage-III/IV HNSCC tumours of Indian patients.
The alterations [mutation, hypermethylation, homozygous deletion and loss of heterozygosity/microsatellite size alteration (LOH/MA)] in the CDKN2A were found to be highest in 57% of the samples, followed by CCND1 amplification and LOH/MA at the RB1 locus in 14% and 8.5% of the samples, respectively. No dominant CDK4 Arg24Cys mutation was seen in our samples. Comparatively high frequency of CDKN2A alterations (except homozygous deletion) was found in dysplastic head and neck lesions and remained almost constant or increased during progression of the tumour, whereas the homozygous deletion of CDKN2A and the alterations in CCND1 and RB1 genes were seen mainly in the later stages of the tumour.
Our study suggested that mutation/hypermethylation/allelic alterations (LOH/MA) of CDKN2A were associated with the development of dysplastic head and neck lesions. All the other alterations might provide some cumulative effect during progression of later stages of the tumour to have selective growth advantages.
KeywordsHead and neck squamous cell carcinoma CDKN2A-CCND1-CDK4-RB1 Mutation Hypermethylation Homozygous deletion Loss of heterozygosity Microsatellite size alteration
We are grateful to the Director of Chittaranjan National Cancer Institute (CNCI), Calcutta, Dr. S. Gupta, Director of the Cancer Centre and Welfare Home, Calcutta, and Drs. E. Zabarovsky, A Dam and S Mondal for their active support during this work. Financial support for this work was provided by grant no. BT/MB/05/002/94 from the Department of Biotechnology of the Government of India.
- Kannan K, Munirajan AK, Krishnamurthy J, Bhuvarahamurthy V, Mohanprasad BK, Panishankar KH, Tsuchida N, Sanmugam G (2000) The p16 INK4 alpha/p19ARF gene mutations are infrequent and are mutually exclusive to p53 mutations in Indian oral squamous cell carcinomas. Int J Oncol 16:585–590PubMedGoogle Scholar
- Kyomoto R, Kumazawa H, Toda Y, Sakaida N, Okamura A, Inawaga M, Shintaku M, Yamashita T, Hiai H, Fukumoto M (1997) Cyclin-D1-gene amplification is a more potent prognostic factor than its protein overexpression in human head-and-neck squamous-cell carcinoma. Int J Cancer 74:576–581Google Scholar
- Li X, Lee NK, Ye YW, Waber PG, Schweitzer C, Cheng QC, Nisen PD (1994) Allelic loss at chromosome 3p, 8p, 13q and 17p associated with poor prognosis in head and neck cancer. J. Natl. Cancer Inst 86:1524–1529Google Scholar
- Mao L, El-Naggar AK (1999) Molecular changes in the multistage pathogenesis of head and neck cancer. In: Srivastava S, et al. (eds) Molecular pathology of early cancer. IOS Press, pp 189–205Google Scholar
- Saranath D, Bhoite LT, Deo MG (1993) Molecular lesions in human oral cancer: the Indian scene. Oral Oncol 29B:107–112Google Scholar
- Zhang SY, Klein-Szanto AJP, Sauter ER, Safarenko M, Mitsunaga S, Nobori T, Carson DA, Ridge JA, Goodrow TL (1994) Higher frequency of alterations in the p16/CDKN2 gene in squamous cell carcinoma cell lines than in primary tumors of head and neck. Cancer Res 54:5050–5053Google Scholar