Session: 503. Clonal Hematopoiesis, Aging, and Inflammation: Poster III
Hematology Disease Topics & Pathways:
Research, Epidemiology, Clinical Research, Registries
Methods: We used the MitoHPC pipeline to quantify mtDNA heteroplasmy from whole genome sequencing data obtained from buffy coat. We defined a variant allele frequency between 5 and 95% as heteroplasmic and identified predicted deleterious consequences of mtDNA variants using a recently developed local constraint-based score, the modified mitochondrial local constraint score sum (mMSS). CHIP variants were called from whole exome sequencing data. CLL was identified using ICD-10 codes from cancer registry data linked to the UKB. We evaluated the associations of mtDNA heteroplasmy, L-CHIP, and incident CLL using Cox proportional hazards models adjusting for age, sex, smoking, and a history of cancer diagnosis in individuals who did not have a history of CLL or myeloid neoplasms (MN). Individuals with an absolute lymphocyte count over 5,000/uL were also removed, as they likely represented undiagnosed CLL.
Results: In the current study, we included 419,229 individuals from the UKB. The median age was 58 (50, 63) years, 45.8% (n = 191,955) were men and 94.8% (n = 395,888) were self-identified as White. Heteroplasmy was present in 118,515 (28.3%) individuals, while L-CHIP was present in 10,747 (2.6%) individuals. Overall, there were 463 cases of incident CLL with a median follow-up time of 7.6 (5.2, 9.9) years. Heteroplasmy prevalence and mMSS were higher in individuals with L-CHIP compared to those without and enriched in high-risk L-CHIP subsets (VAF ≥ 10% and multiple mutations). Consistent with previous reports, L-CHIP was associated with an increased incidence of CLL (HR = 5.1; 95% CI 3.9–6.7; P < 0.0001).
Within the whole cohort, we found that individuals with heteroplasmy were at significantly higher risk of developing CLL (HR = 1.5; 95% CI 1.3–1.8; P < 0.0001). Additionally, likely deleterious mutations as determined by mMSS, were associated with significantly higher incidence of CLL (HR = 4.2; 95% CI 3.2–5.5; P <0.0001). In individuals without L-CHIP, we also demonstrated that heteroplasmy prevalence was an independent predictor of CLL risk (HR = 1.5; 95% CI 1.2–1.8; P < 0.0001). Moreover, in individuals without L-CHIP, mMSS (HR = 4.4; 95% CI 3.3–5.9; P <0.0001) remained significantly associated with incident CLL. The fact that heteroplasmy and mMSS remained significantly associated with CLL in L-CHIP negative individuals, suggests that this association was not merely a marker of underlying L-CHIP but that it likely plays a biologically significant role in the expansion and/or transformation of the underlying lymphoid clones.
Conclusions: Overall, mitochondrial heteroplasmy appears to be a novel risk factor for CLL development even in a CHIP negative population. Our study also suggests that heteroplasmy is not only a marker of clonal expansion, but altered mitochondrial function may play an important biological role in the expansion and/or oncogenic transformation of the pre-malignant lymphoid clone.
Disclosures: No relevant conflicts of interest to declare.
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