Mitochondrial DNA copy number and future risk of B-cell lymphoma in a nested case-control study in the prospective EPIC cohort

Abstract

Key Points• This study strengthens the previous observation of elevated mitochondrial DNA copy number and future risk of chronic lymphocytic leukemia.It has been suggested that mitochondrial dysfunction and DNA damage are involved in lymphomagenesis. Increased copy number of mitochondrial DNA (mtDNA) as a compensatory mechanism of mitochondrial dysfunction previously has been associated with B-cell lymphomas, in particular chronic lymphocytic leukemia (CLL). However, current evidence is limited and based on a relatively small number of cases. Using a nested case-control study, we extended these findings with a focus on subtype-specific analyses. Relative mtDNA copy number was measured in the buffy coat of prospectively collected blood of 469 lymphoma cases and 469 matched controls. The association between mtDNA copy number and the risk of developing lymphoma and histologic subtypes was examined using logistic regression models. We found no overall association between mtDNA and risk of lymphoma. Subtype analyses revealed significant increased risks of CLL (n 5 102) with increasing mtDNA copy number (odds ratio 5 1.34, 1.44, and 1.80 for quartiles 2-4, respectively; P trend 5 .001). mtDNA copy number was not associated with follow-up time, suggesting that this observation is not strongly influenced by indolent disease status. This study substantially strengthens the evidence that mtDNA copy number is related to risk of CLL and supports the importance of mitochondrial dysfunction as a possible mechanistic pathway in CLL ontogenesis. (Blood. 2014;124(4):530-535)

Mitochondrial DNA copy number in whole blood and glioma risk: A case control study

“…For example, in a recent report from Zhang et al, levels of mtDNA copy number were significantly higher in glioma tumor tissues ( n = 124) than non‐neoplastic brain tissues ( n = 27) . Our results are also consistent with reports from other cancer sites, including melanoma, lung cancer, renal cell carcinoma, breast cancer, chronic lymphocytic leukemia, non‐Hodgkin lymphoma, colorectal cancer, and pancreatic cancer . More intriguingly, the positive association is not only observed in case control studies, but also in nested case control studies .…”

Acquired TERT promoter mutations stimulate TERT transcription in mantle cell lymphoma

“…In our study, we found that mitochondrial DNA (mtDNA) copy number was higher in lymphoma cells carrying an acquired TERTp mutation, suggesting that TERT overexpression modulates mtDNA regulation. The exact mechanism through which altered mtDNA may contribute to lymphomagenesis still remains unclear; however, mitochondrial biogenesis is a biologic pathway to be considered [34].…”

Metabolism pathways in chronic lymphocytic leukemia

“…Although chemotherapy was shown to induce heterotrophic mtDNA mutations in CLL [29], Meierhofer et al found that blood transfusions might have ‘contaminated’ the tested samples with donors’ blood cell mitochondria [30] harboring abnormalities in hot spots that are frequently mutated in the general population [31]. Nevertheless, although the mtDNA structure of patients with CLL is no different from that of normal individuals, several studies showed that an increase in mtDNA copy numbers is associated with an increased risk for the development of CLL and non-Hodgkin’s Lymphoma [32,33]. …”