Skip to main content
SpringerLink
Log in

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

  • Original Paper
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

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).

Methods

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.

Results

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.

Conclusions

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2A–E.
Fig. 3.

Similar content being viewed by others

References

  • Callender T, El-Naggar AK, Lee MS, Frankenthaler R, Luna MA, Batsakis JG (1994) Prad-1 (CCND1)/Cyclin D1 oncogene amplification in primary head and neck squamous cell carcinoma. Cancer 74:152–158

    CAS  PubMed  Google Scholar 

  • Cerilli LA, Swartzbaugh JR, Saadut R, Marshall CE, Rumpel CA, Moskaluk CA Jr, Frierson H (1999) Analysis of chromosome 9p21 deletion and p16 mutation in salivary gland carcinomas. Hum Pathol 30:1242–1246

    CAS  PubMed  Google Scholar 

  • Dasgupta S, Mukherjee N, Roy S, Roy A, Sengupta A, Roychowdhury S, Panda CK (2002) Mapping of the candidate tumor suppressor genes' loci on human chromosome 3 in head and neck squamous cell carcinoma of Indian patient population. Oral Oncol 38:6–15

    Article  CAS  PubMed  Google Scholar 

  • Heyman M, Rasool O, Brandter LB, Liu Y, Grander D, Soderhall S, Gustavsson G, Einhorn S (1996) Prognostic importance of p15INK4B and p16INK4A gene inactivation in childhood acute lymphocytic leukemia. J Clin Oncol 14:1512–1520

    CAS  PubMed  Google Scholar 

  • 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 16:585–590

    CAS  PubMed  Google Scholar 

  • Klangby BU, Okan I, Magnusson KP, Wendland M, Lind P, Wiman KG (1998) P16/INK4a and p15/INK4b gene methylation and absence of p16/INK4a mRNA and protein expression in Burkitt's lymphoma. Blood 91:1680–1687

    CAS  PubMed  Google Scholar 

  • Knudson AG Jr (1995) Mutation and cancer: a personal odyssey. Adv Cancer Res 67:1–23

    CAS  PubMed  Google 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 74:576–581

    Google 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 86:1524–1529

    CAS  Google Scholar 

  • Liew CL, Li HM, Lo KW, Leow CK, Chan JY, Hin LY, Lau WY, Lai PBS, Lim BK, Huang J, Leung WT, Wu S, Lee JCK (1999) High frequency of p16INK4A gene alterations in hepatocellular carcinoma. Oncogene 18:789–795

    CAS  PubMed  Google Scholar 

  • Lin SC, Chang KW, Chang CS, Liu TY, Tzeng YS, Yang FS, Wong YK (2000) Alterations of p16/MTS1 gene in oral squamous cell carcinomas from Taiwanese. J Oral Pathol Med 29:159–166

    Article  CAS  PubMed  Google Scholar 

  • Lunderberg AS, Weinberg RA (1999) Control of the cell cycle and apoptosis. Eur J Cancer 35:531–539

    Article  PubMed  Google Scholar 

  • MacGrogan D, Levy A, Bostwick D, Wagner M, Wells D, Bookstein R (1994) Loss of chromosome arm 8p loci in prostate cancer: mapping by quantitative allelic imbalance. Genes Chromosomes Cancer 10:151–159

    CAS  PubMed  Google 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 189–205

  • Matsuda H, Konishi N, Hiasa Y, Hayashi Y, Tsuzuki T, Tao M, Kitahori Y, Yoshioka N, Kirita T, Sugimura M (1996) Alterations of p16/CDKN2, p53 and ras genes in oral squamous cell carcinoma and premalignant lesions. J Oral Pathol Med 25:232–238

    CAS  PubMed  Google Scholar 

  • Nagai MA (1999) Genetic alterations in head and neck squamous cell carcinomas. Braz J Med Biol Res 32:897–904

    CAS  PubMed  Google Scholar 

  • Nakahara Y, Shintani S, Mihara M, Ueyama Y, Matsumura T (2001) High frequency of homozygous deletion and methylation of p16(INK4A) gene in oral squamous cell carcinomas. Cancer Lett 163:221–228

    Article  CAS  PubMed  Google Scholar 

  • Papadimitrakopoulou V, Izzo J, Lippman SM, Lee JS, Fan YH, Clayman G, Ro JY, Hittelman WN, Lotan R, Hong WK, Mao L (1997) Frequent inactivation of p16INK4a in oral premalignant lesions. Oncogene 14:1799–1803

