| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Department of Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021 [F. L., A. P. A.]; Departments of Pathology and Dermatology, New York Hospital-Cornell Medical Center, New York, New York 10021 [J. K. B., J. A. R., C. R. S.]; Department of Oncology, Massachusetts General Hospital, Cambridge, Massachusetts 02139 [F. G. H.]; Departments of Biochemistry and Molecular Biology, University of Southern California School of Medicine and Institute for Genetic Medicine, Los Angeles, California 90033 [J. F. F., J. W. F., J. M. G., M. J. S., G. J. W.]; and Queensland Institute of Medical Research, Brisbane, Australia 4029 [G. J. W.]
Sporadic and familial malignant melanoma susceptibility has been linked to defects in the chromosomal region 9p21. Recently, a putative 9p21 tumor suppressor gene, the cyclin dependent kinase inhibitor 2 (CDKN2) or p16 gene, has been shown to be deleted, mutated, or rear-ranged in a high percentage of sporadic melanoma cell lines, as well as mutated in the germline of a proportion of familial melanoma patients. CDKN2 encodes a Mr 16,000 protein (p16) that plays a key role in cell cycle control by binding to the cyclin-dependent kinase 4 enzyme and inhibiting its ability to phosphorylate critical substrates necessary for transition past the G1 phase of the cell cycle. Thus, mutations or deletions of the CDKN2 gene could result in abnormal proliferation via defective cell cycle control. The correlation of 9p21 cytogenetic and molecular alterations with the clinical stages of melanoma progression suggests that dysfunction of a gene within this chromosomal region is critical to the evolution of melanoma. However, it remains unclear whether this gene is the CDKN2 gene. If so, then loss of p16 is potentially an initiating or early event in melanoma progression. To address the issues of what is the potential involvement of the CDKN2 gene in sporadic melanoma and precisely when during the clinically evident stages of melanoma progression defects in CDKN2 occur, we have evaluated by immunohistochemistry the expression of p16 protein in 103 melanocytic lesions representing all stages in the progression of melanoma. Our results suggest that loss of p16 protein expression is (a) not necessary for tumor initiation in malignant melanoma because all melanomas in situ and the majority of primary invasive melanomas retain expression of this protein; and (b) potentially more related to invasiveness or the ability to metastasize, because 52% of primary invasive tumors and 72% of metastatic lesions show partial or complete loss of expression of p16.
1 This work was supported in part by the Cancer Research fund of the Damon Runyon-Walter Winchell Foundation (F. G. H.), the Donald E. and Delia B. Baxter Foundation (J. W. F.), and a S. J. Martin fellowship from the National Health Medical Research Council of Australia (G.J.W.).
2 To whom requests for reprints should be addressed, at Memorial Sloan-Kettering Cancer Center, Box 167, 1275 York Avenue, New York, NY 10021.
Received 2/16/95. Accepted 5/19/95.
