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PLoS One. 2014 May 30;9(5):e97842. doi: 10.1371/journal.pone.0097842. eCollection 2014.

Impact of gene dosage on gene expression, biological processes and survival in cervical cancer: a genome-wide follow-up study.

Author information

1
Unidad de Medicina Genómica, Facultad de Medicina, Universidad Nacional Autónoma de México/Hospital General de México, México, D.F. México.
2
Servicio de Oncología, Hospital General de México, México, D.F. México.
3
Servicio de Genética, Hospital General de México/Facultad de Medicina, Universidad Nacional Autónoma de México, México, D.F. México.
4
Laboratorio de Genómica de Enfermedades Complejas, Instituto Nacional de Medicina Genómica. México, D.F. México.
5
Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, México, D.F. México.
6
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.

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.

PMID:
24879114
PMCID:
PMC4039463
DOI:
10.1371/journal.pone.0097842
[Indexed for MEDLINE]
Free PMC Article

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