BACKGROUND: Adrenocortical carcinoma (ACC) is associated with poor survival rates. The objective of the study was to analyze ACC gene expression profiling data for prognostic biomarkers and therapeutic targets. METHODS: We profiled 44 ACC and 4 normal adrenals on Affymetrix U133 Plus 2 expression microarrays. Pathway and transcriptional enrichment analysis was performed. Protein levels were determined by Western blot. Drug efficacy was assessed against ACC cell lines. Previously published expression datasets were analyzed for validation. RESULTS: Pathway enrichment analysis identified marked dysregulation of cyclin-dependent kinases and mitosis. Overexpression of PTTG1, which encodes securin, a negative regulator of p53, was identified as a marker of poor survival. Median survival for patients with tumors expressing high PTTG1 levels (log2 ratio of PTTG1 to average β-actin <-3.04) was 1.8 years compared with 9.0 years if tumors expressed lower levels of PTTG1 (P < .0001). Analysis of a previously published dataset confirmed the association of high PTTG1 expression with a poor prognosis. Treatment of 2 ACC cell lines with vorinostat decreased securin levels and inhibited cell growth (median inhibition concentrations of 1.69 μmol/L and 0.891 μmol/L, for SW-13 and H295R, respectively). CONCLUSION: Overexpression of PTTG1 is correlated with poor survival in ACC. PTTG1/securin is a prognostic biomarker and warrants investigation as a therapeutic target.
BACKGROUND:Adrenocortical carcinoma (ACC) is associated with poor survival rates. The objective of the study was to analyze ACC gene expression profiling data for prognostic biomarkers and therapeutic targets. METHODS: We profiled 44 ACC and 4 normal adrenals on Affymetrix U133 Plus 2 expression microarrays. Pathway and transcriptional enrichment analysis was performed. Protein levels were determined by Western blot. Drug efficacy was assessed against ACC cell lines. Previously published expression datasets were analyzed for validation. RESULTS: Pathway enrichment analysis identified marked dysregulation of cyclin-dependent kinases and mitosis. Overexpression of PTTG1, which encodes securin, a negative regulator of p53, was identified as a marker of poor survival. Median survival for patients with tumors expressing high PTTG1 levels (log2 ratio of PTTG1 to average β-actin <-3.04) was 1.8 years compared with 9.0 years if tumors expressed lower levels of PTTG1 (P < .0001). Analysis of a previously published dataset confirmed the association of high PTTG1 expression with a poor prognosis. Treatment of 2 ACC cell lines with vorinostat decreased securin levels and inhibited cell growth (median inhibition concentrations of 1.69 μmol/L and 0.891 μmol/L, for SW-13 and H295R, respectively). CONCLUSION: Overexpression of PTTG1 is correlated with poor survival in ACC. PTTG1/securin is a prognostic biomarker and warrants investigation as a therapeutic target.
Authors: Martin Fassnacht; Massimo Terzolo; Bruno Allolio; Eric Baudin; Harm Haak; Alfredo Berruti; Staffan Welin; Carmen Schade-Brittinger; André Lacroix; Barbara Jarzab; Halfdan Sorbye; David J Torpy; Vinzenz Stepan; David E Schteingart; Wiebke Arlt; Matthias Kroiss; Sophie Leboulleux; Paola Sperone; Anders Sundin; Ilse Hermsen; Stefanie Hahner; Holger S Willenberg; Antoine Tabarin; Marcus Quinkler; Christelle de la Fouchardière; Martin Schlumberger; Franco Mantero; Dirk Weismann; Felix Beuschlein; Hans Gelderblom; Hanneke Wilmink; Monica Sender; Maureen Edgerly; Werner Kenn; Tito Fojo; Hans-Helge Müller; Britt Skogseid Journal: N Engl J Med Date: 2012-05-02 Impact factor: 91.245
Authors: Thomas J Giordano; Rork Kuick; Tobias Else; Paul G Gauger; Michelle Vinco; Juliane Bauersfeld; Donita Sanders; Dafydd G Thomas; Gerard Doherty; Gary Hammer Journal: Clin Cancer Res Date: 2009-01-15 Impact factor: 12.531
Authors: Juan A Bernal; Rosa Luna; Agueda Espina; Icíar Lázaro; Francisco Ramos-Morales; Francisco Romero; Carmen Arias; Augusto Silva; María Tortolero; José A Pintor-Toro Journal: Nat Genet Date: 2002-09-23 Impact factor: 38.330
Authors: Karl Y Bilimoria; Wen T Shen; Dina Elaraj; David J Bentrem; David J Winchester; Electron Kebebew; Cord Sturgeon Journal: Cancer Date: 2008-12-01 Impact factor: 6.860
Authors: Katja Kiseljak-Vassiliades; Yu Zhang; Adwitiya Kar; Raud Razzaghi; Mei Xu; Katherine Gowan; Christopher D Raeburn; Maria Albuja-Cruz; Kenneth L Jones; Hilary Somerset; Lauren Fishbein; Stephen Leong; Margaret E Wierman Journal: Endocrinology Date: 2018-07-01 Impact factor: 4.736
Authors: N Gurvits; H Repo; E Löyttyniemi; M Nykänen; J Anttinen; T Kuopio; K Talvinen; P Kronqvist Journal: Cell Oncol (Dordr) Date: 2016-03-16 Impact factor: 6.730
Authors: Ilkka Heikkinen; Alhadi Almangush; Jaana Hagström; Ibrahim O Bello; Joonas H Kauppila; Laura K Mäkinen; Caj Haglund; Pentti Nieminen; Tuula Salo; Ilmo Leivo Journal: Eur Arch Otorhinolaryngol Date: 2016-04-18 Impact factor: 2.503