Zeroing in on the Genetic Roots of Fibroids

Cynthia Morton, PhD

In the effort to identify genetic drivers of fibroids, the lab of Cynthia Morton, PhD, at Brigham and Women’s Hospital (BWH) is at an international crossroads. In recent years, Morton and investigators worldwide have been studying the molecular and genetic background of fibroids that may contribute to their development and growth.

Dr. Morton and recent graduate student Scott Gallagher, PhD, lead a large international team that has zeroed in on more than two dozen novel loci associated with the risk to develop fibroids. As the team learns more about the biological mechanisms underlying fibroids, they also are finding overlapping genetic origins with endometriosis.

“Understanding  the genetic risk for developing these tumors would help inform women as to what kind of medical management they might want to choose,” said Dr. Morton, director of Cytogenetics Research and the Kenneth J. Ryan, MD, distinguished chair in Obstetrics and Gynecology in the BWH Department of Obstetrics and Gynecology. Women typically present with multiple fibroids at the time of initial diagnosis. For a woman to learn that her uterus is primed genetically to develop these tumors may be helpful information as she chooses between a myomectomy or hysterectomy. “If a woman knows she is likely to develop additional uterine fibroids, she might think ‘I don’t want to be back here in three years with the same problem,’ and opt for the hysterectomy.”

Ongoing work in Dr. Morton’s lab and others are identifying genetic markers that mediate the transition from normal myometrial tissue to fibroids. The research also suggests potential therapeutic avenues.

Groundbreaking work from Finland has identified recurrent and mutually exclusive alterations in a small number of key genes to lead to molecularly distinct subclasses of leiomyomas. Each subclass shows subclass-specific transcriptional differences in various key driver pathways. Netta Makinen, PhD a member of the Finnish team, is currently a research fellow in Morton’s lab at BWH, where they continue to identify the range of molecular changes in order potentially to address these tumors clinically.

Because some women have multiple fibroids that may represent different molecular subclasses, it is important to understand the mechanisms underlying their tumorigenesis to know which medical treatments would be effective, Dr. Makinen noted.

“The next goal is to figure out the exact biological mechanisms underlying each of these different subclasses so we could see if the subclasses have something (or nothing) in common to guide treatment development,” said Dr. Makinen. “My colleagues in Finland hypothesize that the different types of tumors respond differently to treatment options. It’s also important for clinicians to understand that the tumors might behave differently from each other.”

Is it too early to be thinking about targeted therapies? Not necessarily, says Dr. Morton.

“If we can really understand the biological implications of the genes that cause this, we can begin to think about personalized therapies that could be developed,” she said. “The field of gene editing has moved ahead so quickly, it may not be so far in the future.”

The work among colleagues from around the world, Dr. Makinen explained, is “a huge team effort.”

“You don’t do these things by yourself,” she noted. “Even if we are heading from different directions, everyone is aiming for the same goal – to help patients.”