Largest Genomic Study of Cervical Cancer Identifies Novel Targets for Therapy

Largest Genomic Study of Cervical Cancer Identifies Novel Targets for Therapy

An extensive analysis of the genomic and molecular characteristics of cervical cancers has revealed that most of these cancers could be treated by targeting at least one of two major signaling pathways: the PI3K/MAPK and the TGF-beta pathways.

The study also identified a unique set of endometrial-like cervical cancers that are predominantly HPV-negative and show high frequency of mutations that could be targeted with approved or investigational drugs.

The study, “Integrated genomic and molecular characterization of cervical cancer,” was published in Nature.

“The vast majority of cases of are caused by persistent infection with oncogenic types of HPV. 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,” Douglas Lowy, MD, National Cancer Institute (NCI) acting director, said in a news release.

“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,” Lowy said. “Therefore, cervical cancer is still a disease in need of effective therapies, and this latest TCGA [The Cancer Genome Atlas] analysis could help advance efforts to find drugs that target important elements of cervical cancer genomes in addition to the HPV genes.”

In an attempt to identify novel molecular associations and altered signaling pathways that could be used as prognostic therapeutic targets for cervical cancer, researchers from the NCI and the National Human Genome Research Institute (NHGRI), both parts of the National Institutes of Health, worked with The Cancer Genome Atlas (TCGA) Research Network to conduct an extensive analysis of 228 primary cervical cancers.

Their findings revealed that a subset of cervical cancers, which shared many similarities with endometrial cancers, were mainly HPV-negative. These cancers showed high frequencies of mutations in the KRAS, ARID1A, and PTEN genes, which could be targeted with agents that are currently in clinical development. However, additional studies are required to understand whether HPV-negative tumors respond differently to targeted therapies.

“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,” said Jean-Claude Zenklusen, PhD, 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,” he said.

The researchers also identified novel mutations associated with cervical cancer, including SHKBP1, ERBB3, CASP8, HLA-A, and TGFBR2. They also report that many of the samples exhibited activating mutations in the BCAR4 gene. This is a long noncoding RNA that renders cells more sensitive to the breast cancer drug Tykerb (lapatinib), suggesting that tumors with high BCAR4 levels could be treated with this drug.

The team also found that certain cancers have amplification of the PD-L1 and PD-L2 genes, suggesting they could respond to immunotherapy drugs.

Looking at all the molecular alterations seen in each sample, the TCGA analysis revealed that nearly 70 percent of cervical cancers had genomic alterations in the PI3K/MAPK or the TGB-beta signaling pathways, suggesting that such pathways could provide targets for therapy.

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Inês Martins holds a BSc in Cell and Molecular Biology from Universidade Nova de Lisboa and is currently finishing her PhD in Biomedical Sciences at Universidade de Lisboa. Her work has been focused on blood vessels and their role in both hematopoiesis and cancer development.

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