title: Impact of gene dosage on gene expression, biological processes and survival in cervical cancer: a genome-wide follow-up study.
abstract: We investigated the role of tumor copy number (CN)-altered genome (CN-AG) in the carcinogenesis of cervical cancer (CC), especially its effect on gene expression, biological processes, and patient survival. Fifty-nine human papillomavirus 16 (HPV16)-positive CCs were investigated with microarrays-31 for mapping CN-AG and 55 for global gene expression, with 27 CCs in common. Five-year survival was investigated in 55 patients. Deletions and amplifications >2.5 Mb were defined as CN alterations. The %CN-AG varied from 0 to 32.2% (mean = 8.1±8.9). Tumors were classified as low (mean = 0.5±0.6, n = 11), medium (mean = 5.4±2.4, n = 10), or high (mean = 19.2±6.6, n = 10) CN. The highest %CN-AG was found in 3q, which contributed an average of 55% of all CN alterations. Genome-wide, only 5.3% of CN-altered genes were deregulated directly by gene dosage. In contrast, the rate in fully duplicated 3q was twice as high. Amplification of 3q explained 23.2% of deregulated genes in whole tumors (r2 = 0.232, p = 0.006; analysis of variance), including genes located in 3q and other chromosomes. A total of 862 genes were deregulated exclusively in high-CN tumors, but only 22.9% were CN altered. This suggests that the remaining genes are not deregulated directly by gene dosage, but by mechanisms induced in trans by CN-altered genes. Anaphase-promoting complex/cyclosome (APC/C)-dependent proteasome proteolysis, glycolysis, and apoptosis were upregulated, whereas cell adhesion and angiogenesis were downregulated exclusively in high-CN tumors. The high %CN-AG and upregulated gene expression profile of APC/C-dependent proteasome proteolysis were associated with poor patient survival (p<0.05, log-rank test). Along with glycolysis, they were linearly associated with FIGO stage (r>0.38, p<0.01, Spearman test). Therefore, inhibition of APC/C-dependent proteasome proteolysis and glycolysis could be useful for CC treatment. However, whether they are indispensable for tumor growth remains to be demonstrated.
authors.affiliation: Unidad de Medicina Genómica, Facultad de Medicina, Universidad Nacional Autónoma de México/Hospital General de México, México, D.F. México.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Medina-Martinez
authors.affiliation: Unidad de Medicina Genómica, Facultad de Medicina, Universidad Nacional Autónoma de México/Hospital General de México, México, D.F. México.
authors.forename: Valeria
authors.initials: V
authors.lastname: Barrón
authors.affiliation: Servicio de Oncología, Hospital General de México, México, D.F. México.
authors.forename: Edgar
authors.initials: E
authors.lastname: Roman-Bassaure
authors.affiliation: Unidad de Medicina Genómica, Facultad de Medicina, Universidad Nacional Autónoma de México/Hospital General de México, México, D.F. México.
authors.forename: Eligia
authors.initials: E
authors.lastname: Juárez-Torres
authors.affiliation: Unidad de Medicina Genómica, Facultad de Medicina, Universidad Nacional Autónoma de México/Hospital General de México, México, D.F. México.
authors.forename: Mariano
authors.initials: M
authors.lastname: Guardado-Estrada
authors.affiliation: Unidad de Medicina Genómica, Facultad de Medicina, Universidad Nacional Autónoma de México/Hospital General de México, México, D.F. México.
authors.forename: Ana María
authors.initials: AM
authors.lastname: Espinosa
authors.affiliation: Unidad de Medicina Genómica, Facultad de Medicina, Universidad Nacional Autónoma de México/Hospital General de México, México, D.F. México.
authors.forename: Miriam
authors.initials: M
authors.lastname: Bermudez
authors.affiliation: Servicio de Genética, Hospital General de México/Facultad de Medicina, Universidad Nacional Autónoma de México, México, D.F. México.
authors.forename: Fernando
authors.initials: F
authors.lastname: Fernández
authors.affiliation: Servicio de Genética, Hospital General de México/Facultad de Medicina, Universidad Nacional Autónoma de México, México, D.F. México.
authors.forename: Carlos
authors.initials: C
authors.lastname: Venegas-Vega
authors.affiliation: Laboratorio de Genómica de Enfermedades Complejas, Instituto Nacional de Medicina Genómica. México, D.F. México.
authors.forename: Lorena
authors.initials: L
authors.lastname: Orozco
authors.affiliation: Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, México, D.F. México.
authors.forename: Edgar
authors.initials: E
authors.lastname: Zenteno
authors.affiliation: Servicio de Genética, Hospital General de México/Facultad de Medicina, Universidad Nacional Autónoma de México, México, D.F. México.
authors.forename: Susana
authors.initials: S
authors.lastname: Kofman
authors.affiliation: Unidad de Medicina Genómica, Facultad de Medicina, Universidad Nacional Autónoma de México/Hospital General de México, México, D.F. México; Departamento de Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, México, D.F. México.
authors.forename: Jaime
authors.initials: J
authors.lastname: Berumen
mesh_terms: D000328:Adult; D000368:Aged; D063646:Carcinogenesis / Q000235:genetics; D002877:Chromosomes, Human / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D018628:Gene Dosage; D020869:Gene Expression Profiling; D052138:Genes, Neoplasm / Q000235:genetics; D023281:Genomics; D052162:Human papillomavirus 16 / Q000502:physiology; D006801:Humans; D008875:Middle Aged; D016019:Survival Analysis; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000473:pathology / Q000821:virology; D055815:Young Adult