With Christopher Vellano, PhD, of The University of Texas MD Anderson Cancer Center
By Sarah DiGiulio
Cervical cancer is responsible for more than 500,000 new cases of cancer and more than 250,000 deaths around the world every year, according to data from the International Agency for Research on Cancer (Int J Cancer 2014:136;E359-E386). A large majority of those tumors have been linked to HPV injection—but, importantly, not all cases.
A new study has identified a unique set of eight cervical cancers that are predominantly HPV-negative, characterized by mutations in the KRAS, ARID1A, and PTEN genes, and molecularly similar to endometrial cancers. The study was published online ahead of print in Nature (doi:10.1038/nature21386).
"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," noted NCI Acting Director Douglas Lowy, MD. "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," he continued. "Therefore, cervical cancer is still a disease in need of effective therapies, and this latest [from The Cancer Genome Atlas (TCGA)] analysis could help advance efforts to find drugs that target important elements of cervical cancer genomes in addition to the HPV genes."
For the study, TCGA researchers analyzed 178 primary cervical cancers. More than 70 percent of the tumors had genetic alterations in either the PI3K/MAPK or TGF-β signaling pathways, or both, suggesting the importance of targeting molecules within these pathways.
ERBB3, CASP8, HLA-A, SHKBP1, and TGFBR2 were all identified as significantly mutated genes for the first time in cervical cancer, with ERBB3 being a potential therapeutic target. And BCAR4 was found to be amplified in some cases.
The researchers also found nearly three-quarters of cervical cancers had genomic alterations in either one or both of the PI3K/MAPK and TGF-β signaling pathways. The findings are important because they could point to important new targets for therapies—especially at a time when immunotherapies are playing increasing roles in cancer therapy and effective targets are needed for therapies to work.
Study coauthor Christopher Vellano, PhD, Research Project Manager in the Department of Systems Biology at The University of Texas MD Anderson Cancer Center, Houston, explained further what the most important revelations from this study were—and why they are important.
1. What conclusions were made from this research that was previously unknown about the genetics of cervical cancers?
"There have been several other genomic studies [that] have analyzed fewer samples across fewer molecular platforms. Our study integrates DNA methylation, mutation, mRNA, miRNA, protein, pathway analysis, and HPV data to present a larger and broader molecular profile of cervical cancer subgroups.
"An important finding is the identification of HPV-negative cervical cancers—of which most can be characterized molecularly as endometrial-like with KRAS, ARID1A, and PTEN mutations. [Another] key finding in this study is that, although HPV is a significant player and present in 95 percent of cervical cancers, there are a small percentage of HPV-negative tumors that will need to be further studied.
"Our study highlights novel genomic alterations and key markers of cervical cancer subgroups and for the first time identifies SHKBP1, ERBB3, CASP8, HLA-A, and TGFBR2 as novel significantly mutated genes in cervical cancer."
2. In what ways might these findings affect the way cervical cancer is treated clinically?
"Genomic alterations in the PI3K/MAPK and TGF-β signaling pathways indicate the clinical potential of therapies targeting molecules in these pathways. Alterations in BCAR4 are therapeutically relevant given BCAR4 can be indirectly targeted by lapatinib.
"Amplifications in CD274/PD-L1 and PDCD1LG2/PD-L2 suggest that immunotherapies warrant evaluation in cervical cancer. In addition, genomic alterations in ERBB2 and ERBB3 within adenocarcinomas suggest [there is the] potential for treating this subgroup with HER2- and HER3-targeted therapies."
3. What is most important for practicing oncologists and cancer care providers to know about this research?
"Molecular analysis of patient samples will be important in guiding patients to the appropriate therapies, and we hope the results of this study will serve as a significant resource for clinical translation.
"More comprehensive studies will be needed to evaluate the characteristics and importance of the HPV-negative/endometrial-like cervical cancers. In addition, studies should validate therapeutic markers identified here as well as continue to identify new targets."