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The genomics of cervical cancer

Cervical cancer is a disease in which malignant (cancer) cells form in the tissues of the cervix. Most cases are caused by long-lasting infections with certain types of human papillomavirus (HPV). These infections lead to genetic changes that raise the risk for cervical cancer.

Different types of HPV can cause different genetic changes, which vary in their association with cancer risk. HPV vaccination before sexual activity can reduce the risk of HPV infection and thus cervical cancer. If found and treated in its early stages, cervical cancer can usually be cured, but new therapeutic approaches are needed.

To gain new insights into cervical cancer, researchers with The Cancer Genome Atlas (TCGA) Research Network analyzed the genomes of 178 primary cervical cancers. The study was supported by NIH’s National Cancer Institute (NCI) and National Human Genome Research Institute (NHGRI). Results appeared on January 23, 2017, in Nature.

The scientists identified 3 general clusters of cervical cancer based on the presence of different HPV and other genomic features. The team found that more than 70% of the tumors had genomic alterations in either one or both of the PI3K/MAPK and TGF-beta signaling pathways. These might thus serve as future targets for potential therapies. Two genes that code for known immunotherapy targets were amplified within many tumors: CD274 and PDCD1LG2. This insight may lead to ways to predict whether a tumor will respond to immunotherapy.

The researchers associated several previously unidentified genetic mutations with cervical cancer, including MED1, ERBB3, CASP8, HLA-A, and TGFBR2. These may serve as potential therapeutic targets. Several tumors showed aberrations involving the BCAR4 gene, which has been tied to estrogen-resistant breast cancer. Lapatinib, an oral drug that inhibits a key pathway in breast cancer, might be effective against cervical cancers with this alteration.

A unique set of 8 cervical cancers showed molecular similarities to endometrial cancers. These endometrial-like cancers were mainly HPV-negative, and they all had high frequencies of mutations in the KRAS, ARID1A, and PTEN genes. The findings provide potential therapeutic targets for these types of cervical cancers.

“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,” explains NCI Acting Director Dr. Douglas Lowy. “Therefore, cervical cancer is still a disease in need of effective therapies, and this latest TCGA analysis could help advance efforts to find drugs that target important elements of cervical cancer genomes in addition to the HPV genes.”

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