Molecular profiling of cervical cancer is revolutionizing treatment
The Cancer Genome Atlas Research Network. Integratedgenomic and molecular characterization of cervical cancer. Nature. 2017;543(7645):378−384.
Effective treatments for cervical cancer could be close at hand, thanks to a recent explosion of knowledge at the molecular level about how specific cancers arise and what drives them other than HPV. The Cancer Genome Atlas Research Network (TCGA) recently published the results of its genomic and proteomic analyses, which yielded distinct profiles for 178 cervical cancers with important patterns common to other cancers, such as uterine and breast cancer. These recently published findings on cervical cancer highlight areas of gene and protein dysfunction it shares with these other cancers, which could open the doors for new targets for treatments already developed or in the pipeline.
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Cancers develop in any given tissue through the altered function of different genes and signaling pathways in the tissue's cells. The latest extensive investigation conducted by the TCGA network has identified significant mutations in 5 genes previously unrecognized in association with cervical cancer, bringing the total now to 14.
Several highlights are featured in the TCGA's recently published work. One discovery is the amplification of genes CD274 and PDCD1LG2, which are involved with the expression of 2 cytolytic effector genes and are therefore likely targets for immunotherapeutic strategies. Another line of exploration, whole-genome sequencing, has detected an aberration in some cervical cancer tissue with the potential for immediate application. Duplication and copy number gain of BCAR4, a noncoding RNA, facilitates cell proliferation through the HER2/HER3 pathway, a target of the tyrosine-kinase inhibitor, lapatinib, which is currently used to treat breast cancer.
The integration of data from multiple layers of analysis (FIGURE 2) is helping investigators identify variations in cancers. DNA methylation, for instance, is a means by which cells control gene expression. An analysis of this process in cervical tumor tissue has revealed additional cancer subgroups in which messenger RNA increases the transition of epithelial cells to invasive mesenchymal cells. Targeting that process in these subgroups would likely enhance the effectiveness of novel small-molecule inhibitors and some standard cytotoxic chemotherapy.
It is this kind of detailed molecular knowledge--which is far more clinically meaningful than information provided by standard histology--that will 1) define cancer typing at a more precise level, 2) guide the development of targeted individualized treatments, and 3) give new hope to patients with aggressive cancers. While much of the malignant transformation is HPV driven, other genetic patterns can be targeted. Therapeutic investigation is now moving forward, focusing on the recently revealed similarities between cancers in different parts of the body. The National Cancer Institute, in conjunction with clinical partners across the country, is enrolling patients with different tumor types in its NCI-MATCH (Molecular Analysis for Therapy Choice) trial. In brief, patients who have a tumor (regardless of origin or tissue type) containing specific molecular abnormalities already recognized in another cancer and targeted by an existing drug will receive that treatment to determine if it will prove effective. For more information, visit the NCI-MATCH website:
https://www.cancer.gov/about-cancer/treatment/clinical-trials/nci-supported/nci-match.
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