Abstract
The role of mitochondrial DNA (mt-DNA) changes, especially those in the regulatory D-loop region in Acute Myeloid Leukemia (AML) remains investigational. Consecutive 151 de novo pediatric AML patients, (≤18 yr) were prospectively enrolled from June 2013-August 2016, to assess the prognostic impact of mt-DNA D-loop variations (somatic/germline) on survival. For each patient, D-loop region was sequenced on baseline bone marrow and buccal swab, and mother’s blood sample. In 151 AML subjects, 1490 variations were found at 237 positions; 80.9% were germline and 19.1% somatic. The mean number of variations per position was 6.3. Variations with frequency ≥6 were analyzed for their impact on survival and 4 categories were created, namely “somatic-protective”, “somatic-hazardous”, “germline-protective” and “germline- hazardous”. Although, somatic-protective could not predict event free survival (EFS) or overall survival (OS), somatic-hazardous [(OS) HR = 2.33, p = 0.06] and germline-hazardous [(OS) HR = 2.85, p < 0.01] significantly predicted OS and EFS. Notably, the germline-protective, could significantly predict EFS (HR = 0.31, p = 0.03) and OS (HR = 0.19, p < 0.01), only when variations at ≥2 positions were present. On multivariate analysis, three positions namely 16111, 16126, 16362 and karyotype were found to be predictive of EFS. A prognostic index (PI) was developed using nomogram PI = (0.8*karyotype) + (1.0*c16111) + (0.7*t16362) + (1.2*t16126). Hazard ratio for EFS increased significantly with increasing PI reaching to a maximum of 3.3 (p < 0.01). In conclusion, the impact of mt-DNA D-loop variations on outcomes in pediatric AML depends on their nature (germline/somatic), position and mutational burden, highlighting their potential role as evolving prognostic biomarkers.
Highlights
Mitochondria are a unique organelle and so is the mitochondrial DNA
Out of 200 subjects, 49 patients were excluded from the study, (5 patients were acute promyelocytic leukemia, 15 patients had only one visit, 4 patients had an unsatisfactory buccal swab, 15 patients had failed sequencing and for 10 patients’s the mother sample was not available)
Variations in the mitochondrial DNA D-loop region have been observed in different solid malignancies and their incidence varies from 21% to 80% depending on the cancer type [13, 14,15,16,17,18,19,20,21]
Summary
Mitochondria are a unique organelle and so is the mitochondrial DNA (mt-DNA). The human mitochondrial genome is 16,569 base pair (bp) in length, with double-stranded circular DNA molecules containing 37 genes [1]. Role of mitochondria in various human malignancies including leukemia has been long proposed and explored with varying outcomes [3,4,5]. This genome includes a non-coding displacement region (D-loop) which consists of 1122 bp (16024 – 577 bp) of mitochondrial DNA. It acts as a promoter region for both the heavy and light strands of the mt-DNA, and contains essential transcription and replication elements [6]. It is not surprising that mitochondrial dysfunction has been linked to human degenerative diseases and cancers, including leukemia [9, 10]
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