Abstract
Alterations in the cyclin-dependent kinase (CDK)-retinoblastoma (RB) machinery disrupt cell-cycle regulation and are being targeted in drug development. To understand the cancer types impacted by this pathway, we analyzed frequency of abnormalities in key cell-cycle genes across 4,864 tumors using next-generation sequencing (182 or 236 genes; Clinical Laboratory Improvement Amendments laboratory). Aberrations in the cell-cycle pathway were identified in 39% of cancers, making this pathway one of the most commonly altered in cancer. The frequency of aberrations was as follows: CDKN2A/B (20.1% of all patients), RB1 (7.6%), CCND1 (6.1%), CCNE1 (3.6%), CDK4 (3.2%), CCND3 (1.8%), CCND2 (1.7%), and CDK6 (1.7%). Rates and types of aberrant cell-cycle pathway genes differed between cancer types and within histologies. Analysis of coexisting and mutually exclusive genetic aberrations showed that CCND1, CCND2, and CCND3 aberrations were all positively associated with CDK6 aberrations [OR and P values, multivariate analysis: CCND1 and CDK6 (OR = 3.5; P < 0.0001), CCND2 and CDK6 (OR = 4.3; P = 0.003), CCND3 and CDK6 (OR = 3.6; P = 0.007)]. In contrast, RB1 alterations were negatively associated with multiple gene anomalies in the cell-cycle pathway, including CCND1 (OR = 0.25; P = 0.003), CKD4 (OR = 0.10; P = 0.001), and CDKN2A/B (OR = 0.21; P < 0.0001). In conclusion, aberrations in the cell-cycle pathway were very common in diverse cancers (39% of 4,864 neoplasms). The frequencies and types of alterations differed between and within tumor types and will be informative for drug development strategies. Mol Cancer Ther; 15(7); 1682-90. ©2016 AACR.
Highlights
The cyclin D–cyclin-dependent kinase (CDK)–retinoblastoma (RB) pathway is a key gatekeeper for the G1 phase of the cell cycle
The G1 phase is controlled by the cyclin D and CDK4/6 complex, leading to phosphorylation of the RB protein and subsequent E2F-mediated transcription of target genes that are required for G1 cell-cycle progression [4–6]
Patients We investigated the CCND1/2/3, CDK4/6, CCNE1, CDKN2A/B, and RB1 aberration status of patients with diverse malignancies that were referred for NGS from December 2011 to November 2013 (N 1⁄4 4,864; Table 1 and Supplementary Tables S1 and S2)
Summary
The cyclin D–cyclin-dependent kinase (CDK)–retinoblastoma (RB) pathway is a key gatekeeper for the G1 phase of the cell cycle. Aberrations in the cell-cycle pathway have been implicated in human cancer that leads to tumor proliferation, chromosomal instability, and attenuation of genomic integrity [1–3]. The RB tumor suppressor protein is crucial in regulating the G1 phase. The G1 phase is controlled by the cyclin D and CDK4/6 complex, leading to phosphorylation of the RB protein and subsequent E2F-mediated transcription of target genes that are required for G1 cell-cycle progression [4–6]. Recent literature suggests that the cyclin D1 and CDK4/6 complex adds just one phosphate group to the RB Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).
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