Mount Sinai Scientists Find Novel Ovarian Cancer Biomarker with IPA

John Martignetti

John Martignetti, Associate Professor at the Icahn School of Medicine at Mount Sinai

Treatment options for ovarian cancer haven’t changed much in three decades — but a powerful new biomarker identified by scientists at Mount Sinai has shed light on why some patients respond well to the gold-standard chemotherapy regimen while others do not. They discovered IRF1 in just seven samples with Ingenuity Pathway Analysis (IPA) from QIAGEN.

In this study, scientists led by John Martignetti, Associate Professor at the Icahn School of Medicine at Mount Sinai, relied on a unique ovarian cancer biorepository he established seven years ago with Director of Gynecologic Oncology Peter Dottino. The biobank includes a longitudinal collection of blood and tissue specimens, creation of cell lines for all tumors, and the development of animal models for some patients as part of the personalized cancer therapy program at the Icahn Institute for Genomics and Multiscale Biology.

With this remarkable resource, the team identified a novel prognostic biomarker indicating whether a patient will respond well or poorly to the standard chemotherapy used for this aggressive type of cancer. In a project detailed in a recent publication in the journal Gynecologic Oncology, Martignetti and his colleagues dug into their biorepository to figure out why some patients with ovarian cancer respond to chemo while others become resistant. They chose just a few samples: four from people who eventually became resistant to platinum treatment, and three from patients who remained sensitive to the treatment over time.

Martignetti’s team performed a complete transcriptome analysis of the samples to determine whether gene expression levels in the tumors would have revealed each patient’s outcome. “That’s when we turned to IPA,” he says. Martignetti collaborated with QIAGEN scientists Jean-Noel Billaud and Richard Halpert for intensive analysis of the transcriptome data. “Using IPA and the Upstream Regulator Analysis module, with just seven cases, we found two really strong predictors for differences between the platinum-sensitive and the platinum-resistant patients,” he says. These two biomarker candidates, IRF1 and IRF7, were both linked to immune response — and conveniently, the former activated the latter, so the scientists focused their studies on IRF1.

Of course, identifying IRF1 from so few samples made it a candidate — but one that needed to be validated. Results from a second study of 31 samples, as well as an online resource that allowed them to look at IRF1 expression levels across more than 1,200 high-grade serous ovarian cancer samples, were consistent: “If you have high IRF1 levels, you have better progression-free survival and better overall survival rates,” Martignetti says.

He says that IPA was an instrumental analysis tool in this project. “The Upstream Regulator Analysis was important in pulling together all the disparate pathways that were being activated and upregulated to find the commonality of the IRF1 pathway,” Martignetti says. “That’s not something we could have done manually. We would not have seen that relationship without IPA.”

For more on this study,  follow-up research on the biomarker, and Mount Sinai’s ovarian cancer biorepository, please read the case study.