NEW YORK (GenomeWeb News) – A new study has identified dozens of gene dosage and expression changes in cervical cancer that seem to contribute to everything from cancer development and progression to treatment outcomes.
In a paper appearing online today in PLoS Genetics, a Norwegian research team integrated information from copy number, ploidy, gene expression, and gene ontology experiments for tumors from nearly 150 women with cervical cancer to try to pinpoint genes involved in carcinogenesis, treatment resistance, and relapse.
In so doing, they identified dozens of recurrent gains and losses — including losses on chromosomes 3, 13, and 21 — linked to poor treatment outcomes.
"Our results indicated that gene dosage alterations play a causative role in the carcinogenesis and chemoradioresistance of cervical cancer and pinpointed candidate biomarkers of the disease," senior author Heidi Lyng, a radiation biology researcher at the Norwegian Radium Hospital in Oslo, and her co-authors wrote.
Locally advanced cervical cancer is typically treated with radiotherapy combined with adjuvant cisplatin chemotherapy. Even so, nearly a third of cases return within a few years. That pattern, combined with the side effects associated with radio- and chemotherapy treatments, prompted Lyng and her team to look for new ways of characterizing cervical cancer in the hopes of developing more personalized treatments.
"We have been studying cervical cancer for many years," Lyng told GenomeWeb Daily News. "Now we are into the molecular era. We are able to use genomic screening methods."
In an effort to find so-called "driver" genes involved in cervical cancer development, progression, and treatment resistance, Lyng and her team first did gene dosage analyses — determined by dividing copy number by ploidy — on biopsy samples from 97 individuals with locally advanced cervical cancer.
To do this, they used arrays containing 4,549 BAC and PAC clones to do array comparative genomic hybridization on the samples, and flow cytometry to discern tumor ploidy.
When they honed in on the most frequent or high-amplitude gains and losses, the researchers found 14 recurrent gains and 15 recurrent losses that affected more than 42 percent of the genome. For example, between 44 and 76 percent of those tested had gains affecting chromosomes 1, 3, 5, 20 or the X chromosome or losses on chromosomes 2, 3, 4, 11, or 13.
In terms of gene dosage affects on treatment outcomes, the team also found specific losses involving chromosomes 3, 13, and 21 that were linked to poorer progression-free survival. "We hope these can be prognostic markers in the clinic," Lyng said.
Relapse risk was especially high for cases involving losses on chromosome 21, they noted, with survival probability dropping from 91 percent (in individuals with none of the chromosome 3, 13, or 21 losses) to just 44 percent for individuals with specific chromosome 21 losses.
By incorporating gene expression results from cDNA microarray for 100 cervical cancer patients, including 95 assessed by array CGH, the team found nearly 200 genes for which expression changes coincided with gene dosage data — results that they subsequently verified using the Illumina gene expression BeadArrays to test tumors from 52 women from the array CGH experiment as well as another 41 women with cervical cancer.
Expression patterns for four genes correlated with treatment outcome: the RYBP and GBE1 genes on chromosome 3 and the chromosome 13 genes FAM48A and MED4.
And when they evaluated the functions associated with potential driver mutations, the team detected an over-representation of pathways connected to processes such as carbohydrate metabolism, apoptosis, transcription, and translation. They were also surprised to see changes involving protein transport and molecular localization related genes, Lyng noted.
The results of the current study and others like it may yield biomarkers for guiding cervical cancer treatment or provide cervical cancer treatment targets. Lyng said. But, she warned, that will likely take time.
"The candidate driver genes represent novel biomarkers that may be utilized in the handling of cervical cancers," the team concluded. "Diagnostic assessment of the biomarkers may help to understand the evolutionary status and therefore the biology of the cancer in individual patients."
They are currently doing more detailed follow-up studies aimed at understanding the potential of genetic profiles for guiding treatment, Lyng said. The team is also undertaking cellular studies aimed at better understanding the effects of targeting specific pathways in the cell.