Investigators with The Cancer Genome Atlas Research Network, including a researcher from the University of Alabama at Birmingham, have identified novel genomic and molecular 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, published online today in Nature, conducted a comprehensive 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 TCGA 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 nation and the world.
Akinyemi Ojesina, M.D., Ph.D., assistant professor in the UAB Department of Epidemiology in the School of Public Health, has been involved with the study for the past three years and is a corresponding author on this paper. “Essentially, we performed comprehensive genomic analyses of cervical cancers, and identified genetic mutations that are novel drivers of the disease. This is extremely exciting because we can now develop targeted therapies.”
Cervical cancer accounts for more than 500,000 new cases of cancer and more than 250,000 deaths each year worldwide.
“The vast majority of cases of cervical cancer are caused by persistent infection with oncogenic types of HPV, and effective preventive vaccines against the most oncogenic forms of HPV have been available for a number of years, with vaccination having the long-term potential to reduce the number of cases of cervical cancer,” said NCI Acting Director Douglas Lowy, M.D. “However, most women who will develop cervical cancer in the next couple of decades are already beyond the recommended age for vaccination and will not be protected by the vaccine. Therefore, cervical cancer is still a disease in need of effective therapies, and this latest TCGA analysis could help advance efforts to find drugs that target important elements of cervical cancer genomes in addition to the HPV genes.”
According to Ojesina, an associate scientist at the UAB Comprehensive Cancer Center and adjunct faculty investigator at the HudsonAlpha Institute for Biotechnology, many aspects of this study are intriguing. 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 virtually 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, also published in Nature in 2014, that HPV infection may not be involved in all cases of cervical cancer,” said Ojesina, who is a major contributor to the TCGA Cervical Cancer Analysis Working Group.
Perhaps 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.
“In the last few decades, 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 TCGA analysis identified several novel mutated genes in cervical cancer, including MED1, 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.
In terms of next steps, Ojesina and the other authors hope to determine whether HPV-positive and HPV-negative tumors will respond differently to targeted therapies.
The list of TCGA Research Network list of participants is available online.