Genomic Study IDs New Drug Targets for Cervical Cancer

Veronica Hackethal, MD

February 06, 2017

A comprehensive genomic analysis of cervical cancer has identified several new mutations and genomic changes in important cell signaling pathways in cervical cancer. It has also found a small subgroup of tumors that are negative for human papillomavirus (HPV). The findings open up new approaches to treatment, the researchers suggest.

The study was conducted by the Cancer Genome Atlas (TCGA) Research Network and was published online January 23 in Nature.

"The TCGA publication represents the largest high-quality multiomics analysis of cervix carcinoma yet developed," project co-chair Gordon Mills, MD, University of Texas MD Anderson Cancer Center, Houston, told Medscape Medical News in an email.

"Importantly, it identifies a new series of cancer-associated events that could represent new targets and direct therapeutic opportunities. A number of cervix cancers have signatures suggesting they may likely benefit from immune oncology agents," Dr Mills commented.

Results also showed that a subset of tumors was negative for HPV and appeared to be more like endometrial than cervical tumors.

"Only a low percentage — about 4% in the sample set ― are not related to HPV. I believe that these tumors are molecularly and likely functionally endometrial cancers and should be treated as if they were endometrial cancers rather than as cervix cancers. However, their rarity will require extensive clinical studies to confirm this," Dr Mills added.

Worldwide, cervical cancer causes more deaths every year than any other gynecologic tumor. Persistent HPV infection causes 95% of cervical cancers, the reserachers note in their article. Although effective vaccines exist, weak uptake and the age cutoff for vaccination mean that many women are still at risk for cervical cancer.

The immune system usually clears HPV within months, but some cases persist and express viral oncogenes that lead to increased somatic mutations and genomic instability. In some cases, HPV can integrate into the human genome.

"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. 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," Douglas Lowy, MD, acting director of the National Cancer Institute (NCI), commented in a press release.

New Findings

In the study, researchers used molecular and integrative genetic profiling to analyze 228 primary, invasive cervical tumors. The results revealed many firsts.

More than 70% of tumors had genetic mutations in the PI3K/MAPK and TGFβ signaling pathways. A subset of tumors with mutated PI3K/MAPK pathways also had strongly occurring mutations in ERBB2 (also called HER2) and ERBB3 (also called HER3). These results suggest that HER2- and HER3-directed therapies may target these pathways, according to the authors.

Integrated clustering analysis of 178 tumors identified three clusters of cervical cancer: keratin-low squamous, keratin-high squamous, and adenocarcinoma-rich clusters. Further analysis revealed a subgroup that was associated with worse outcomes and had a high epithelial mesenchymal transition (EMT) score, which is associated with initiation of metastasis. The results may be therapeutically important because targeting EMT may increase tumor sensitivity to small-molecule inhibitors and cytotoxic chemotherapy.

Whole-exome sequencing of 192 tumors identified several new significantly mutated genes in cervical cancer, including SHKBP1, CASP8, HLA-A, TGFBR2, and ERBB3. ERBB3 may have immediate applicability as a therapeutic target, the authors note.

Analyses also identified new amplification of the immunotherapy targets CD274 (which codes for the PD-L1 checkpoint protein) and PDCDILG2 (which codes for the PD-L2 checkpoint protein), suggesting that checkpoint inhibitors may have a role in treating some types of cervical cancer.

Results also revealed, for the first time, gene amplification and fusion events in BCAR4, which produces a Iong noncoding (lnc) RNA that activates the HER2/3 pathway and promotes metastasis and cell proliferation in estrogen-resistant breast cancer. In vitro studies have shown that lapatinib, an EGFR/HER2 inhibitor, may block BCAR4-driven cell growth. These results point to lapatinib as a potential therapeutic agent in BCAR-4-positive cervical cancer, according to the authors.

The researchers note that 83% of all HPV-positive cancers (141/169) showed viral integration into the human genome. All HPV-18-related cases (n = 18) showed HPV integration; 76% of HPV-16-related cases did so.

Gene-expression classifier analysis showed that 4.5% (8/178) of cervical cancer samples were classified as endometrial-like. Of these, most (7/9) were HPV negative and had a high frequency of mutations in KRAS (27%), ARIDIA (33%), and PTEN (20%), the last two of which may provide therapeutic targets.

The identification of HPV-negative endometrial-like tumors confirms that not all cervical cancers are related to HPV infection. Dr Jean-Claude Zenklusen

"The identification of HPV-negative endometrial-like tumors confirms that not all cervical cancers are related to HPV infection and that a small percentage of cervical tumors may be due to strictly genetic or other factors," Jean-Claude Zenklusen, PhD, director of the NCI's TCGA program office, highlighted in a press release.

The study was supported by the National Institutes of Health. The authors have disclosed no relevant financial relationships.

Nature. Published online January 23, 2017. Abstract

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