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Loss of CDKN 2A expression is a frequent event in primary invasive melanoma and correlates with sensitivity to the CDK 4/6 inhibitor PD 0332991 in melanoma cell lines
Author(s) -
Young Richard J.,
Waldeck Kelly,
Martin Claire,
Foo Jung H.,
Cameron Donald P.,
Kirby Laura,
Do Hongdo,
Mitchell Catherine,
Cullinane Carleen,
Liu Wendy,
Fox Stephen B.,
DuttonRegester Ken,
Hayward Nicholas K.,
Jene Nicholas,
Dobrovic Alexander,
Pearson Richard B.,
Christensen James G.,
Randolph Sophia,
McArthur Grant A.,
Sheppard Karen E.
Publication year - 2014
Publication title -
pigment cell and melanoma research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.618
H-Index - 105
eISSN - 1755-148X
pISSN - 1755-1471
DOI - 10.1111/pcmr.12228
Subject(s) - cyclin dependent kinase , melanoma , cdk inhibitor , cancer research , retinoblastoma protein , loss of heterozygosity , biology , cyclin d1 , microbiology and biotechnology , gene , cell cycle , genetics , allele
Summary We have investigated the potential for the p16‐cyclin D‐ CDK 4/6‐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 ( CNV s) in CDK 4, CCND 1, and CDKN 2A and immunohistochemistry to determine protein expression. CNV s were common in melanoma, with gain of CDK 4 or CCND 1 in 37 and 18% of cases, respectively, and hemizygous or homozygous loss of CDKN 2A in 56%. Three‐quarters of all patients demonstrated a CNV in at least one of the three genes. The combination of CCND 1 gain with either a gain of CDK 4 and/or loss of CDKN 2A was associated with poorer melanoma‐specific survival. In 47 melanoma cell lines homozygous loss, methylation or mutation of CDKN 2A gene or loss of protein (p16 INK 4A ) predicted sensitivity to the CDK 4/6 inhibitor PD 0332991, while RB 1 loss predicted resistance.