Investigators with The Cancer Genome Atlas Research Network, including a researcher from the UAB, have identified novel genomic characteristics of cervical cancer that will aid in the subclassification of the disease and may help target therapies that are most appropriate for each individual patient.
The new study conducted an analysis of the genomes of 178 primary cervical cancers, and found that more than 70 percent of the tumors had genomic alterations in either one or both of two important cell signaling pathways. The researchers also found that a subset of tumors did not show evidence of human papillomavirus infection.
The study was jointly managed by the National Cancer Institute and the National Human Genomic Research Institute, and was performed by a consortium of more than 150 researchers at dozens of institutions across the world.
Akinyemi Ojesina, MD, PhD, assistant professor in the UAB Department of Epidemiology, has been involved with the study for the past three years. "We performed genomic analyses of cervical cancers, and identified genetic mutations that are novel drivers of the disease," he said. "This is exciting because we can now develop targeted therapies."
The study researchers found that a unique set of eight cervical cancers showed molecular similarities to endometrial cancers. Most of these endometrial-like cancers were HPV-negative, and they had strikingly high frequencies of mutations in the PTEN, ARID1A and KRAS genes.
It has been thought that all cases of cervical cancer are caused by HPV, and just two HPV types are responsible for about 70 percent of all cases. "Basically, this study confirms some of our previous work that HPV infection may not be involved in all cases of cervical cancer," Ojesina said.
One of the most important parts of this study has to do with identifying targets for immunotherapy. Investigators examined genes that code for known immune targets to see whether any were amplified, which may predict responsiveness to immunotherapy. They found amplification of several such genes, specifically CD274 (which encodes the PD-L1 immune checkpoint protein) and PDCD1LG2 (which encodes the PD-L2 immune checkpoint protein). Several checkpoint inhibitors have been shown to be effective immunotherapeutic agents.
"Immunotherapy has emerged as one of the most promising areas of cancer therapy," Ojesina said. "Some treatments boost the body's immune system in a general way, and others help train the immune system to attack cancer cells specifically. We have now found evidence of mutations in genes that normally put 'brakes' on the immune system, suggesting treatment with drugs that take those brakes off may be effective against cervical cancer cells."
In addition, the analysis identified several novel mutated genes in cervical cancer, includingMED1, ERBB3, CASP8, HLA-A and TGFBR2. The researchers also identified several cases with gene fusions involving the gene BCAR4, which produces a long noncoding RNA that has been shown to induce responsiveness to an oral drug that inhibits a key pathway in breast cancer known as lapatinib. Therefore, BCAR4 may be a potential therapeutic target for cervical cancers with this alteration.
Also, when analyzing the biology behind the molecular alterations in the cervical cancer tumors, researchers found that nearly three-quarters of cervical cancers had genomic alterations in either one or both of the PI3K/MAPK and TGF-beta signaling pathways, which may also provide targets for therapy.
Next, Ojesina and the other authors hope to determine whether HPV-positive and HPV-negative tumors will respond differently to targeted therapies.