SPOC1, a novel PHD-finger protein: Association with residual disease and survival in ovarian cancer Gerrit Mohrmann 1–3 , Jan G. Hengstler 4 * , Thomas G. Hofmann 3 , Sabine U. Endele 1,2 , Brendan Lee 5 , Christiane Stelzer 6 , Bernhard Zabel 6 , Juergen Brieger 7 , Dirk Hasenclever 8 , Berno Tanner 9 , Jens Sagemueller 4 , Jalid Sehouli 10 , Hans Will 3 and Andreas Winterpacht 1,2 ** 1 Institute of Human Genetics, University of Erlangen-Nuremberg, Erlangen, Germany 2 Institute of Human Genetics, University of Hamburg, Hamburg, Germany 3 Heinrich-Pette-Institute for Experimental Virology and Immunology, University of Hamburg, Hamburg 4 Center for Toxicology, Institute of Legal Medicine and Rudolf-Boehm-Institute of Pharmacology and Toxicology, University of Leipzig, Leipzig 5 Department of Molecular and Human Genetics and Howard Hughes Medical Institute, Baylor College of Medicine, Houston TX, USA 6 Children’s Hospital, University of Mainz, Mainz, Germany 7 Department of Otorhinolaryngology, School of Medicine, University Hospital, Mainz, Germany 8 Institute of Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany 9 Department of Gynecology, University of Mainz, Mainz, Germany 10 Department of Obstetrics and Gynecology, Charite, Berlin, Germany We report the identification of a novel human gene (SPOC1) which encodes a protein with a PHD-finger domain. The gene is located in chromosomal region 1p36.23, a region implicated in tumor development and progression. RNA in situ hybridization experi- ments showed strong SPOC1 expression in some rapidly prolifer- ating cell types, such as spermatogonia, but not in nonpro- liferating mature spermatocytes. In addition, high SPOC1 mRNA expression was observed in several ovarian cancer cell lines. This prompted us to systematically examine SPOC1 expression in ovar- ian cancer in relation to prognosis. SPOC1 mRNA expression was quantified in tumor tissue of 103 patients with epithelial ovarian cancer. Interestingly, SPOC1 was associated with residual disease, whereby patients with unresectable tumors showed higher levels compared to patients without residual tumor tissue after surgery ( p = 0.029). The univariable proportional hazards model showed an association between SPOC1 expression and survival ( p = 0.043, relative risk = 1.535). Median survival time was 1,596 days for patients with low SPOC1 expression vs. only 347 days for patients with high expression, using Kaplan-Meier analysis. However, SPOC1 was not associated with survival when multivariable anal- ysis was adjusted for residual disease. This can be explained by the correlation between residual disease and SPOC1 expression. In conclusion, SPOC1 is a novel PHD-finger protein showing strong expression in spermatogonia and ovarian cancer cells. SPOC1 overexpression was associated with unresectable carcino- mas and shorter survival in ovarian cancer. ' 2005 Wiley-Liss, Inc. Key words: ovarian cancer; PHD finger; survival time; transcription Ovarian cancer is the leading cause of death from gynecologic malignancy and the fifth leading cause of cancer death among women. From a histologic point of view, cancer of the ovary can be broadly characterized as epithelial, germ cell or stromal in ori- gin. EOC, which arises as a result of genetic alterations sustained by the ovarian surface epithelium, 1 is the most common form, accounting for > 90% of all ovarian cancers. Unfortunately, due to the fact that often there are no early symptoms, two-thirds of patients are diagnosed at an advanced stage (FIGO III or IV). Sur- vival rate is < 20% despite aggressive surgery and chemother- apy. 2–3 In addition, many patients have only a partial response to postoperative chemotherapy and/or will develop chemotherapy resistance. 4 Together, these factors result in a poor prognosis for ovarian cancer patients. Therefore, prognostic factors which may be used to identify groups of patients in whom more specific bio- logic treatments or more aggressive therapy is indicated are of great medical importance. 5,6 Current routinely used markers are mainly based on clinicopathologic criteria, like FIGO stage, histo- logic subtype, histologic grade, factors associated with tumor dis- semination and volume of residual disease following cytoreductive surgery. 2 In addition, a series of new factors have been proposed to have prognostic significance; 7–11 however, the clinical significance of these markers is still debatable, and none is routinely used to select therapy for patients with ovarian cancer. 9,12 Little is known about the molecular etiology of ovarian cancer. In any case, it is widely accepted that the pathway leading to for- mation of a tumor is a multistep process involving the accumula- tion of genetic alterations in several oncogenes and tumor- suppressor genes, and only a few of these have been studied in some detail in ovarian cancer. Studies using CGH have revealed several regions of recurrent, abnormal DNA sequence copy num- ber that may encode genes involved in the genesis or progression of the disease. 13 Mutations or copy number changes have been identified in a number of genes, including BRCA1, TP53, RB1, OPCML, PIK3CA, HER2-neu and EEF1A2. 14–21 In this study, we identified a novel human PHD-finger gene (SPOC1). The PHD or LAP domain is a short sequence motif of approximately 50–80 amino acids, characterized by a unique Cys 4 -His-Cys 3 pattern that is found in >400 eukaryotic pro- teins. 22,23 Many of these proteins represent transcription factors which are involved in chromatin-mediated transcriptional regula- tion via chromatin remodeling or histone acetylation 22,24–28 and in tumor development, like head-and-neck squamous cell carcino- *Correspondence to: Center for Toxicology, Institute of Legal Medi- cine and Rudolf-Boehm-Institute of Pharmacology and Toxicology, University of Leipzig, D-04107 Leipzig, Germany. Fax: þ49-341-9724609. E-mail: jan.hengstler@mail.uni-leipzig.de **Correspondence to: Institut fu ¨r Humangenetik, Friedrich-Alexander- Universita ¨t Erlangen-Nu ¨rnberg, Schwabachanlage 10, D-91054 Erlangen, Germany. Fax: þ49-9131-209297. E-mail: winterp@humgenet.uni-erlangen.de Received 10 June 2004; Accepted after revision 15 November 2004 DOI 10.1002/ijc.20912 Published online 11 April 2005 in Wiley InterScience (www.interscience. wiley.com). Abbreviations: BMBF, Federal Ministry of Education and Research; CGH, comparative genomic hybridization; CI, confidence interval; DEPC, diethylpyrocarbonate; DIG, digoxigenin; EOC, epithelial ovarian cancer; EST, expressed sequence tag; GAPDH, glyceraldehyde-3-phosphate dehy- drogenase; huPO, human phosphoprotein; LAP, leukemia-associated pro- tein; OD, optical density; PHD, plant homeodomain; RR, relative risk; SPOC, survival time–associated PHD protein in ovarian cancer. Grant sponsor: German BMBF; Grant sponsor: Deutsche Forschungsge- meinschaft; Grant numbers: HO 2438/2-1, WI664/6-2; Grant sponsor: Deutsche Krebshilfe; Grant number: Wi2-10-1624; Grant sponsor: Hep- Net; Grant number: 01KI0102; Grant sponsor: Stiftung fu ¨r Neurovirale Erkrankungen. Int. J. Cancer: 116, 547–554 (2005) ' 2005 Wiley-Liss, Inc. Publication of the International Union Against Cancer