Angiogenesis-Related Gene Expression Profile with Independent Prognostic Value in Advanced Ovarian Carcinoma

PLOS ONE, Dec 2008

Background Ovarian carcinoma is the most important cause of gynecological cancer-related mortality in Western societies. Despite the improved median overall survival in patients receiving chemotherapy regimens such as paclitaxel and carboplatin combination, relapse still occurs in most advanced diseased patients. Increased angiogenesis is associated with rapid recurrence and decreased survival in ovarian cancer. This study was planned to identify an angiogenesis-related gene expression profile with prognostic value in advanced ovarian carcinoma patients. Methodology/Principal Findings RNAs were collected from formalin-fixed paraffin-embedded samples of 61 patients with III/IV FIGO stage ovarian cancer who underwent surgical cytoreduction and received a carboplatin plus paclitaxel regimen. Expression levels of 82 angiogenesis related genes were measured by quantitative real-time polymerase chain reaction using TaqMan low-density arrays. A 34-gene-profile which was able to predict the overall survival of ovarian carcinoma patients was identified. After a leave-one-out cross validation, the profile distinguished two groups of patients with different outcomes. Median overall survival and progression-free survival for the high risk group was 28.3 and 15.0 months, respectively, and was not reached by patients in the low risk group at the end of follow-up. Moreover, the profile maintained an independent prognostic value in the multivariate analysis. The hazard ratio for death was 2.3 (95% CI, 1.5 to 3.2; p<0.001). Conclusions/Significance It is possible to generate a prognostic model for advanced ovarian carcinoma based on angiogenesis-related genes using formalin-fixed paraffin-embedded samples. The present results are consistent with the increasing weight of angiogenesis genes in the prognosis of ovarian carcinoma.

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Angiogenesis-Related Gene Expression Profile with Independent Prognostic Value in Advanced Ovarian Carcinoma

et al. (2008) Angiogenesis-Related Gene Expression Profile with Independent Prognostic Value in Advanced Ovarian Carcinoma. PLoS ONE 3(12): e4051. doi:10.1371/journal.pone.0004051 Angiogenesis-Related Gene Expression Profile with Independent Prognostic Value in Advanced Ovarian Carcinoma Marta Mendiola 0 Jorge Barriuso 0 Andre s Redondo 0 Adria n Marin o-Enrquez 0 Rosario Madero 0 Enrique Espinosa 0 Juan A ngel Fresno Vara 0 Iker Sa nchez-Navarro 0 Gine s Herna ndez-Cortes 0 Pilar 0 Zamora 0 Elia Pe rez-Ferna ndez 0 Mara Miguel-Martn 0 Asuncio n Sua rez 0 Jose Palacios 0 Manuel Gonza lez-Baro n 0 David Hardisson 0 Syed A. Aziz, Health Canada, Canada 0 1 Department of Pathology, Hospital Universitario La Paz, Universidad Auto noma de Madrid , Madrid , Spain , 2 Translational Oncology Unit, Hospital Universitario La Paz, Universidad Auto noma de Madrid , Madrid , Spain , 3 Unit of Biostatistics, Hospital Universitario La Paz, Universidad Auto noma de Madrid , Madrid , Spain , 4 Fundacio n para la Investigaci o n Biome dica del Hospital Universitario La Paz (FIBHULP) , Madrid , Spain , 5 Department of Pathology, Hospital Universitario V rgen del Roc o , Sevilla , Spain Background: Ovarian carcinoma is the most important cause of gynecological cancer-related mortality in Western societies. Despite the improved median overall survival in patients receiving chemotherapy regimens such as paclitaxel and carboplatin combination, relapse still occurs in most advanced diseased patients. Increased angiogenesis is associated with rapid recurrence and decreased survival in ovarian cancer. This study was planned to identify an angiogenesis-related gene expression profile with prognostic value in advanced ovarian carcinoma patients. Methodology/Principal Findings: RNAs were collected from formalin-fixed paraffin-embedded samples of 61 patients with III/IV FIGO stage ovarian cancer who underwent surgical cytoreduction and received a carboplatin plus paclitaxel regimen. Expression levels of 82 angiogenesis related genes were measured by quantitative real-time polymerase chain reaction using TaqMan low-density arrays. A 34-gene-profile which was able to predict the overall survival of ovarian carcinoma patients was identified. After a leave-one-out cross validation, the profile distinguished two groups of patients with different outcomes. Median overall survival and progression-free survival for the high risk group was 28.3 and 15.0 months, respectively, and was not reached by patients in the low risk group at the end of follow-up. Moreover, the profile maintained an independent prognostic value in the multivariate analysis. The hazard ratio for death was 2.3 (95% CI, 1.5 to 3.2; p,0.001). Conclusions/Significance: It is possible to generate a prognostic model for advanced ovarian carcinoma based on angiogenesis-related genes using formalin-fixed paraffin-embedded samples. The present results are consistent with the increasing weight of angiogenesis genes in the prognosis of ovarian carcinoma. - Funding: Financial support was given by Fondo de Investigacio n Sanitaria, Instituto de Salud Carlos III, Ministerio de Sanidad y Consumo, Spain (FIS07/0651 to MM, JB, AR, GHC, and DH), CM05/00143 to JB, and CP05/00248 to JAFV); and Fundacio n de Investigacio n Medica Mutua Madrilen a (MM, JB, AR, AME, EE, JAFV, GHC, and DH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. . These authors contributed equally to this work. Ovarian carcinoma is the most important cause of gynecological cancer-related mortality in Western societies [1]. This is due to the fact that approximately 60% of cases are diagnosed at late stages of disease [2]. While patients with stage I disease have a 5 year overall survival of 90%, patients with stage IIIIV have less than 20% [3,4]. Despite the highly lethal nature of epithelial ovarian cancer, the clinical course of advanced disease is still difficult to predict in an individual patient. Usually, the management of ovarian cancer involves surgery in order to achieve surgical cytoreduction followed by chemotherapy [5]. Combination platinum-paclitaxel chemotherapy has become a standard first line treatment for the advanced-stage disease [6]. Outcome is significantly improved with this regimen, thus 60 to 70% of patients initially respond to platinum-based chemotherapy, and approximately 40 to 50% achieve complete clinical remission. However even in this last group, at least half of the patients experience a recurrence within 4 years [7]. Classical parameters such as age at diagnosis, extent of disease (as expressed as FIGO stage), residual disease after surgery, and the histopathological features of the tumor are important prognostic factors [5]. Nonetheless, these prognostic factors are imperfect predictors of outcome. This could be due, in (...truncated)


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Marta Mendiola, Jorge Barriuso, Andrés Redondo, Adrián Mariño-Enríquez, Rosario Madero, Enrique Espinosa, Juan Ángel Fresno Vara, Iker Sánchez-Navarro, Ginés Hernández-Cortes, Pilar Zamora, Elia Pérez-Fernández, María Miguel-Martín, Asunción Suárez, José Palacios, Manuel González-Barón, David Hardisson. Angiogenesis-Related Gene Expression Profile with Independent Prognostic Value in Advanced Ovarian Carcinoma, PLOS ONE, 2008, Volume 3, Issue 12, DOI: 10.1371/journal.pone.0004051