Cervical Cancer: Newly Discovered Gene Mutations May Lead to More Targeted Therapies

A comprehensive genomic analysis of cervical cancer led researchers to identify recurrent genetic mutations not previously found, including one for which a targeted treatment has already been approved for treating a common form of breast cancer.

The researchers, reporting their findings in Nature, reported 13 mutations that occurred frequently enough across the samples to be considered significant in cervical cancer. Of those, eight had not previously been tied to the disease, and two had never been seen in any cancer type.

The study focused on whole-exome sequencing analysis of 115 cervical carcinoma–normal paired samples from patients in Norway and Mexico. In addition, the researchers did transcriptome sequencing of 79 cases and whole-genome sequencing of 14 tumor-normal pairs.

Based on their findings, the researchers suggest that by focusing on the mutations there may be new strategies for fighting the disease.

"Cancer is a disease that affects the whole world, and one question that always arises is: is a given cancer type similar or different across populations?" said Matthew Meyerson, one of the paper's senior coauthors and a professor of pathology and medical oncology at Dana-Farber Cancer Institute, in a news release. "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."

Among the statistically significant findings, the researchers reported that HPV integration sites were higher in tumors with HPV integration compared with expression of the same genes in tumors without viral integration at the same site. The higher levels of gene expression at the HPV integration sites often were amplified, leading to many copies being made in the genome.

"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.

The findings also revealed somatic point mutations in the gene ERBB2 in a subset of the tumors. While mutations in ERBB2, also known as the HER2 gene, had not been previously linked to cervical cancer, HER2 mutations are known in breast cancer and treatments already exist that target the gene.

"This suggests that a subset of cervical cancer patients could be candidates for clinical trials involving ERBB2 inhibitors, which are available and FDA-approved," said Akinyemi Ojesina, a postdoctoral fellow in Matthew Meyerson's lab and a first coauthor of the paper.

Among the novel mutations discovered was that in the gene MAPK1, which is one of the final steps in the mitogen-activated protein kinase signaling pathway that plays a role in cell growth regulation. While previous discoveries have reported cancer-driving mutations in other genes in the pathway, the authors said the mutation of MAPK1 has not been reported previously. Again, the authors suggested the finding could lead to possible therapeutics targeting the gene.

Pertinent Points:
- In a comprehensive genomic analysis, researchers discovered 13 mutations that occurred frequently enough to be considered significant in cervical cancer.
- The findings included a mutation to the HER2 gene, for which there is already an FDA-approved targeted therapy in breast cancer.
- The researchers also point to eight mutations not previously tied to cervical cancer and two mutations never before connected to any type of cancer.

References:

Ojesina AI, Lichtenstein L, Freeman SS, et al. Landscape of genomic alterations in cervical carcinomas. Nature. December 25, 2013. doi:10.1038/nature12881.