Smoking associated with mutations linked to myelodysplastic syndrome
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Key takeaways:
- Individuals who smoked had more genetic mutations associated with myelodysplastic syndrome than nonsmokers.
- Patients with longer smoking histories had a higher number of mutations and greater likelihood of disease progression.
SAN DIEGO — Genetic mutations related to myelodysplastic syndrome occurred significantly more often among people who smoked than nonsmokers, according to study results presented at ASH Annual Meeting and Exposition.
Additionally, long-term smokers exhibited greater risk for disease progression.
“This is the first study to show a clear association between smoking and myelodysplastic syndrome,” Sangeetha Venugopal, MD, MS, assistant professor in the leukemia program at Sylvester Comprehensive Cancer Center at University of Miami Miller School of Medicine, told Healio. “Patients newly diagnosed with myelodysplastic syndrome must be counseled to stop smoking, as it leads to disease progression and decreased overall survival.”
Background and methods
Prior research showed smoking increased genetic mutations in solid tumors such as lung cancer or throat cancer, Venugopal said.
“We wanted to evaluate if tobacco smoking is associated with pathogenic mutations in myelodysplastic syndrome,” she said.
Venugopal and colleagues analyzed data from the prospective NHLBI/NCI National MDS Natural History study, which enrolled patients suspected to have or who had recently been diagnosed with myelodysplastic syndrome.
The cohort included 1,898 people, 52% of whom had a self-reported smoking history.
Men (68% vs. 54%) and older individuals (age 70 to 79 years, 45% vs. 34%) accounted for a higher percentage of those with a smoking history than no smoking history.
Mutation frequency among smokers and nonsmokers served as the primary endpoint. Disease progression and OS served as secondary endpoints.
Results and next steps
Myelodysplastic syndrome occurred at similar rates among smokers and nonsmokers (41% vs. 37%).
Univariate analysis showed a similar number of mutations between smokers and nonsmokers (mean, 2 in each group). Results showed the highest mean number of mutations for those with myelodysplastic syndrome/myeloproliferative neoplasm overlap (3.3), followed by myelodysplastic syndrome (2.3) and those with clonal cytopenia of undetermined significance (1.5).
However, multivariable regression models adjusted for age, sex and disease group showed a higher rate of mutations among smokers (mean, 2 vs. 1.4; P = .04).
The number of mutations increased significantly per pack-year of smoking history (P = .006). Individuals in the 75th percentile of pack-years smoked had 1.8 times more mutations than nonsmokers, and those in the 90th percentile had 3.5 times more mutations.
Univariate analysis showed smokers had higher prevalence of mutations in gene pathways for chromatin modification (15% vs. 11%; P < .01) and RNA splicing (26% vs. 19%; P < .001). They also had higher prevalence of mutations in specific genes, including ASXL1 (12% vs. 8%, P < .01), SF3B1 (9% vs. 6%; P < 0.05), U2AF1 (6% vs. 3%; P < .05) and ZRSR2 (2% vs. 1%; P < .05).
Multivariable analysis showed mutation prevalence increased with pack-years smoked in gene pathways for chromatin modification and RNA splicing (P < .03 for both). Prevalence of mutations in ASXL1 and ETNK1 (P < .05 for both) also increased with pack-years smoked.
Long-term smokers had higher 5-year cumulative incidence of disease progression ( 20 years vs. < 20 years, 27% vs. 18%, P < 0.05).
Analysis based on disease group showed significantly lower OS for smokers than nonsmokers among those with clonal cytopenia of undetermined significance (HR = 1.1; 95% CI, 1.03-3.55). The difference did not reach statistical significance for those with myelodysplastic syndrome (HR = 1.21; 95% CI, 0.53-1.3).
Venugopal and colleagues acknowledged study limitations, including the fact it included patients already diagnosed with myelodysplastic syndrome or clonal cytopenia of undetermined significance
“It will be interesting to see if smoking promotes the development of [myelodysplastic syndrome],” Venugopal said.
For more information:
Sangeetha Venugopal, MD, MS, can be reached at svenugopal@miami.edu.
Perspective
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Mikkael A. Sekeres, MD
I remember when I was a medical student and I naively walked into one patient's room. The patient had advanced lung cancer and I started talking to her about smoking cessation. The patient looked at me like I had three heads and she said, “Why should I stop smoking? The cat is already out of the bag. I have lung cancer.”One of the ramifications of this study is that the data suggest a patient with a new diagnosis of MDS who smokes should be counseled to stop smoking, as it appears smoking contributes to the acquisition of new genetic mutations that can lead to worsening of myelodysplastic syndrome and even evolution of the cancer to acute myeloid leukemia.
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Venugopal S, et al. Abstract 4597. Presented at: ASH Annual Meeting and Exposition; Dec. 7-10, 2024; San Diego.
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