Impact of Gene Dosage on Gene Expression, Biological Processes and Survival in Cervical Cancer: A Genome-Wide Follow-Up Study: e97842

• Published in: PloS one Vol. 9; no. 5
• Main Authors: Medina-Martinez, Ingrid, Barron, Valeria, Roman-Bassaure, Edgar, Juarez-Torres, Eligia, Guardado-Estrada, Mariano, Espinosa, Ana Maria, Bermudez, Miriam, Fernandez, Fernando, Venegas-Vega, Carlos, Orozco, Lorena
• Format: Journal Article
• Language: English
• Published: 01.05.2014
• Subjects: Human papillomavirus 16
• ISSN: 1932-6203
• DOI: 10.1371/journal.pone.0097842

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 plus or minus 8.9). Tumors were classified as low (mean = 0.5 plus or minus 0.6, n = 11), medium (mean = 5.4 plus or minus 2.4, n = 10), or high (mean = 19.2 plus or minus 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.