Amplification of CDK4 and MDM2 in malignant melanoma

Amplification of the 12q13–15 region is a common event in several human tumors including liposarcomas, gliomas, and osteosarcomas. We have demonstrated high‐level amplification of 12q14 in a subset of uncultured malignant melanomas (3 of 53). High‐resolution mapping of the amplicon using quantitative PCR revealed a bipartite amplicon consisting of a primary 50‐kb amplicon centered on CDK4 and a secondary amplicon centered on MDM2, without amplification of the intervening 11 Mb of genomic DNA. Analysis of mRNA and protein levels in melanomas with 12q14 amplification demonstrated overexpression of target genes CDK4 and MDM2 without loss of CDKN2A‐P16 (P16INK4A) or CDKN2A‐P14ARF (P14ARF) expression, important regulators of the RB1 and TP53 pathways, which are commonly lost or mutated in melanoma. These results suggest that coamplification of CDK4 and MDM2 may substitute for loss of P16INK4A and P14ARF function in a subset of melanomas. © 2006 Wiley‐Liss, Inc.

[1]  S. Knuutila,et al.  CDK4 is a probable target gene in a novel amplicon at 12q13.3–q14.1 in lung cancer , 2005, Genes, chromosomes & cancer.

[2]  J. Coindre,et al.  Evaluation of MDM2 and CDK4 amplification by real‐time PCR on paraffin wax‐embedded material: a potential tool for the diagnosis of atypical lipomatous tumours/well‐differentiated liposarcomas , 2004, The Journal of pathology.

[3]  A. Jemal,et al.  Cancer Statistics, 2004 , 2004, CA: a cancer journal for clinicians.

[4]  Daniel Pinkel,et al.  Classifying melanocytic tumors based on DNA copy number changes. , 2003, The American journal of pathology.

[5]  L. Chin,et al.  Both products of the mouse Ink4a/Arf locus suppress melanoma formation in vivo , 2003, Oncogene.

[6]  L. Chin.  The genetics of malignant melanoma: lessons from mouse and man , 2003, Nature Reviews Cancer.

[7]  N. Hayward.  Genetics of melanoma predisposition , 2003, Oncogene.

[8]  L. Chin,et al.  Components of the Rb pathway are critical targets of UV mutagenesis in a murine melanoma model , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[9]  H. Taubert,et al.  Alternative and aberrant splicing of MDM2 mRNA in human cancer. , 2002, Cancer cell.

[10]  H. Moch,et al.  Amplification pattern of 12q13-q15 genes (MDM2, CDK4, GLI) in urinary bladder cancer , 2002, Oncogene.

[11]  K. Hemminki,et al.  Genetic status of cell cycle regulators in squamous cell carcinoma of the oesophagus: the CDKN2A (p16(INK4a) and p14(ARF) ) and p53 genes are major targets for inactivation. , 2002, Carcinogenesis.

[12]  F. Speleman,et al.  Quantification of MYCN, DDX1, and NAG Gene Copy Number in Neuroblastoma Using a Real-Time Quantitative PCR Assay , 2002, Modern Pathology.

[13]  M. Barbacid,et al.  Invasive melanoma in Cdk4-targeted mice , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[14]  C. Cordon-Cardo,et al.  HDM2 protein overexpression, but not gene amplification, is related to tumorigenesis of cutaneous melanoma. , 2001, Cancer research.

[15]  V. P. Collins,et al.  Alterations of the tumor suppressor genes CDKN2A (p16(INK4a)), p14(ARF), CDKN2B (p15(INK4b)), and CDKN2C (p18(INK4c)) in atypical and anaplastic meningiomas. , 2001, The American journal of pathology.

[16]  L. Chin,et al.  Dual Inactivation of RB and p53 Pathways in RAS-Induced Melanomas , 2001, Molecular and Cellular Biology.

[17]  W. Gerald,et al.  Inactivation of the apoptosis effector Apaf-1 in malignant melanoma , 2001, Nature.

[18]  T. Godfrey,et al.  Gene amplifications characterize acral melanoma and permit the detection of occult tumor cells in the surrounding skin. , 2000, Cancer research.

[19]  P. Meltzer,et al.  Separate amplified regions encompassing CDK4 and MDM2 in human sarcomas , 1996, Genes, chromosomes & cancer.

[20]  P. Meltzer,et al.  Refined mapping of 12q13-q15 amplicons in human malignant gliomas suggests CDK4/SAS and MDM2 as independent amplification targets. , 1996, Cancer research.

[21]  V. Collins.  Gene amplification in human gliomas , 1995, Glia.

[22]  A. Look,et al.  Coamplification of the CDK4 gene with MDM2 and GLI in human sarcomas. , 1993, Cancer research.