Reference Detail

Ref Type

Journal Article

PMID

(24495407)

Authors

Young RJ, Waldeck K, Martin C, Foo JH, Cameron DP, Kirby L, Do H, Mitchell C, Cullinane C, Liu W, Fox SB, Dutton-Regester K, Hayward NK, Jene N, Dobrovic A, Pearson RB, Christensen JG, Randolph S, McArthur GA, Sheppard KE

Title

Loss of CDKN2A expression is a frequent event in primary invasive melanoma and correlates with sensitivity to the CDK4/6 inhibitor PD0332991 in melanoma cell lines.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Pigment cell & melanoma research	27	4	2014 Jul	590-600	Pigment Cell Melanoma Res

URL

Abstract Text

We have investigated the potential for the p16-cyclin D-CDK4/6-retinoblastoma protein pathway to be exploited as a therapeutic target in melanoma. In a cohort of 143 patients with primary invasive melanoma, we used fluorescence in situ hybridization to detect gene copy number variations (CNVs) in CDK4, CCND1, and CDKN2A and immunohistochemistry to determine protein expression. CNVs were common in melanoma, with gain of CDK4 or CCND1 in 37 and 18% of cases, respectively, and hemizygous or homozygous loss of CDKN2A in 56%. Three-quarters of all patients demonstrated a CNV in at least one of the three genes. The combination of CCND1 gain with either a gain of CDK4 and/or loss of CDKN2A was associated with poorer melanoma-specific survival. In 47 melanoma cell lines homozygous loss, methylation or mutation of CDKN2A gene or loss of protein (p16(INK) (4A) ) predicted sensitivity to the CDK4/6 inhibitor PD0332991, while RB1 loss predicted resistance.

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Molecular Profile	Treatment Approach
CDKN2A E69*	CDK4/6 Inhibitor
CDKN2A V106fs	CDK4/6 Inhibitor
CDKN2A R80*	CDK4/6 Inhibitor
CDKN2A S56fs	CDK4/6 Inhibitor
CDKN2A Y44fs	CDK4/6 Inhibitor
CDKN2A S43fs	CDK4/6 Inhibitor
CDKN2A S43Ifs*76	CDK4/6 Inhibitor
CDKN2A A102fs	CDK4/6 Inhibitor
CDKN2A E33fs	CDK4/6 Inhibitor
CDKN2A C72fs	CDK4/6 Inhibitor
CDKN2A Q50fs	CDK4/6 Inhibitor
CDKN2A W15fs	CDK4/6 Inhibitor
CDKN2A P81fs	CDK4/6 Inhibitor
CDKN2A F90fs	CDK4/6 Inhibitor
CDKN2A Q50*	CDK4/6 Inhibitor
CDKN2A E120*	CDK4/6 Inhibitor
CDKN2A A68fs	CDK4/6 Inhibitor
CDKN2A A17fs	CDK4/6 Inhibitor
CDKN2A S12*	CDK4/6 Inhibitor
CDKN2A A60fs	CDK4/6 Inhibitor
CDKN2A R24fs	CDK4/6 Inhibitor
CDKN2A Y44Lfs*76	CDK4/6 Inhibitor
CDKN2A R58fs	CDK4/6 Inhibitor
CDKN2A W110*	CDK4/6 Inhibitor
CDKN2A Y44*	CDK4/6 Inhibitor
CDKN2A W15*	CDK4/6 Inhibitor
CDKN2A M52fs	CDK4/6 Inhibitor
CDKN2A W110fs	CDK4/6 Inhibitor
CDKN2A G23fs	CDK4/6 Inhibitor
CDKN2A E119*	CDK4/6 Inhibitor
CDKN2A T77fs	CDK4/6 Inhibitor
CDKN2A V82fs	CDK4/6 Inhibitor
CDKN2A C72*	CDK4/6 Inhibitor
CDKN2A R58*	CDK4/6 Inhibitor
CDKN2A L65fs	CDK4/6 Inhibitor
CDKN2A L78fs	CDK4/6 Inhibitor
CDKN2A del	CDK4/6 Inhibitor
CDKN2A A76fs	CDK4/6 Inhibitor
CDKN2A E88*	CDK4/6 Inhibitor
CDKN2A L16fs	CDK4/6 Inhibitor
CDKN2A T79fs	CDK4/6 Inhibitor
CDKN2A loss	CDK4/6 Inhibitor

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References