Detection of somatic mutations in the mitochondrial DNA control region D‑loop in brain tumors: The first report in Malaysian patients

Abstract

Although the role of nuclear-encoded gene alterations has been well documented in brain tumor development, the involvement of the mitochondrial genome in brain tumorigenesis has not yet been fully elucidated and remains controversial. The present study aimed to identify mutations in the mitochondrial DNA (mtDNA) control region D-loop in patients with brain tumors in Malaysia. A mutation analysis was performed in which DNA was extracted from paired tumor tissue and blood samples obtained from 49 patients with brain tumors. The D-loop region DNA was amplified using the PCR technique, and genetic data from DNA sequencing analyses were compared with the published revised Cambridge sequence to identify somatic mutations. Among the 49 brain tumor tissue samples evaluated, 25 cases (51%) had somatic mutations of the mtDNA D-loop, with a total of 48 mutations. Novel mutations that had not previously been identified in the D-loop region (176 A-deletion, 476 C>A, 566 C>A and 16405 A-deletion) were also classified. No significant associations between the D-loop mutation status and the clinicopathological parameters were observed. To the best of our knowledge, the current study presents the first evidence of alterations in the mtDNA D-loop regions in the brain tumors of Malaysian patients. These results may provide an overview and data regarding the incidence of mitochondrial genome alterations in Malaysian patients with brain tumors. In addition to nuclear genome aberrations, these specific mitochondrial genome alterations may also be considered as potential cancer biomarkers for the diagnosis and staging of brain cancers.

Whole mitochondrial genome sequencing highlights mitochondrial impact in gastric cancer

“…Moreover, the regions with more tumor-exclusive variants were the MT- DLOOP1 and MT- DLOOP2 (16% each). This corroborates previous studies that associated an increase of variants in such control regions to the development of different types of cancer, including hepatocellular carcinoma 39 , brain tumor 40 , oral squamous cell carcinoma 41 , colon cancer 42 and gastric cancer 43 . Further, a study have associated five variants in these genes with gastric cancer, including A73G and T16519C 44 , which we found frequently in our tumor samples but not in internal control samples.…”

Discovery of a Ruthenium Complex for the Theranosis of Glioma through Targeting the Mitochondrial DNA with Bioinformatic Methods

“…To identify the affinity sites of RC-7 in mtDNA, several mtDNA fragments and their mutant sites in glioma as reported were synthesized [23,24], in which seq. 1 comes from the regulatory region (D-loop region) of mtDNA, and seq.…”

Mitochondrial DNA Alterations in Glioblastoma (GBM)

“…Most mtDNA mutations are missense transitions, unequally distributed between HSP and LPS strands [ 48 ], as they are most likely to be functionally involved as modifiers of GBM tumorigenic processes [ 3 ]. Most somatic point mutations of mtDNA are present in the D-LOOP region, leading to dysregulations in replication and transcription processes, resulting in mtDNA copy number variations, mitochondrial dysfunction, and excessive production of ROS [ 3 , 47 , 49 ]; mutations associated with GBM can be found in almost all mtDNA genome ( Table 1 ).…”

“…The D-LOOP region is the main hotspot for somatic mtDNA mutations, especially in a repeated sequence of cytosines between nucleotides 303 to 315, called polycytosine tract (poly-C), or D310 [ 41 , 50 , 51 , 53 ], which can be used for clinical follow-up of GBM [ 56 ]. Another D-LOOP hotspot polymorphism is T16189C, which although frequently observed, does not correlate with GBM etiology [ 49 , 50 , 51 , 54 ]. However, several less frequent alterations, like C16069T, T16126C, C16186T, G16274A, C16355T, and T16362C, were described as associated with GBM tumorigenesis [ 54 ].…”