Suchergebnisse

Mitochondrial genomes are separated from the nuclear genome for most of the cell cycle by the nuclear double membrane, intervening cytoplasm, and the mitochondrial double membrane. Despite these physical barriers, we show that somatically acquired mitochondrial-nuclear genome fusion sequences are present in cancer cells. Most occur in conjunction with intranuclear genomic rearrangements, and the features of the fusion fragments indicate that nonhomologous end joining and/or replication-dependent DNA double-strand break repair are the dominant mechanisms involved. Remarkably, mitochondrial-nuclear genome fusions occur at a similar rate per base pair of DNA as interchromosomal nuclear rearrangements, indicating the presence of a high frequency of contact between mitochondrial and nuclear DNA in some somatic cells. