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Cervical Cancer Analysis Yields Novel Changes, Therapeutic Targets

NEW YORK (GenomeWeb) – An integrated analysis of cervical cancer has uncovered novel molecular alterations and has identified potential therapeutic markers.

Researchers from the Cancer Genome Atlas Research Network characterized the genomes, proteomes, and more of 228 primary cervical cancers. As they reported today in Nature, the team uncovered novel somatic genomic mutations, copy-number alterations, and structural rearrangements, and confirmed previously reported changes. A number of these molecular alterations hinted at possible targeted treatment approaches for subtypes of cervical cancer.

"Together, these findings provide insight into the molecular subtypes of cervical cancers and rationales for developing clinical trials to treat populations of cervical cancer patients with distinct therapies," the researchers wrote in their paper.

The team conducted sequencing and integrated analysis on a core set of 178 cervical cancer samples, while also sequencing a further 14 samples and gauging protein levels on 155 samples, including some from the core set as well as others. The core set of 178 tumors included 144 squamous cell carcinomas, 31 adenocarcinomas, and three adenosquamous carcinomas.

Whole-exome sequencing uncovered more than 43,000 somatic mutations. Using the MutSig2CV algorithm, the researchers found 14 significantly mutated genes, including five never before linked to cervical cancer: SHKBP1, ERBB3, CASP8, HLA-A, and TGFBR2. They concluded that ERBB3 could be a therapeutic target.

The tumor samples harbored an average 88 somatic copy-number alterations each, and the researchers uncovered novel recurrent amplifications and deletions. Both tumors with high levels of copy number changes — mostly squamous — and tumors with low amounts of copy number changes — mostly adenocarcinomas — had amplifications that involved CD274 and PDCD1LG2 that correlated with the expression of two immune cytolytic effector genes. This, the researchers noted, raises the possibility that immunotherapies might work for a portion of cervical cancers.

Similarly, structural rearrangements affecting BCAR4, a metastasis-promoting lncRNA that activates the HER2/3 pathway, suggests that EGFR/HER2 inhibitors like lapatinib might be a potential therapeutic for a subset of tumors.

The research team also clustered the tumors into groups based on their copy number, methylation, mRNA, and miRNA profiles. Using iCluster, they split the tumors into three groups: ones that expressed high amounts of keratin, ones that expressed low amounts of keratin, and a cluster that was mostly adenocarcinomas.

The high-keratin cluster, which was comprised mostly of squamous tumors, lacked KRAS mutations but had high expression levels of the tumor suppressors miR-99a-5p and miR-203a. At the same time, the adenocarcinoma-rich cluster lacked HLA-A mutations and largely overlapped with an miRNA cluster that was marked by high expression of miR-375 and low expression of miR-205-5p and miR-944.

A protein-based analysis also uncovered three clusters that were broadly similar to the iCluster-generated groupings and EMT mRNA scores, while unsupervised clustering based on miRNA yielded six clusters that also overlapped with the iCluster groups.

Analysis with the Mutual Exclusivity Modules in cancer algorithm uncovered differences across cervical cancers in RTK, PI3K, and MAPK pathway alterations. Some 70 percent of cervical cancers had alterations affecting PI3K/MAPK or TGFβ, or both, the researchers noted, suggesting that agents targeting these pathways could have clinical significance.

In addition, some 95 percent of the core set of tumors the researchers analyzed were HPV-positive, and most had the HPV-A, the European variant. The HPV A7 tumors were enriched in the low keratin and adenocarcinoma iClusters, and were low levels of CpG island hypermethylation, the researchers noted. At the same time, HPV A7 tumors had higher activation of p53 and p63 signaling and lower FOXA1 signaling levels than HPV A7 tumors.

"Through comprehensive molecular and integrative profiling, we identified novel genomic and proteomic characteristics that sub-classify cervical cancers," the researchers wrote.

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