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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

2014; Wiley; Volume: 27; Issue: 4 Linguagem: Inglês

10.1111/pcmr.12228

1755-148X

Richard J. Young, Kelly Waldeck, Claire Martin, Jung H. Foo, Donald P. Cameron, Laura Kirby, Hongdo Do, Catherine Mitchell, Carleen Cullinane, Wendy Liu, Stephen B. Fox, Ken Dutton‐Regester, Nicholas K. Hayward, Nicholas Jene, Alexander Dobrovic, Richard B. Pearson, James G. Christensen, Sophia Randolph, Grant A. McArthur, Karen E. Sheppard,

Chromatin Remodeling and Cancer

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.