Two Gene Mutations Linked To Deadly Ovarian Cancer

Dr. Terry Magnuson PhD Vice Dean for Research Department of Genetics, School of Medicine University of North Carolina at Chapel Hill Chapel Hill, North Carolina 27599MedicalResearch.com Interview with:
Dr. Terry Magnuson PhD
Vice Dean for Research
Department of Genetics, School of Medicine
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina 27599

Medical Research: What is the background for this study? What are the main findings?

Response: Ovarian clear-cell carcinoma is a lethal form of ovarian cancer with limited therapeutic options. Recent patient-derived tumor sequencing studies support a strong genetic basis for the disease, but the roles of gene mutations in cancer causation are still unclear. We observed rapid induction of ovarian clear-cell carcinoma in mice that were genetically engineered to carry mutations in ARID1A and PIK3CA−the two most frequently mutated genes. Comparisons between human and mouse tumors uncovered a downstream role for the Interleukin-6 (IL-6) cytokine-signaling pathway in tumor progression. Thus, ARID1A and PIK3CA mutations cause ovarian clear-cell carcinoma and promote tumor cell growth by acting upon the IL-6 signaling pathway.

Medical Research: What should clinicians and patients take away from your report?

Response: The growing number of patient-derived tumor sequencing studies, such as The Cancer Genome Atlas (TCGA), has expanded the list of potential cancer causing mutations in humans. With this new “blueprint” of the cancer genome, we now have the instructions necessary to build “better” mouse models of cancer. These models are essential to our understanding of cancer and will serve as experimental drug testing platforms in pre-clinical drug settings.

The identification of the IL-6 pathway as a target of disease progression in our mouse model of ovarian clear-cell carcinoma exemplifies this idea. Efforts to implement anti-IL6 antibody therapy (Siltuximab) in cancer treatment are currently underway. Thus, IL-6 pathway inhibition may prove to be a safe and alternative therapeutic option for patients with ovarian clear-cell carcinoma.

Medical Research: What recommendations do you have for future research as a result of this study?

Response: The IL-6 pathway is strong promoter of tumor cell growth, but its role in tumor initiation, metastases, and the tumor microenvironment is less clear. Moreover, the prevalence of this cytokine signaling pathway in inflamed tissues and in tumors, offers us the opportunity to hone in on the role of inflammatory signaling pathways or chronic inflammatory states in cancer. These pathways have the ability to augment tumor cell growth and the organism or environment in which the tumor resides. Ultimately, the systemic involvement of these pathways contributes to a steep decline in cancer patient wellness. Future studies involving genetically engineered mice will allow us to model there involvement in the whole organism and at every stage of the disease process.

Citation:

Coexistent ARID1A–PIK3CA mutations promote ovarian clear-cell tumorigenesis through pro-tumorigenic inflammatory cytokine signalling

Chandler RL1, Damrauer JS1, Raab JR1, Schisler JC2, Wilkerson MD1, Didion JP1, Starmer J1, Serber D1, Yee D1, Xiong J3, Darr DB3, de Villena FP1, Kim WY4, Magnuson T1.

Nat Commun. 2015 Jan 27;6:6118. doi: 10.1038/ncomms7118.


MedicalResearch.com Interview with Dr. Terry Magnuson PhD (2015). Two Gene Mutations Linked To Deadly Ovarian Cancer