    Article  CAS  PubMed  Google Scholar 

  • Park JS, Dong SM, Kim HS, Lee JY, Um SJ, Park IS, Kim SJ, Namkoong SE (1999) Detection of p16 gene alteration in cervical cancer using tissue microdissection and LOH study. Cancer Lett 136:101–108

    Article  CAS  PubMed  Google Scholar 

  • Pollock PK, Pearson JV, Hayward NK (1996) Compilation of somatic mutations of the CDKN2 gene in human cancers: non-random distribution of base substitutions. Genes Chromosomes Cancer 15:77–88

    Article  CAS  PubMed  Google Scholar 

  • Saranath D, Bhoite LT, Deo MG (1993) Molecular lesions in human oral cancer: the Indian scene. Oral Oncol 29B:107–112

    CAS  Google Scholar 

  • Schuyer M, Staveren I, Klijn JGM, Burg MEL, Stoter G, Henzen-Logmans SC, Foekens JA, Berns EMJJ (1996) Sporadic CDKN2A gene alterations in human ovarian tumors. Br J Cancer 74:1069–1073

    CAS  PubMed  Google Scholar 

  • Shahnavaz SA, Bradley G, Regezi JA, Thakker N, Gao L, Hogg D, Jordan RC (2001) Patterns of CDKN2A gene loss in sequential oral epithelial dysplasias and carcinomas. Cancer Res 61:2371–2375

    CAS  PubMed  Google Scholar 

  • Shintani S, Nakahara Y, Mihara M, Ueyama Y, Matsumura T (2001) Inactivation of the p14(ARF), p15(INK4B) and p16(ink4a) genes is a frequent event in human oral squamous cell carcinomas. Oral Oncol 37:498–504

    Article  CAS  PubMed  Google Scholar 

  • Tsai CH, Yang CC, Chou LS, Chou MY (2001) The correlation between alteration of p16 gene and clinical status in oral squamous cell carcinoma. J Oral Pathol Med 30:527–531

    Article  CAS  PubMed  Google Scholar 

  • van der Riet P, Nawroz H, Hruban RH, Corio R, Tokino K, Koch W, Sidransky D (1994) Frequent loss of chromosome 9p21–22 early in head and neck cancer progression. Cancer Res 54:1156–1158

    PubMed  Google Scholar 

  • Wu CL, Roz L, Mckown S, Sloan P, Read AP, Holland S, Porter S, Scully C, Paterson I, Tavasoli M, Thakker N (1999) DNA studies underestimate the major role of CDKN2A inactivation in oral and oropharyngeal squamous cell carcinomas. Genes Chromosomes Cancer 25:16–25

    Article  CAS  PubMed  Google Scholar 

  • Yoo GH, Xu HJ, Brennan JA, Westra W, Hruban RH, Koch W, Benedict F, Sidransky D (1994) Infrequent inactivation of the retinoblastoma gene despite frequent loss of chromosome 13q in head and neck squamous cell carcinoma. Cancer Res 54:4603–4606

    CAS  PubMed  Google Scholar 

  • Zabarovsky ER, Lerman MI, Minna JD (2002) Tumor suppressor genes on chromosome 3p involved in the pathogenesis of lung and other cancers. Oncogene 21:6915–6935

    Article  CAS  PubMed  Google 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 54:5050–5053

    CAS  Google Scholar 

  • Zuo L, Weger J, Yang Q, Goldstein AM, Tucker MA, Waker GJ, Hayward N, Dracopoli NC (1996) Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma. Nat Genet 12:97–99

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

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.

Author information

Authors and Affiliations

  1. Department of Oncogene Regulation, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Calcutta 700026, India

    Anusri Tripathi (Bhar), Neelanjana Chunder & Chinmay Kumar Panda

  2. Department of Human Genetics and Genomics, Indian Institute of Chemical Biology, Calcutta 700032, India

    Soma Banerjee & Susanta Roychowdhury

  3. Department of Pathology, Bankura Sammilani Medical College, West Bengal, India

    Anup Roy

  4. Cancer Centre and Welfare Home, Calcutta 700063, India

    Arunava Sengupta

  5. Anthropology and Human Genetics unit, Indian Statistical Institute, Calcutta 700108, India

    Bidyut Roy

Authors
  1. Anusri Tripathi (Bhar)
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Soma Banerjee
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Neelanjana Chunder
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anup Roy
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Arunava Sengupta
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Bidyut Roy
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Susanta Roychowdhury
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Chinmay Kumar Panda
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chinmay Kumar Panda.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tripathi (Bhar), A., Banerjee, S., Chunder, N. et al. 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. J Cancer Res Clin Oncol 129, 642–650 (2003). https://doi.org/10.1007/s00432-003-0485-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-003-0485-z

Keywords

Search

Navigation