This article has been cited by other articles:
|
|
 |
|
  V. G. Prieto, A. A. Mourad-Zeidan, V. Melnikova, M. M. Johnson, A. Lopez, A. H. Diwan, A. J.F. Lazar, S. S. Shen, P. S. Zhang, J. A. Reed, et al. Galectin-3 Expression Is Associated with Tumor Progression and Pattern of Sun Exposure in Melanoma. Clin. Cancer Res., November 15, 2006; 12(22): 6709 - 6715. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Grafstrom, S. Egyhazi, U. Ringborg, J. Hansson, and A. Platz Biallelic Deletions in INK4 in Cutaneous Melanoma Are Common and Associated with Decreased Survival Clin. Cancer Res., April 15, 2005; 11(8): 2991 - 2997. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Ghosh, N. Nadiminty, J. E. Fitzpatrick, W. L. Alworth, T. J. Slaga, and A. P. Kumar Eugenol Causes Melanoma Growth Suppression through Inhibition of E2F1 Transcriptional Activity J. Biol. Chem., February 18, 2005; 280(7): 5812 - 5819. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Hoek, D. L. Rimm, K. R. Williams, H. Zhao, S. Ariyan, A. Lin, H. M. Kluger, A. J. Berger, E. Cheng, E. S. Trombetta, et al. Expression Profiling Reveals Novel Pathways in the Transformation of Melanocytes to Melanomas Cancer Res., August 1, 2004; 64(15): 5270 - 5282. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. Garcia, B. Martinez-Delgado, A. Cebrian, A. Martinez, J. Benitez, and C. Rivas Different Incidence and Pattern of p15INK4b and p16INK4a Promoter Region Hypermethylation in Hodgkin's and CD30-Positive Non-Hodgkin's Lymphomas Am. J. Pathol., September 1, 2002; 161(3): 1007 - 1013. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. R. A.-E. Hussein and G. S. Wood Molecular Aspects of Melanocytic Dysplastic Nevi J. Mol. Diagn., May 1, 2002; 4(2): 71 - 80. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Gessner, U. Liebers, H. Kuhn, P. Stiehl, C. Witt, J. Schauer, and G. Wolff BAX and p16INK4A are independent positive prognostic markers for advanced tumour stage of nonsmall cell lung cancer Eur. Respir. J., January 1, 2002; 19(1): 134 - 140. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Polsky, A. Z. Young, K. J. Busam, and R. M. Alani The Transcriptional Repressor of p16/Ink4a, Id1, Is Up-Regulated in Early Melanomas Cancer Res., August 1, 2001; 61(16): 6008 - 6011. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Sturm, H. Petrowsky, R. Volz, M. Lorenz, S. Radetzki, T. Hillebrand, G. Wolff, S. Hauptmann, B. Dorken, and P. T. Daniel Analysis of p53/BAX/p16ink4a/CDKN2 in Esophageal Squamous Cell Carcinoma: High BAX and p16ink4a/CDKN2 Identifies Patients With Good Prognosis J. Clin. Oncol., April 15, 2001; 19(8): 2272 - 2281. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.S. Chim, R. Liang, C.Y.Y. Tam, and Y.L. Kwong Methylation of p15 and p16 Genes in Acute Promyelocytic Leukemia: Potential Diagnostic and Prognostic Significance J. Clin. Oncol., April 1, 2001; 19(7): 2033 - 2040. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Serrano, S. U. Goebel, P. L. Peghini, I. A. Lubensky, F. Gibril, and R. T. Jensen Alterations in the p16INK4a/CDKN2A Tumor Suppressor Gene in Gastrinomas J. Clin. Endocrinol. Metab., November 1, 2000; 85(11): 4146 - 4156. [Abstract] [Full Text]
|
|
|
|
 |
|
 F. Mouriaux, C.-A. Maurage, P. Labalette, B. Sablonnière, F. Malecaze, and J.-M. Darbon Cyclin-Dependent Kinase Inhibitory Protein Expression in Human Choroidal Melanoma Tumors Invest. Ophthalmol. Vis. Sci., September 1, 2000; 41(10): 2837 - 2843. [Abstract] [Full Text]
|
|
|
|
|
|
A. R. Cachia, J. O. Indsto, K. M. McLaren, G. J. Mann, and M. J. Arends CDKN2A Mutation and Deletion Status in Thin and Thick Primary Melanoma Clin. Cancer Res., September 1, 2000; 6(9): 3511 - 3515. [Abstract] [Full Text]
|
|
|
|
