Obesity may increase risk for blood cancer
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Key takeaways:
- Nearly 6% of the study population had clonal hematopoiesis of indeterminate potential.
- CHIP appeared associated with increased waist-to-hip ratio.
Obesity appeared strongly associated with clonal hematopoiesis of indeterminate potential — a blood condition linked to increased risk for blood cancer, according to study results published in The Journal of Clinical Investigation.
Targeting clonal hematopoiesis of indeterminate potential (CHIP)-mutant cells with nifedipine, MCC950, anakinra or metformin may be a feasible treatment approach for these individuals, researchers noted.
Rationale and methodology
“CHIP is a blood condition where blood cells accumulate genetic mutations that increase the risk for the development of blood cancer and cardiovascular disease,” Reuben Kapur, PhD, director of the Herman B. Wells Center for Pediatric Research at Indiana University School of Medicine, told Healio. “Although CHIP is common in aging, the risk factors that contribute to the condition are poorly understood. This research aimed to provide additional insight into potential risk factors for CHIP, such as obesity.”
Researchers analyzed exome sequencing and clinical data from 47,466 individuals (mean age at enrollment, 56.5 years; 45% male; 43.9% never smoked; 82.6% self-reported European descendants) with validated CHIP measurements included in the U.K. Biobank.
They then tested different treatment combinations to target CHIP-mutant cells and find potential therapeutic approaches for the condition.
Findings
Results showed the presence of CHIP in 5.8% of the study population. The most common mutations identified included DNMT3A (3.7%) and TET2 (1%) genes.
Patients had a mean BMI of 27.3 kg/m² and overall mean waist-to-hip ratio of 0.87; 43% had overweight and 23.6% had obesity.
After adjusting for major covariates, researchers found an association of CHIP with a 0.0028 increase in waist-to-hip ratio (P = .03).
“We also found in mouse models with obesity and CHIP that mutated blood cells grow more quickly,” Kapur said.
Results additionally showed that treatment with a calcium channel blocker, either alone or in combination with metformin, appeared to suppress the growth of mutant CHIP cells and partially restored normal hematopoiesis.
Implications
The findings support the notion that finding ways to maintain a healthy weight and keeping one’s level of systemic inflammation in check may lower the risk for developing blood cancer with age, Kapur told Healio.
“Initial findings also suggest that common medications used for treating blood pressure and diabetes may play a role in regulating the growth of mutated blood cells,” he said. “Future studies will focus on examining individuals who are on blood pressure and diabetes medications and investigate their long-term risks for developing blood cancer.”
References:
- IU researchers find link between obesity and blood cancer (press release). Available at: https://www.newswise.com/articles/iu-researchers-find-link-between-obesity-and-blood-cancer?sc=sphr&xy=10046820. Published May 16, 2023. Accessed June 16, 2023.
- Pasupuleti SK, et al. J Clin Invest. 2023;doi:10.1172/JCI163968.
For more information:
Reuben Kapur, PhD, can be reached at rkapur@iupui.edu.
Perspective
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Abhay Singh, MD
Pasupuleti and colleagues report CHIP and associated inflammation in one of the most prevalent diseases globally — that is, obesity. This study corroborates the relationship between obesity and CHIP propagation. Large population-based studies previously have suggested increased risk for myelodysplastic syndrome (MDS) with increasing BMI.
Our recently reported evaluation of the Splendid Study Cohort noted only one MDS case among 5,000 patients who underwent weight-loss surgery compared with 24 MDS cases among 25,000 patients in the nonsurgical group (adjusted HR = 0.14; P = 0.06).
Intuitively, CHIP being a pre-leukemic state, the hypothesis generated was that CHIP incidence would be lower among those with greater weight loss via surgery and, hence, lower incidence of MDS. On a similar note, recent studies also reported a strong association of normal BMI with lower prevalence of CHIP.
Despite compelling associations or instinctive hypotheses, concrete data were missing. Pasupuleti and colleagues have eloquently defined role of obesity in augmenting CHIP. Thus, bringing forth and highlighting the role of nutrition, physical activity and adiposity on cardiometabolic and myeloid malignancy onset and outcomes. Previously, it had been shown that clonal hematopoiesis aggravates insulin resistance in obese mice. The current study reporting obesity-associated inflammation potentiating clonal progression may lead to promising clinical studies of the future.
The current study provides an exceptional foundation to inform clinical trials of tomorrow, where drugs targeted toward inflammation, blood pressure or type 2 diabetes may be repurposed as drugs for myeloid malignancy prevention. Agents that target CHIP mutations are an unmet need, and such agents would have wide clinical utility. Effective drugs with low toxicity targeted to CHIP and inflammation could result in a paradigm-shifting therapeutic strategy for blood cancer prevention. The study by Pasupuleti and colleagues provides necessary evidence and impetus to inform prevention trials of the future.
References:
- Aminian A, et al. JAMA. 2022;doi:10.1001/jama.2022.9009.
- Fuster JJ, et al. Cell Rep. 2020;doi:10.1016/j.celrep.2020.108326.
- Haring B, et al. J Am Heart Assoc. 2021;doi:10.1161/JAHA.120.018789.
- Ma X, et al. Am J Epidemiol. 2009;doi:10.1093/aje/kwp074.
- Mishra R, et al. Abstract e18865. Presented at: ASCO Annual Meeting; June 2-6, 2023; Chicago.
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