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

Medina-Martínez, Ingrid; Barrón, Valeria; Román-Bassaure, Edgar; Juárez-Torres, Eligia; Guardado-Estrada, Mariano; Espinosa, Ana; Bermúdez, Miriam; Fernández, Fernando; Venegas-Vega, Carlos; Orozco, Lorena; Zenteno, Edgar; Kofman, Susana; Berumen, Jaime

doi:10.1371/journal.pone.0097842

Cited by 42 publications

(42 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…A total of 25 unrelated Mexican male patients (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16) years old) with deficient I2S activity (n = 14), confirmed deficient I2S activity and genotype (n = 4), or only clinically suspected MPSII (n = 7), and their mothers (n = 24, Table 1) and other affected male (n = 1) and female (n = 16) relatives were included (Table S1, Supporting Information). A positive family history of MPSII was documented in 7 of 24 patients (28%; family history was unknown for a single case).…”

Section: Methodsmentioning

confidence: 99%

Wide allelic heterogeneity with predominance of large IDS gene complex rearrangements in a sample of Mexican patients with Hunter syndrome

et al. 2016

View full text Add to dashboard Cite

Hunter syndrome or mucopolysaccharidosis type II (MPSII) is caused by pathogenic variants in the IDS gene. This is the first study that examines the mutational spectrum in 25 unrelated Mexican MPSII families. The responsible genotype was identified in 96% of the families (24/25) with 10 novel pathogenic variants: c.133G>C, c.1003C>T, c.1025A>C, c.463_464delinsCCGTATAGCTGG, c.754_767del, c.1132_1133del, c.1463del, c.508-1G>C, c.1006+1G>T and c.(-217_103del). Extensive IDS gene deletions were identified in four patients; using DNA microarray analysis two patients showed the loss of the entire AFF2 gene, and epilepsy developed in only one of them. Wide allelic heterogeneity was noted, with large gene alterations (e.g. IDS/IDSP1 gene inversions, partial to extensive IDS deletions, and one chimeric IDS-IDSP1 allele) that occurred at higher frequencies than previously reported (36% vs 18.9-29%). The frequency of carrier mothers (80%) is consistent with previous descriptions (>70%). Carrier assignment allowed molecular prenatal diagnoses. Notably, somatic and germline mosaicism was identified in one family, and two patients presented thrombocytopenic purpura and pancytopenia after idursulfase enzyme replacement treatment. Our findings suggest a wide allelic heterogeneity in Mexican MPSII patients; DNA microarray analysis contributes to further delineation of the resulting phenotype for IDS and neighboring loci deletions.

show abstract

Section: Methodsmentioning

confidence: 99%

Wide allelic heterogeneity with predominance of large IDS gene complex rearrangements in a sample of Mexican patients with Hunter syndrome

et al. 2016

View full text Add to dashboard Cite

show abstract

“…The robustness of the prognostic signature for predicting survival in cervical cancer patients was evaluated in the validation cohorts GSE52903 and GSE39001 [19,20]. The differential expression levels of the corresponding genes were compared by Student's t-test.…”

Section: Validation Of the Robustness Of The Prognostic Signaturementioning

confidence: 99%

A Five-Genes-Based Prognostic Signature for Cervical Cancer Overall Survival Prediction

