Genomic Study of Cervical Cancer Identifies Potential Treatment Targets

Electron micrograph of a negatively stained human papilloma virus (HPV) which occurs in human warts. Warts on the hands and feet have never been known to progress to cancer. However, after many years cervical warts can become cancerous.

SOURCE: The Web site of the National Cancer Institute (http://www.cancer.gov)

Researchers have completed a comprehensive genomic analysis of cervical cancer in two patient populations. The study, which appears online inNature, identified recurrent genetic mutations not previously found in cervical cancer, including at least one for which targeted treatments have been approved in other forms of cancer.

The research team performed whole exome sequencing on samples from 115 patients with cervical cancer from Norway and Mexico. In some cases, the researchers also conducted whole genome sequencing or transcriptome sequencing (focusing on gene expression). In each case, researchers compared genomic data derived from cervical cancer tumors with genomic data from healthy tissue from the same individual to determine mutations in the genome that led to cancer development.

“One question that always arises is: is a given cancer type similar or different across populations?” explained Matthew Meyerson, MD, PhD, one of the paper’s co-senior authors in a press release. Meyerson is a professor of Pathology and Medical Oncology at Dana-Farber Cancer Institute and a senior associate member of the Broad Institute. “While we don’t have the complete answer yet in this case, what we are seeing is that, in two different populations, the causes of cervical cancer are similar and, fundamentally in both cases, it comes down to HPV-genome interaction.”

Research teams from US, Mexico, and Norway cooperated in the study in order to sequence samples from a diverse pool of patients with cervical cancer.

“Without this sort of international collaboration, the genomic view of a disease can be limited. By analyzing genomic data from diverse populations, we can discover patterns to disease progression in context of the full range of human genetic variation,” said co-senior author Helga Salvesen. Salvesen, a professor of Clinical Medicine at University of Bergen, Norway, was a visiting scientist at the Broad Institute when the study was conducted.

The study identified 13 mutations that occurred frequently enough across the samples to be considered significant in cervical cancer. Eight of these mutations had not been linked to the disease previously, and two had not previously been seen in any cancer type.

Among the most notable findings were somatic point mutations in the geneERBB2(HER2), which was found in a small but significant subset of the tumors. Mutations in this gene had not previously been linked to cervical cancer.

“This suggests that a subset of cervical cancer patients could be candidates for clinical trials involving ERBB2 inhibitors, which are available and FDAapproved,” explained Akinyemi Ojesina, a postdoctoral fellow in Matthew Meyerson’s lab at the Broad Institute and Dana-Farber. Ojesina served as a co-first author of the paper along with Lee Lichtenstein of Broad’s Cancer Genome Analysis Group. “It is an exciting finding that could be translatable to the clinic.”

The team also identified a novel mutation in the geneMAPK1.MAPK1is one of the final steps in the MAP kinase signaling pathway. Mutations in other genes in the pathway have been known to drive cancer, but this is the first time thatMAPK1itself has been found to be mutated. The finding opens up the possibility thatMAPK1, like other genes in the MAP kinase signaling pathway, may be a viable therapeutic target.

Another key finding noted in the press release was the prevalence of mutations in genes affecting the immune system. Mutations in the geneHLA-Awere previously found to drive squamous cell lung cancer. In this study, another gene in the same complex,HLA-B, was found to be commonly mutated in cervical squamous cell carcinoma.

Finally, transcriptome sequencing, which allowed the team to analyze gene expression, enabled researchers to learn more about how HPV is driving cervical cancer.

This study looked at where, in the genome, HPV inserted itself and found that HPV integration sites were associated with higher levels of gene expression and were often amplified, resulting in many copies of those sections of the genome. This connection between HPV integration and gene expression suggests that the virus may be driving cancer by promoting and elevating the activity of mutated genes, according to the press release.

“Our findings further elucidate the key role HPV is playing in the development of cervical cancer, which in turn emphasizes the importance of combating the disease by vaccinating against HPV,” Meyerson said.

“In metastatic cervical cancer, more effective systemic therapy is urgently needed,” Salvesen explained. “So far, our knowledge regarding genetic alterations as potential targets for therapeutics has been limited, and no targeted therapeutics are yet in routine clinical use. The present study — in particular the findings related toERBB2— thus represents a unique and comprehensive new tool to guide clinical trial design in the future.”

Ojesina AI, Lichtenstein L, Freeman SS, et al. Landscape of genomic alterations in cervical carcinomas [letter].Nature