A group of researchers have pinpointed various gene-dosage alterations that they believe may play a role in the carcinogenesis of cervical cancer. Their study also revealed genetic losses and gains associated with chemoradioresistance and certain candidate biomarkers.
The findings are published in the November 13 issue of PLoS Genetics in a paper titled “Gene Dosage, Expression, and Ontology Analysis Identifies Driver Genes in the Carcinogenesis and Chemoradioresistance of Cervical Cancer.”
The investigators examined more than 140 patients diagnosed and treated at the Norwegian Radium Hospital. Screening of their genomes revealed a set of biological processes that were already known to be hallmarks of cancer associated with gains and losses of specific genes. Moreover, they identified novel loci associated with resistance to chemo- and radiotherapy and depict the genes involved.
Gene-dosage and expression profiles of 102 locally advanced cervical cancers were generated by microarray techniques. The Illumina expression method was used to confirm the gene-expression results in 52 patients. 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 three 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 gene ontology 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 analyses yielded 57 candidate drivers of 24 genetic events, including novel loci responsible for chemoradioresistance. The authors emphasize that the results need to be further validated before they can be considered for use in clinical decision making.