Zhao

Huang

Zou

et al. 2020

International Journal of Genomics

View full text Add to dashboard Cite

Aims. This study is aimed at identifying a prognostic signature for cervical cancer. Main Methods. The gene expression data and clinical information of cervical cancer and normal cervical tissues were acquired from The Cancer Genome Atlas and from three datasets of the Gene Expression Omnibus database. DESeq2 and Limma were employed to screen differentially expressed genes (DEGs). The overlapping DEGs among all datasets were considered the final DEGs. Then, the functional enrichment analysis was performed. Moreover, the Cox proportional hazards regression was performed to establish a prognostic signature of the DEGs. The Kaplan-Meier analysis was applied to test the model. Relationships between gene expression and clinicopathological parameters in cervical cancer, including age, HPV status, histology, stage, and lymph node metastasis, were analysed by the chi-square test. The somatic mutations of these prognostic genes were assessed through cBioPortal. The robustness of the model was verified in another two independent validation cohorts. Key Findings. In total, 169 overlapping upregulated genes and 29 overlapping downregulated genes were identified in cervical cancer compared with normal cervical tissues. Functional enrichment analysis indicated that the DEGs were mainly enriched in DNA replication, the cell cycle, and the p53 signalling pathway. Finally, a 5-gene- (ITM2A, DSG2, SPP1, EFNA1, and MMP1) based prognostic signature was built. According to this model, each patient was given a prognostic-related risk value. The Kaplan-Meier analysis showed that a higher risk was related to worse overall survival in cervical cancer, with an area under the receiver operating characteristic curve of 0.811 for 15 years. The validity of this model in the prediction of cervical cancer outcome was verified in another two independent datasets. In addition, our study also found that the low expression of ITM2A was associated with cervical adenocarcinoma. Interestingly, DSG2 was associated with the HPV status of cervical cancer. Significance. Our study constructed a prognostic model in cervical cancer and discovered two novel genes, ITM2A and DSG2, associated with cervical carcinogenesis and survival.

show abstract

“…Author details Tianjia Genomes Tech CO., LTD., Hefei, Anhui, China. 8 Department of Functional Discipline, School of medicine Jinhua, Jinhua, Zhejiang, China.…”

Section: Supplementary Informationmentioning

confidence: 99%

TOP2A and CENPF are synergistic master regulators activated in cervical cancer

Yu¹,

Chen

Zhang

et al. 2020

BMC Med Genomics

View full text Add to dashboard Cite

Background Identification of master regulators (MRs) using transcriptome data in cervical cancer (CC) could help us to develop biomarkers and find novel drug targets to fight this disease. Methods We performed differential expression (DE) analyses of public microarray and RNA-seq transcriptome data of CC and normal cervical tissues (N). Virtual Inference of Protein activity by Enriched Regulon analysis (VIPER) was used to convert the DE outcomes to differential activity (DA) signature for MRs. Synergy analysis was conducted to study synergistic effect of MR-pairs. TCGA and microarray data were used to test the association of expression of a MR and a clinical feature or a molecular feature (e.g. somatic mutations). Various bioinformatic tools/websites (DAVID, GEPIA2, Oncomine, cBioPortal) were used to analyze the expression of the top MRs and their regulons. Results Ten DE and 10 DA signatures were generated for CC. Two MRs, DNA topoisomerase II alpha (TOP2A) and centromere protein F (CENPF) were found to be up-regulated, activated and synergistic in CC compared to N across the 10 datasets. The two MRs activate a common set of genes (regulons) with functions in cell cycle, chromosome, DNA damage etc. Higher expression of CENPF was associated with metastasis. High expression of both MRs is associated with somatic mutation of a set of genes including tumor suppressors (TP53, MSH2, RB1) and genes involved in cancer pathways, cell cycle, DNA damage and repair. The magnitude of up-regulation and the absolute expression level of both MRs in CC are significantly higher compared to many other cancer types. Conclusion TOP2A and CENPF are a synergistic pair of MRs that are overexpressed and activated in CC. Their high expression is correlated with some prognosis features (e.g. metastasis) and molecular features (e.g. somatic mutations) and distinctly high in CC vs. many other cancer types. They may be good biomarkers and anticancer drug targets for CC.

show abstract

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

Cited by 42 publications

References 50 publications

Wide allelic heterogeneity with predominance of large IDS gene complex rearrangements in a sample of Mexican patients with Hunter syndrome

Wide allelic heterogeneity with predominance of large IDS gene complex rearrangements in a sample of Mexican patients with Hunter syndrome

A Five-Genes-Based Prognostic Signature for Cervical Cancer Overall Survival Prediction

TOP2A and CENPF are synergistic master regulators activated in cervical cancer

Contact Info

Product

Resources

About