Loss of 9p leads to p16INK4A down‐regulation and enables RB/E2F1‐dependent cell cycle promotion in gastrointestinal stromal tumours (GISTs)

• DOI: 10.1002/path.2352
• Publication Date: 2008-03-18T13:21:38Z
• Authors: F Haller; C Löbke; M Ruschhaupt; S Cameron; H‐J Schulten; S Schwager; A von Heydebreck; B Gunawan; C Langer; G Ramadori; H Sültmann; A Poustka; U Korf; L Füzesi
• Keywords: Cyclin-dependent kinase 6; Cyclin E; Cyclin A; Cyclin D

Loss of chromosome 9p is a reliable predictor malignant behaviour in gastrointestinal stromal tumours (GISTs). p16INK4A located at 9p21 inhibits the CDK4/6/cyclin D complex from phosphorylating RB. Phosphorylation RB through early G(1) phase frees transcription factor E2F1 and enables mRNA genes essential for G(1)/S transition. This study aims to determine impact loss on protein expression further key cell cycle regulators different phases cycle. Sixty primary GISTs previously characterized by comparative genomic hybridization were analysed p16INK4A, p15INK4B, CDK4, CDK6, cyclin D, p21CIP1p27KIP1, CDK2, E, B, E2F1, using quantitative RT-PCR. The p21CIP1, p27KIP1 phosphorylated (S807/S811) was evaluated arrays as novel highly sensitive platform profiling abundance phosphorylation. In parallel, nuclear percentages immunohistochemical staining quantified tissue microarray. with had significantly higher proliferation rates, metastatic shorter disease-free survival. On molecular level, reduced well p16INK4A. more these tumours, together increased E2F1. Furthermore, up-regulation late G1/S promoters CDK2 E. We conclude that accompanied G1 inhibitor p16(INK4A) down-regulation facilitates phosphorylation RB, enabling E2F1-dependent provides possible basis accelerated particularly loss.