title: Deletion at 6q24.2-26 predicts longer survival of high-grade serous epithelial ovarian cancer patients.
abstract: 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.
authors.affiliation: Human Genetics Group, Spanish National Cancer Research Center (CNIO), C/ Melchor Fernández Almagro 3, 28029, Madrid, Spain.
authors.forename: Marta M
authors.initials: MM
authors.lastname: Kamieniak
authors.affiliation: Structural Computational Biology Group, Spanish National Cancer Research Center (CNIO), C/ Melchor Fernández Almagro 3 28029, Madrid, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Rico
authors.affiliation: Cancer Epidemiology Centre, Cancer Council Victoria, 615 St Kilda Road, Melbourne 3004, Australia; Center for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Level 3, 207 Bouverie Street Carlton, Melbourne 3010, Victoria, Australia.
authors.forename: Roger L
authors.initials: RL
authors.lastname: Milne
authors.affiliation: Human Genetics Group, Spanish National Cancer Research Center (CNIO), C/ Melchor Fernández Almagro 3, 28029, Madrid, Spain.
authors.forename: Ivan
authors.initials: I
authors.lastname: Muñoz-Repeto
authors.affiliation: Structural Computational Biology Group, Spanish National Cancer Research Center (CNIO), C/ Melchor Fernández Almagro 3 28029, Madrid, Spain.
authors.forename: Kristina
authors.initials: K
authors.lastname: Ibáñez
authors.affiliation: Molecular Cytogenetics Group, Spanish National Cancer Research Center (CNIO), C/ Melchor Fernández Almagro 3, 28029 Madrid, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Grillo
authors.affiliation: Human Genetics Group, Spanish National Cancer Research Center (CNIO), C/ Melchor Fernández Almagro 3, 28029, Madrid, Spain.
authors.forename: Samuel
authors.initials: S
authors.lastname: Domingo
authors.affiliation: Departments of Genetics, Reproduction, and Fetal Medicine, IBIS, University Hospital Virgen del Rocio/CSIC/University of Seville, Avda. Manuel Siurot, s/n., 41013 Sevilla, Spain; Biomedical Network Research Centre on Rare Diseases (CIBERER), Spain.
authors.forename: Salud
authors.initials: S
authors.lastname: Borrego
authors.affiliation: Pathology Department, Fundación Jiménez Díaz, Avda. Reyes Católicos, 2, 28040 Madrid, Spain.
authors.forename: Alicia
authors.initials: A
authors.lastname: Cazorla
authors.affiliation: Oncology Department, Hospital General de Albacete, Calle Hermanos Falco, 37, 02006 Albacete, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: García-Bueno
authors.affiliation: Oncology Department, Fundación Hospital Alcorcón, Calle Valdelaguna, 1, 28922 Alcorcón, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Hernando
authors.affiliation: Medical Oncology Service, Oncologic Center Clara Campal, Calle Oña, 10, 28050 Madrid, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: García-Donas
authors.affiliation: Breast Cancer Clinical Research Unit, Spanish National Cancer Research Center (CNIO), C/ Melchor Fernández Almagro 3, 28029 Madrid, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Hernández-Agudo
authors.affiliation: Medical Oncology Service, Hospital Sant Pau, Carrer de Sant Quintí, 89, 08026 Barcelona, Spain.
authors.forename: Teresa Ramón
authors.initials: TR
authors.lastname: Y Cajal
authors.affiliation: Familial Cancer Unit and Medical Oncology Department, Hospital 12 de Octubre, Avda de Córdoba, s/n, 28041 Madrid, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Robles-Díaz
authors.affiliation: Medical Oncology Service, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, Calle Doctor Esquerdo, 46, 28007 Madrid, Spain.
authors.forename: Ivan
authors.initials: I
authors.lastname: Márquez-Rodas
authors.affiliation: Obstetrics and Gynecology Department, Institut Universitari Dexeus, Carrer de Sabino Arana, 5, 08028 Barcelona, Spain.
authors.forename: Maite
authors.initials: M
authors.lastname: Cusidó
authors.affiliation: Laboratory of Genetics, Hospital Donostia, Calle Doctor Begiristain, 117, 20080 San Sebastián, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Sáez
authors.affiliation: Department of Internal Medicine, Hospital Severo Ochoa, Avd. de Orellana, s/n., 28911 Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Lacambra-Calvet
authors.affiliation: Human Genetics Group, Spanish National Cancer Research Center (CNIO), C/ Melchor Fernández Almagro 3, 28029, Madrid, Spain; Biomedical Network Research Centre on Rare Diseases (CIBERER), Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Osorio
authors.affiliation: Familial Cancer Clinical Unit, Spanish National Cancer Research Center (CNIO), C/ Melchor Fernández Almagro 3, 28029 Madrid, Spain; Biomedical Network Research Centre on Rare Diseases (CIBERER), Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Urioste
authors.affiliation: Molecular Cytogenetics Group, Spanish National Cancer Research Center (CNIO), C/ Melchor Fernández Almagro 3, 28029 Madrid, Spain; Biomedical Network Research Centre on Rare Diseases (CIBERER), Spain.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Cigudosa
authors.affiliation: Medical Oncology Department, University Hospital Virgen del Rocio, Avda. Manuel Siurot s/n., 41013 Sevilla, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Paz-Ares
authors.affiliation: Pathology Department, Hospital Universitario Ramón y Cajal, Ctra. de Colmenar Viejo, km. 9,100, 28034 Madrid, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Palacios
authors.affiliation: Human Genetics Group, Spanish National Cancer Research Center (CNIO), C/ Melchor Fernández Almagro 3, 28029, Madrid, Spain; Biomedical Network Research Centre on Rare Diseases (CIBERER), Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Benítez
authors.affiliation: Human Genetics Group, Spanish National Cancer Research Center (CNIO), C/ Melchor Fernández Almagro 3, 28029, Madrid, Spain; Biomedical Network Research Centre on Rare Diseases (CIBERER), Spain. Electronic address: mjgarcia@cnio.es.
authors.forename: María J
authors.initials: MJ
authors.lastname: García
mesh_terms: D002872:Chromosome Deletion; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology* / Q000628:therapy; D015996:Survival Rate
keywords: 6q24.2–26 deletion; CGH; HGSOC; Prognosis; Survival