|
|
I. H. N. Wong, Y. M. Dennis Lo, W. Yeo, W. Y. Lau, and P. J. Johnson Frequent p15 Promoter Methylation in Tumor and Peripheral Blood from Hepatocellular Carcinoma Patients Clin. Cancer Res., September 1, 2000; 6(9): 3516 - 3521. [Abstract] [Full Text]
|
|
|
|
|
|
R. Hui, R. D. Macmillan, F. S. Kenny, E. A. Musgrove, R. W. Blamey, R. I. Nicholson, J. F. R. Robertson, and R. L. Sutherland INK4a Gene Expression and Methylation in Primary Breast Cancer: Overexpression of p16INK4a Messenger RNA Is a Marker of Poor Prognosis Clin. Cancer Res., July 1, 2000; 6(7): 2777 - 2787. [Abstract] [Full Text]
|
|
|
|
|
|
O. Straume, L. Sviland, and L. A. Akslen Loss of Nuclear p16 Protein Expression Correlates with Increased Tumor Cell Proliferation (Ki-67) and Poor Prognosis in Patients with Vertical Growth Phase Melanoma Clin. Cancer Res., May 1, 2000; 6(5): 1845 - 1853. [Abstract] [Full Text]
|
|
|
|
|
|
M. Omura-Minamisawa, M. B. Diccianni, A. Batova, R. C. Chang, L. J. Bridgeman, J. Yu, J. Pullen, W. P. Bowman, and A. L. Yu Universal Inactivation of Both p16 and p15 but not Downstream Components Is an Essential Event in the Pathogenesis of T-Cell Acute Lymphoblastic Leukemia Clin. Cancer Res., April 1, 2000; 6(4): 1219 - 1228. [Abstract] [Full Text]
|
|
|
|
 |
|
 I. H. N. Wong, M. H. L. Ng, D. P. Huang, and J. C. K. Lee Aberrant p15 promoter methylation in adult and childhood acute leukemias of nearly all morphologic subtypes: potential prognostic implications Blood, March 15, 2000; 95(6): 1942 - 1949. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Papp, H. Pemsel, R. Zimmermann, R. Bastrop, D. G Weiss, and D. Schiffmann Mutational analysis of the N-ras, p53, p16INK4a, CDK4, and MC1R genes in human congenital melanocytic naevi J. Med. Genet., August 1, 1999; 36(8): 610 - 614. [Abstract] [Full Text]
|
|
|
|
|
|
R. V. Lloyd, L. A. Erickson, L. Jin, E. Kulig, X. Qian, J. C. Cheville, and B. W. Scheithauer p27kip1: A Multifunctional Cyclin-Dependent Kinase Inhibitor with Prognostic Significance in Human Cancers Am. J. Pathol., February 1, 1999; 154(2): 313 - 323. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Villuendas, M. Sanchez-Beato, J. C. Martinez, A. I. Saez, B. Martinez-Delgado, J. F. Garcia, M. S. Mateo, L. Sanchez-Verde, J. Benitez, P. Martinez, et al. Loss of p16/INK4A Protein Expression in Non-Hodgkin's Lymphomas Is a Frequent Finding Associated with Tumor Progression Am. J. Pathol., September 1, 1998; 153(3): 887 - 897. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Pinyol, F. Cobo, S. Bea, P. Jares, I. Nayach, P. L. Fernandez, E. Montserrat, A. Cardesa, and E. Campo p16INK4a Gene Inactivation by Deletions, Mutations, and Hypermethylation Is Associated With Transformed and Aggressive Variants of Non-Hodgkin's Lymphomas Blood, April 15, 1998; 91(8): 2977 - 2984. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Lahti, H. Li, and V. J. Kidd Elimination of Cyclin D1 in Vertebrate Cells Leads to an Altered Cell Cycle Phenotype, Which Is Rescued by Overexpression of Murine Cyclins D1, D2, or D3 but Not by a Mutant Cyclin D1 J. Biol. Chem., April 18, 1997; 272(16): 10859 - 10869. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. S. Nairn, S. Kazianis, B. B. McEntire, L. Della Coletta, R. B. Walter, and D. C. Morizot A CDKN2-like polymorphism in Xiphophorus LG V is associated with UV-B-induced melanoma formation in platyfish-swordtail hybrids PNAS, November 12, 1996; 93(23): 13042 - 13047. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. Alani, A. Z. Young, and C. B. Shifflett Id1 regulation of cellular senescence through transcriptional repression of p16/Ink4a PNAS, July 3, 2001; 98(14): 7812 - 7816. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
