Circos plot showing cervical cancer chromosomes affected by HPV oncogenes. [Cancer Genome Research Network
Circos plot showing cervical cancer chromosomes affected by HPV oncogenes. [Cancer Genome Research Network

Scientists at The Cancer Genome Atlas (TCGA) Research Network have identified novel genomic and molecular characteristics of cervical cancer that should aid in the subclassification of the disease, and may help target therapies that are most appropriate for each patient. The new study, published recently in Nature through an article entitled “Integrated genomic and molecular characterization of cervical cancer,” is a comprehensive analysis of the genomes from 178 primary cervical cancers—in which investigators found that over 70 percent of the tumors had genomic alterations in either one or both of two important cell signaling pathways.

Moreover, the researchers found, unexpectedly, that a subset of tumors did not show evidence of human papillomavirus (HPV) infection. “The vast majority of cases of cervical cancer are caused by persistent infection with oncogenic types of HPV,” explained National Cancer Institute (NCI) Acting Director Douglas Lowy, M.D. “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.”

“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,” Dr. Lowy added. “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.”

Particularly interesting for the current study was the identification of a unique set of eight cervical cancers that showed molecular similarities to endometrial cancers. These endometrial-like cancers were mainly HPV-negative, and they all had high frequencies of mutations in the KRAS, ARID1A, and PTEN genes.

“The identification of HPV-negative endometrial-like tumors confirms that not all cervical cancers are related to HPV infection and that a small percentage of cervical tumors may be due to strictly genetic or other factors,” noted Jean-Claude Zenklusen, Ph.D., director of NCI's TCGA program office. “This aspect of the research is one of the most intriguing findings to come out of the TCGA program, which has been looking at more than 30 tumor types over the past decade.”

Since immunotherapies have become increasingly important for cancer therapy, the investigators examined genes that code for known immune targets to see if any were amplified—providing a potential predictive responsiveness to immunotherapy. What they found was 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.

Additionally, 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 lapatinib, an oral drug that inhibits a key pathway in breast cancer. Therefore, BCAR4 could become a potential therapeutic target for cervical cancers with this alteration.

When analyzing the biology behind the molecular alterations in these tumors, the 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. The authors noted that an important question raised by this study is whether HPV-positive and HPV-negative tumors will respond differently to targeted therapies.

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