Cyclin alterations in diverse cancers: Outcome and co-amplification network

Abstract

Cyclin genes are key regulatory components of the cell cycle. With the development of new agents, cyclin-related genes are becoming increasingly important as they can be targeted. Yet, the biological implications of these alterations have not been fully studied. Clinical characteristics and outcome parameters were compared for patients harboring cyclin alterations versus not. CCN alterations were found in 13% of our population (50/392; all amplifications) and were associated with breast cancer (P < 0.0001), a higher median number of concomitant molecular alterations (P < 0.0001), and liver metastases (P = 0.046). Harboring a cyclin amplification was not associated with overall survival, the time to metastasis/recurrence, nor with the best progression-free survival. In a Cox regression model, gastrointestinal histology (P < 0.0001), PTEN (P < 0.0001), and CDK alterations (P = 0.041) had a significant association with poorer overall survival. CCN amplifications significantly correlated with alterations in FGF/FGFR family genes as well as in MET and ARFRP1. An extended correlation study shed light on a network of co-amplifications influenced in part by genes that were localized on the same amplicons. CCN amplifications are common across cancers and had distinctive biological associations. Customized combinations targeting the cyclin pathway as well as the extended co- amplification network may be necessary in order to address resistance mechanisms.

Figure 1. Effects of cyclins on cell cycle

By interacting with CDKs, cyclins form complexes (cyclin D with CDK4/6 and cyclin E with CDK2) that phosphorylate Rb1 (phosphorylated Rb1 is inactive). The Rb protein is a tumor suppressor that plays a pivotal role in the negative control of the cell cycle; Rb1 loss of function is frequently observed in cancer [48]. When Rb1 is phosphorylated, E2F is released and can transcriptionally activate its target genes, enabling the G1/S transition of cell cycle. Cyclin D1 (CCND1) can also be regulated at the transcription level by the RAS-MEK-ERK pathway and at the translation level by mTOR via S6K and 4EBP1 [11, 12, 16, 17]. mTOR inhibitors may attenuate CCND1 action by decreasing translation of CCND1. CDK4/6 inhibitors may attenuate the effects of this pathway as well, especially in the presence of CDK4/6 amplification or CDKN2A/B loss (since CDKN2A/B inhibits CDK4/6 activity). Patients with Rb1 loss or mutations would be expected to be resistant to agents such as mTOR or CDK4/6 inhibitors that act more proximally.

Figure 2. CCN and co-alterations

In panel A, the connectors represent a statistically significant association in a multiple logistic regression model (P < 0.05). The double orange connectors represent a correlation with a P-value < 0.0001; in that case, there was chromosomal co-localization (panel B). Cyclin genes were CCND1, CCND2, CCND3, and CCNE1; FGF/FGFR gene family comprised FGF3/4/6/10/14/19/23 and FGFR1/2/3/4; ERBB comprised ERBB2/3/4; ZNF comprised ZNF217 and ZNF703. In panel B, chromosome co-localizations are represented by the same color. Boxes contain genes that are related family members.