Novel Mutations Detected at Work in Rare Histiocytoses Cases
Published December 2019 | Nature Medicine
Histiocytoses are a collection of rare disorders that share a common trait of excess accumulation of dendritic cells that can lead to tumor formation across many areas of the body. According to the Histiocytosis Association of America, 1 in 200,000 U.S. children per year are born with histiocytosis.
Most of these disorders are now known to be driven by mutations in the mitogen-activated protein kinase (MAPK) pathway mapping to the BRAF and MEK1 and MEK2 kinases in the majority. However, the developmental origins for many groups within this disease category are not yet known.
Now a multi-institutional team of scientists—including co-author Jennifer Picarsic, MD, who serves as Co-Director of the Langerhans Cell Histiocytosis Center—has detailed a new collection of kinase mutations linked to histiocytic neoplasms. The project included experts from Memorial Sloan Kettering Cancer Center, Children’s Hospital of Pittsburgh, and centers in Belgium, Spain and France.
The team performed extensive analysis of 270 patients that uncovered a series of activating receptor tyrosine kinase (RTK) alterations. Key discoveries included finding activating mutations in CSF1R and rearrangements in NTRK, RET and ALK. Adult patients with some of these newly identified mutations showed dramatic responses to the RET inhibitor selpercatinib and the ALK inhibitor crizotinib. Meanwhile, another patient with refractory Langerhans Cell Histiocytosis (LCH) benefitted from the MEK1/2 inhibitor trametinib.
“These findings further support the genetic diversity found in the histiocytic neoplastic lesions and show that with a robust testing platform, we can identify those who may benefit from kinase-inhibitor medications, which have not traditionally been prescribed for these conditions,” Picarsic says. The Langerhans Cell Histiocytosis Center, co-directed by Ashish Kumar, MD, PhD, is one of the few centers worldwide capable of providing inhibitor-based therapy as a first-line treatment based on the patient’s unique mutational profile.
