Oncotarget

Research Papers:

Prognostic impact of mitochondrial DNA D-loop variations in pediatric acute myeloid leukemia

Anudishi Tyagi _, Raja Pramanik, Sreenivas Vishnubhatla, Radhika Bakhshi and Sameer Bakhshi

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Oncotarget. 2019; 10:1334-1343. https://doi.org/10.18632/oncotarget.26665

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Abstract

Anudishi Tyagi1, Raja Pramanik1, Sreenivas Vishnubhatla2, Radhika Bakhshi3 and Sameer Bakhshi1

1Department of Medical Oncology, Dr. B. R. A. Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India

2Department of Biostatistics, All India Institute of Medical Sciences, New Delhi, India

3Department of Biomedical Sciences, Shaheed Rajguru College of Applied Sciences, University of Delhi, New Delhi, India

Correspondence to:

Sameer Bakhshi, email: sambakh@hotmail.com

Keywords: pediatric AML; mitochondrial DNA; D-loop; prognosis; leukemia

Received: October 30, 2018     Accepted: January 31, 2019     Published: February 12, 2019

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.


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