Glioma grade and mortality in relation to sequence variation in the mitochondrial genome

Glioma arises from glial cells and comprises ∼80 % of malignant adult brain tumors. The polymorphic mitochondrial genome plays a key role in maintaining redox homeostasis and generation of reactive oxygen species (ROS). ROS have a well-established role in glial tumors. We investigated associations between germline mtDNA variants and haplogroups with glioma grade and glioblastoma (GBM) survival.

We conducted germline mtDNA sequencing for 388 patients (300 Caucasians, 88 African Americans [AA]) with incident glioma (105 non-GBM, 283 GBM). Across all patients we identified 1431 homoplasmic mtDNA variants, including 692 variants observed only in Caucasians, 474 only in AAs, and 265 in both groups. We estimated Odds Ratios (OR) and 95 % Confidence Intervals (CI) for mtDNA common variants, haplogroups, and gene variant burden in relation to glioma grade and tertiles of survival in GBM patients. Bonferroni and Benjamini-Hochberg correction were applied for multiple comparisons.

No mtDNA haplogroup was associated with glioma grade or patient survival in GBM. Common variants m.3010G>A, m.195T>C, and m.16189T>C were linked to lower-grade glioma risk. For GBM survival, m.1719G>A, m.14766T>C, m.16129G>A, and m.204T>C were associated with a poorer prognosis while variant m.73A>G was associated with an improved prognosis. A higher variant burden in MT-ND1 and MT-ND5 was associated with a better prognosis. No results remained statistically significant after correction.

This is the first comprehensive study of germline mtDNA sequence variation in relation to glioma grade at diagnosis and gliobastoma patient survival. Results warrant further study in larger populations and investigation of biologic mechanisms linking mtDNA polymorphism to these endpoints.