Researchers at Vanderbilt University Medical Center have identified key factors that contribute to the clonal growth of abnormal blood cells experienced by roughly 1 in 10 people over age 70.
Their findings, published Nov. 14 in the journal Haematologica, could lead to improved diagnosis and the first effective treatment for the disorder, called “clonal hematopoiesis of indeterminant potential,” or CHIP.
Triggered by somatic (non-inherited) mutations in blood stem cells, CHIP increases by an estimated 40% the risk of death from cardiovascular, lung and liver disease, as well as other inflammatory conditions.
In the largest longitudinal cohort study of CHIP conducted to date, the researchers analyzed genetic sequences of repeat biosamples donated by 3,000 individuals with the disorder that were linked through VUMC’s biobank, BioVU, to their de-identified electronic medical records.
Led by the paper’s senior author, Alexander Bick, MD, PhD, associate professor of Medicine and director of the Division of Genetic Medicine, the researchers discovered two germline variations (inherited from one’s parents) that interact with somatic mutations to change the clonal expansion rate.
By associating expansion rates with exposure to various medications, they also found evidence that three commonly used immunosuppressive and anti-inflammatory drugs may slow the clonal expansion rate.
The drugs are colchicine, which is used to treat gout, denosumab, a monoclonal antibody used to treat osteoporosis and bone cancer, and methylprednisolone, a corticosteroid used to treat a wide range of inflammatory conditions, from asthma to ulcerative colitis.
The study provides the first definitive evidence that a faster expansion rate, which is associated with one of the germline mutations, increases the risk of abnormal blood counts and rare blood cancers called myeloproliferative neoplasms.
“Using this cohort, we show how germline genetics, medications and preexisting diagnoses impact the clonal hematopoiesis growth rate,” said Yash Pershad, the paper’s co-first author with Taralynn Mack, PhD.
Mack, who recently defended her doctoral dissertation in the Vanderbilt Human Genetics Program, and Pershad, an MD/PhD student in the Vanderbilt Medical Scientist Training Program, are members of Bick’s lab.
“We show how cancer risk for individuals with CHIP changes over time,” Pershad said. “Our work suggests that the monitoring of clinical factors, such as blood counts, captures dynamic clinical risk and that resequencing individuals for CHIP may not be clinically necessary.”
Other VUMC co-authors are Cosmin Bejan, PhD, Jonathan Brett Heimlich, MD, PhD, Yajing Li, MS, Nicole Mickels, Joseph Van Amburg, MS, Jessica Ulloa, Alexander Silver, PhD, Leo Luo, MD, Angela Jones, Paul Brent Ferrell, MD, Ashwin Kishtagari, MD, Yaomin Xu, PhD, and Michael Savona, MD.
This work was supported in part by National Institutes of Health grants DP5OD029586, T32GM007347, F30DK127699, K12CA090625, R01CA262287 and U01OH012271. Support was also provided by a Burroughs Wellcome Fund Career Award for Medical Scientists, the E.P. Evans Foundation, the RUNX1 Research Program, a Pew Charitable Trusts and Alexander and Margaret Stewart Trust Pew-Stewart Scholar for Cancer Research award, the Vanderbilt University Medical Center Brock Family Endowment, a Young Ambassador Award, the Adventure Alle Fund, and the Beverly and George Rawlings Endowment.
