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

Maria Schwaederlé,Razelle Kurzrock,Kelly A Shimabukuro,Paul T Fanta,Gregory A Daniels,Richard B Schwab,David E Piccioni,Barbara A Parker

doi:10.18632/oncotarget.2848

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.

Highlights

Cyclins are key regulatory components of the cyclin/ CDK (Cyclin-Dependent Kinase) complex that regulate the cell cycle, contributing to tumor progression
While cyclin D interacts with CDK4/6, cyclin E interacts with CDK2 to form complexes that play a central role in the G1/S transition of the cell cycle
This complex formed by cyclins and CDKs act by phosphorylating Rb [1, 2], which releases E2F from the complex, allowing it to activate cell cycle progression, Figure 1

Summary

Introduction

Cyclins are key regulatory components of the cyclin/ CDK (Cyclin-Dependent Kinase) complex that regulate the cell cycle, contributing to tumor progression. While cyclin D interacts with CDK4/6, cyclin E interacts with CDK2 to form complexes that play a central role in the G1/S transition of the cell cycle. This complex formed by cyclins and CDKs act by phosphorylating Rb [1, 2], which releases E2F from the complex, allowing it to activate cell cycle progression, Figure 1. PRAD1 was found to be clonally rearranged on chromosome 11q13 with PTH (parathyroid hormone) in parathyroid adenomas, resulting in overexpression of cyclin D1 [3,4,5]. In mantle cell lymphomas, BCL-1 (B-Cell lymphoma-1) is rearranged and juxtaposes BCL-1 and the immunoglobulin heavy chain IGH (t(11;14)(q13;q32)) resulting in overexpression of the BCL-1 (CCND1) protein [6, 7]

Methods

Results

Conclusion