Changes in the human mitochondrial genome after treatment of malignant disease.
Mitochondrial DNA (mtDNA) is the only extrachromosomal DNA in human cells. The mitochondrial genome encodes essential information for the synthesis of the mitochondrial respiratory chain. Inherited defects of this genome are an important cause of human disease. In addition, the mitochondrial genome seems to be particularly prone to DNA damage and acquired mutations may have a role in ageing, cancer and neurodegeneration. We wished to determine if radiotherapy and chemotherapy used in the treatment of cancer could induce changes in the mitochondrial genome. Such changes would be an important genetic marker of DNA damage and may explain some of the adverse effects of treatment. We studied samples from patients who had received radiotherapy and chemotherapy for point mutations within the mtDNA control region, and for large-scale deletions. In blood samples from patients, we found a significantly increased number of point mutations compared to the control subjects. In muscle biopsies from 7 of 8 patients whom had received whole body irradiation as well as chemotherapy, the level of a specific mtDNA deletion was significantly greater than in control subjects. Our studies have shown that in patients who have been treated for cancer there is an increased level of mtDNA damage.
Wardell
Theresa M
TM
Department of Neurology, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH, UK.
Ferguson
Elaine
E
Chinnery
Patrick F
PF
Borthwick
Gillian M
GM
Taylor
Robert W
RW
Jackson
Graham
G
Craft
Alan
A
Lightowlers
Robert N
RN
Howell
Neil
N
Turnbull
Douglass M
DM
D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000187:drug effects* / Q000528:radiation effects*; D003627:Data Interpretation, Statistical; D005260:Female; D005820:Genetic Testing; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000737:chemistry / Q000187:drug effects / Q000528:radiation effects; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000532:radiotherapy; D017354:Point Mutation; D016133:Polymerase Chain Reaction / Q000379:methods; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion; D019914:Taq Polymerase / Q000235:genetics / Q000378:metabolism
D004272:DNA, Mitochondrial; D019914:Taq Polymerase