Recurrent Mutations in Epigenetic Modifiers and JAK-STAT Pathway Seen in Sezary Syndrome, a Rare, Aggressive Leukemia; Results Highlight Genetic Vulnerabilities That Can Be Targeted in Precision Medicine Therapies

Sezary syndrome (SS), an aggressive leukemia of mature T cells, is more complicated at a molecular level than ever suspected, according to investigators from the Perelman School of Medicine at the University of Pennsylvania, and from collaborating institutions. With a poor prognosis and limited options for targeted therapies, fighting SS needs new treatment approaches. The team's results uncover a previously unknown, complex genomic landscape of this cancer, which can be used to design new personalized drug regimens for SS patients based on their unique genetic makeups. SS is a rare condition. Its incidence is estimated to be about 0.3-2 cases per 100,000 in the United States each year, and those patients have a five-year survival rate of less than 30 percent. Penn Medicine has one of the largest referral clinics for treatment of SS patients in the country. Taking a thorough approach to find SS mutations, senior authors Megan S. Lim, M.D., Ph.D., a Professor of Pathology and Laboratory Medicine, and Kojo Elenitoba-Johnson, M.D., the Peter C. Nowell, M.D. Professor and Director of the Center for Personalized Diagnostics, were not disappointed. "We basically found chromosomal chaos in all of our samples," Dr. Elenitoba-Johnson said. The research results were published online on September 29, 2015 in an open-access article in Nature Communications. The title of the article is “Genomic Analyses Reveal Recurrent Mutations in Epigenetic Modifiers and the JAK–STAT Pathway in Sézary Syndrome.” The team integrated three complementary gene sequencing approaches to look for mutations in tumor cells from SS patients: whole-genome sequencing in six subjects, exome sequencing of all protein-coding regions in 66 subjects, and comparing variation in the number of copies of all genes across the genome in 80 subjects.
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