Analysis Identifies Mutations Linked to Cervical Cancer

Sequencing of 115 cervical cancers and paired normal samples has identified recurrent mutations in 13 genes, including eight not previously connected to the disease and two not previously linked to cancer. The study's findings were published in December in Nature by an international team of researchers.

The researchers sequenced the exomes of all 115 tumors, as well as the genomes of 14 tumors, and in each case compared tumor data to data collected from a paired normal sample from the same patient. They also analyzed the transcriptomes of 79 cervical tumors, with data suggesting that integration of human papillomavirus (HPV) increased expression of nearby genes.

Almost all cervical cancers are caused by HPV, one of the most common sexually transmitted viruses. More than half a million women worldwide are diagnosed with cervical cancer every year, and the World Health Organization estimates that 266,000 women died from the disease in 2012. More than 85% of the deaths occurred in less-developed regions where screening may not be affordable or available.

A molecular-level understanding of the disease will help researchers understand HPV's role, as well as identify potential therapeutic targets and diagnostic biomarkers, says one of the study's co-senior authors, Matthew Meyerson, MD, PhD, of Dana-Farber Cancer Institute and Harvard Medical School in Boston, MA, and a senior associate member of the Broad Institute in Cambridge, MA.

The researchers found variations previously identified in cervical squamous cell carcinomas, including mutations in the PIK3CA (14% of cases), PTEN (6%), and STK11 (4%) genes. They also found mutations in ERBB2 (5%), also known as HER2; three of these mutations are thought to be oncogenic drivers for lung and breast cancers. The presence of these mutations in some cervical cancers may suggest that these patients would benefit from anti-ERBB2 therapy.

Among other findings, 9% of tumors from patients with squamous cell carcinoma had mutations in HLA-B; the related gene HLA-A has been previously identified to be mutated in a subset of lung tumors.

“These kinds of lung cancer have responded well to some immunotherapies, so the same therapies may eventually be used for some types of cervical cancer as well,” says Meyerson.

Additional recurrently mutated genes newly identified in cervical cancer included EP300 (16%), FBXW7 (15%), MAPK1 (8%), and NFE2L2 (4%) in squamous cell carcinoma, and ELF3 (13%) and CBFB (8%) in adenocarcinoma.

“For cervical cancer, existing treatments are not very useful,” says Murty Vundavalli, PhD, a cancer geneticist at Columbia University in New York, NY, who did not work on the study. “The main issue should be to identify biomarkers that identify response to specific treatments. Whole-genome studies will ultimately lead to those kinds of approaches.”