As part of a multi-institutional effort, researchers with Huntsman Cancer Institute at the University of Utah have found that patients with multiple myeloma with a genetic variation in the gene FOPNL die, on average, 1 to 3 years sooner than patients without it. The finding was identified with genome-wide association studies and verified in patient populations from North America and Europe. This was the first study to survey the entire human genome for genetic variations influencing survival; it included a total of 1,635 patients. The study’s results were published by Ziv et al in Nature Communications.
The findings are a step toward applying precision medicine to multiple myeloma, a relatively rare but aggressive and incurable disease, with 43% of patients dying within 5 years of diagnosis. Future studies will focus on finding therapies that improve prospects for this newly identified subset, which makes up an estimated 10% to 14% of patients with multiple myeloma.
“This is the largest study of inherited genetics and myeloma survival to date. We were able to identify the FOPNL variant because it has quite a large effect on survival. With even larger collaborative studies, we hope to add to this,” said Nicola Camp, PhD, Huntsman Cancer Institute Investigator, Professor of Medicine and Human Genetics at the University of Utah School of Medicine, and Chair of the International Multiple Myeloma Consortium. “The ability to stratify patients based on their genetic makeup opens the door to personalizing their treatment and care.”
Dr. Camp led the study together with Elad Ziv, MD, at the University of California, San Francisco (UCSF); Celine Vachon, PhD, at the Mayo College of Medicine; and Federico Canzian, PhD, from the German Cancer Research Center. The collaboration includes contributions from 38 scientists at 18 institutions and reports on patient data from clinics across Utah, UCSF, the Mayo Clinic, and several European centers in Italy, Poland, Spain, France, Portugal, and Germany.
Although the researchers don't yet understand why the genetic variation in FOPNL is associated with poor prognosis, there are clues that it could be involved in disease progression through centrosome amplification. Analysis of separate multiple myeloma patient datasets show that those with the worst outcomes have abnormal amounts of FOPNL, and carry another sign of poor prognosis—a high centrosome index. The implication is that disruptions in FOPNL could affect fundamental mechanisms controlling the distribution of genetic material to newly made cells.
“The results point us to a previously unrecognized gene as a determinant of myeloma prognosis. If we understand what about this gene is causing poor prognosis, that may lead to a better fundamental grasp of the pathways that are important in multiple myeloma progression,” said Dr. Ziv, Professor of Medicine at UCSF. “Such knowledge could ultimately lead to better therapies.”
Dr. Ziv is the corresponding author for the Nature Communications article.
The United States–based research was supported by the Huntsman Cancer Institute (HCI), the HCI Cancer Center Support Grant P30 CA042014, Leukemia & Lymphoma Society, National Institutes of Health, National Cancer Institute SEER, Utah State Department of Health, and University of Utah. Other research within the study was supported by Steve and Nancy Grand Multiple Myeloma Translational Initiative, Expression Analysis, the National Cancer Institute, Polish Ministry of Science and Higher Education, and the The Research Fund at Region Sjælland, Denmark.
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