RGD Reference Report - Gene dosage, expression, and ontology analysis identifies driver genes in the carcinogenesis and chemoradioresistance of cervical cancer. - Rat Genome Database

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Gene dosage, expression, and ontology analysis identifies driver genes in the carcinogenesis and chemoradioresistance of cervical cancer.

Authors: Lando, Malin  Holden, Marit  Bergersen, Linn C  Svendsrud, Debbie H  Stokke, Trond  Sundfør, Kolbein  Glad, Ingrid K  Kristensen, Gunnar B  Lyng, Heidi 
Citation: Lando M, etal., PLoS Genet. 2009 Nov;5(11):e1000719. doi: 10.1371/journal.pgen.1000719. Epub 2009 Nov 13.
RGD ID: 12880436
Pubmed: PMID:19911042   (View Abstract at PubMed)
PMCID: PMC2768783   (View Article at PubMed Central)
DOI: DOI:10.1371/journal.pgen.1000719   (Journal Full-text)

Integrative analysis of gene dosage, expression, and ontology (GO) data was performed to discover driver genes in the carcinogenesis and chemoradioresistance of cervical cancers. Gene dosage and expression profiles of 102 locally advanced cervical cancers were generated by microarray techniques. Fifty-two of these patients were also analyzed with the Illumina expression method to confirm the gene expression results. An independent cohort of 41 patients was used for validation of gene expressions associated with clinical outcome. Statistical analysis identified 29 recurrent gains and losses and 3 losses (on 3p, 13q, 21q) associated with poor outcome after chemoradiotherapy. The intratumor heterogeneity, assessed from the gene dosage profiles, was low for these alterations, showing that they had emerged prior to many other alterations and probably were early events in carcinogenesis. Integration of the alterations with gene expression and GO data identified genes that were regulated by the alterations and revealed five biological processes that were significantly overrepresented among the affected genes: apoptosis, metabolism, macromolecule localization, translation, and transcription. Four genes on 3p (RYBP, GBE1) and 13q (FAM48A, MED4) correlated with outcome at both the gene dosage and expression level and were satisfactorily validated in the independent cohort. These integrated analyses yielded 57 candidate drivers of 24 genetic events, including novel loci responsible for chemoradioresistance. Further mapping of the connections among genetic events, drivers, and biological processes suggested that each individual event stimulates specific processes in carcinogenesis through the coordinated control of multiple genes. The present results may provide novel therapeutic opportunities of both early and advanced stage cervical cancers.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
cervical cancer severityIEP 12880436mRNA:decreased expression:uterine cervix (human)RGD 
cervical cancer severityISOMED4 (Homo sapiens)12880436; 12880436mRNA:decreased expression:uterine cervix (human)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Med4  (mediator complex subunit 4)

Genes (Mus musculus)
Med4  (mediator complex subunit 4)

Genes (Homo sapiens)
MED4  (mediator complex subunit 4)


Additional Information