Deletion at 6q24.2–26 predicts longer survival of high-grade serous epithelial ovarian cancer patients

• Published in: Molecular oncology Vol. 9; no. 2; pp. 422 - 436
• Main Authors: Kamieniak, Marta M., Rico, Daniel, Milne, Roger L., Muñoz-Repeto, Ivan, Ibáñez, Kristina, Grillo, Miguel A., Domingo, Samuel, Borrego, Salud, Cazorla, Alicia, García-Bueno, José M., Hernando, Susana, García-Donas, Jesús, Hernández-Agudo, Elena, y Cajal, Teresa Ramón, Robles-Díaz, Luis, Márquez-Rodas, Ivan, Cusidó, Maite, Sáez, Raquel, Lacambra-Calvet, Carmen, Osorio, Ana, Urioste, Miguel, Cigudosa, Juan C., Paz-Ares, Luis, Palacios, José, Benítez, Javier, García, María J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier B.V 01-02-2015; John Wiley & Sons, Inc; John Wiley and Sons Inc
• Subjects: 6q24.2–26 deletion; Breast cancer; CGH; Chromosome Deletion; Chromosomes, Human, Pair 6 - genetics; Copy number; Deoxyribonucleic acid; Disease-Free Survival; DNA; Female; Fluorescence in situ hybridization; Gene expression; Genomes; HGSOC; Humans; Medical prognosis; Medical research; Mutation; Ovarian cancer; Ovarian carcinoma; Ovarian Neoplasms - genetics; Ovarian Neoplasms - mortality; Ovarian Neoplasms - pathology; Ovarian Neoplasms - therapy; Paraffin; Prognosis; Quality of life; Studies; Survival; Survival Rate; Tumors; HGSOC; Prognosis; CGH; Survival; 6q24.2–26 deletion
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1016/j.molonc.2014.09.010

Standard treatments for advanced high-grade serous ovarian carcinomas (HGSOCs) show significant side-effects and provide only short-term survival benefits due to disease recurrence. Thus, identification of novel prognostic and predictive biomarkers is urgently needed. We have used 42 paraffin-embedded HGSOCs, to evaluate the utility of DNA copy number alterations, as potential predictors of clinical outcome. Copy number-based unsupervised clustering stratified HGSOCs into two clusters of different immunohistopathological features and survival outcome (HR = 0.15, 95%CI = 0.03–0.81; Padj = 0.03). We found that loss at 6q24.2–26 was significantly associated with the cluster of longer survival independently from other confounding factors (HR = 0.06, 95%CI = 0.01–0.43, Padj = 0.005). The prognostic value of this deletion was validated in two independent series, one consisting of 36 HGSOCs analyzed by fluorescent in situ hybridization (P = 0.04) and another comprised of 411 HGSOCs from the Cancer Genome Atlas study (TCGA) (HR = 0.67, 95%CI = 0.48–0.93, Padj = 0.019). In addition, we confirmed the association of low expression of the genes from the region with longer survival in 799 HGSOCs (HR = 0.74, 95%CI = 0.61–0.90, log-rank P = 0.002) and 675 high-FIGO stage HGSOCs (HR = 0.76, 95%CI = 0.61–0.96, log-rank P = 0.02) available from the online tool KM-plotter. Finally, by integrating copy number, RNAseq and survival data of 296 HGSOCs from TCGA we propose a few candidate genes that can potentially explain the association. Altogether our findings indicate that the 6q24.2–26 deletion is an independent marker of favorable outcome in HGSOCs with potential clinical value as it can be analyzed by FISH on tumor sections and guide the selection of patients towards more conservative therapeutic strategies in order to reduce side-effects and improve quality of life.
•DNA copy number-based clustering stratifies HGSOCs into groups of different outcome.•Deletion at 6q24.2-26 predicts longer survival of HGSOC patients.•Prognostic value of the 6q24.2–26 deletion is independent of known factors.•Validation in independent series confirmed prognostic utility of the 6q24.2–26 loss.•A combination of lost genes within 6q24.2–26 region may explain the association.