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High Frequency of p16 (CDKN2/MTS-1/INK4A) Inactivation in Head and Neck Squamous Cell Carcinoma^{1, 2,}

Department of Otolaryngology-Head and Neck Surgery, Head and Neck Cancer Research Division [A. L. R., J. C., P. C., R. M. J., W. K., Y. E., D. Se., H. N., D. Si.], Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2196; Departments of Pathology [W. H. W.] and General Surgery [S. A.], Johns Hopkins Hospital, Baltimore, Maryland 21287; and Danish Cancer Society, Division for Cancer Biology, Strandboulevarden 49, opg. Bygn. 4, DK-2100 Copenhagen Ø. Denmark, [J. B.]

The tumor suppressor gene p16 (CDKN2/MTS-1/INK4A) can be inactivated by multiple genetic mechanisms. We analyzed 29 invasive primary head and neck squamous cell carcinomas (HNSCC) for p16 inactivation with immunohistochemistry utilizing a new monoclonal antibody (mAb), DCS-50. p16 staining of the primary lesions was correlated with genetic analysis including: (a) detailed microsatellite analysis of markers at the p16 locus to detect homozygous deletion; (b) sequence analysis of p16; and (c) Southern blot analysis to determine the methylation status of the 5' CpG island of p16. Twenty-four of 29 (83%) head and neck squamous cell carcinoma tumors displayed an absence of p16 nuclear staining using immunohistochemistry. Of these 24 tumors, we found that 16 (67%) harbored homozygous deletions, 5 (21%) were methylated, 1 displayed a rearrangement at the p16 locus, and 1 displayed a frameshift mutation in exon 1. These data suggest that: (a) inactivation of the p16 tumor suppressor gene is a frequent event in squamous cell carcinomas of the head and neck; (b) p16 is inactivated by several distinct and exclusive events including homozygous deletion, point mutation, and promoter methylation; and (c) immunohistochemical analysis for expression of the p16 gene product is an accurate and relatively simple method for evaluating p16 gene inactivation.

¹ Supported by Lung Spore Grant CA-58184-01 and a Collaborative Research Agreement with Oncor, Inc. (Gaithersburg. MD).

² Oncor, Inc. provided research funding for the study described in this article. Under an agreement between Oncor and The Johns Hopkins University, Dr. Sidransky is entitled to a share of sales royalty received by the University from Oncor. Under that agreement, the University and Dr. Sidransky also have received Oncor stock which, under University policy, cannot be traded until 2 years after the first commercial sales of the products related to this research. Dr. Sidransky also serves as a member of the Scientific Advisory Board of OncorMed, Inc., an Oncor subsidiary, which is commercializing some of Oncor's technology. The terms of this arrangement have been reviewed and approved by the University in accordance with its conflict of interest policies.

³ To whom requests for reprints should be addressed, at Head/Neck Surgery, Johns Hopkins University School of Medicine, 818 Ross Research Building, 720 Rutland Avenue, Baltimore, MD 21205-2196.

Received 5/ 7/96. Accepted 6/28/96.

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				S. J. Kuerbitz, J. Malandro, N. Compitello, S. B. Baylin, and J. R. Graff Deletion of p16INK4A/CDKN2 and p15INK4B in Human Somatic Cell Hybrids and Hybrid-derived Tumors Cell Growth Differ., January 1, 1999; 10(1): 27 - 33. [Abstract] [Full Text]

				T. Sano, T. Oyama, K. Kashiwabara, T. Fukuda, and T. Nakajima Expression Status of p16 Protein Is Associated with Human Papillomavirus Oncogenic Potential in Cervical and Genital Lesions Am. J. Pathol., December 1, 1998; 153(6): 1741 - 1748. [Abstract] [Full Text] [PDF]

				K. S.J. Elenitoba-Johnson, R. D. Gascoyne, M. S. Lim, M. Chhanabai, E. S. Jaffe, and M. Raffeld Homozygous Deletions at Chromosome 9p21 Involving p16 and p15 Are Associated With Histologic Progression in Follicle Center Lymphoma Blood, June 15, 1998; 91(12): 4677 - 4685. [Abstract] [Full Text] [PDF]

				S. A. Foster, D. J. Wong, M. T. Barrett, and D. A. Galloway Inactivation of p16 in Human Mammary Epithelial Cells by CpG Island Methylation Mol. Cell. Biol., April 1, 1998; 18(4): 1793 - 1801. [Abstract] [Full Text]

				B. Harvat, A Wang, P Seth, and A. Jetten Up-regulation of p27Kip1, p21WAF1/Cip1 and p16Ink4a is associated with, but not sufficient for, induction of squamous differentiation J. Cell Sci., January 5, 1998; 111(9): 1185 - 1196. [Abstract] [PDF]

				M. Urashima, J. A. DeCaprio, D. Chauhan, G. Teoh, A. Ogata, S. P. Treon, Y. Hoshi, and K. C. Anderson p16INK4A Promotes Differentiation and Inhibits Apoptosis of JKB Acute Lymphoblastic Leukemia Cells Blood, November 15, 1997; 90(10): 4106 - 4115. [Abstract] [Full Text] [PDF]

				J. D. Rawnsley, E. S. Srivatsan, R. Chakrabarti, K. R. Billings, and M. B. Wang Deletion Analysis of the p16/CDKN2 Gene in Head and Neck Squamous Cell Carcinoma Using Quantitative Polymerase Chain Reaction Method Arch Otolaryngol Head Neck Surg, August 1, 1997; 123(8): 863 - 867. [Abstract] [PDF]

				B. J. Nickoloff, V. Chaturvedi, P. Bacon, J.-Z. Qin, M. F. Denning, and M. O. Diaz Id-1 Delays Senescence but Does Not Immortalize Keratinocytes J. Biol. Chem., September 1, 2000; 275(36): 27501 - 27504. [Abstract] [Full Text] [PDF]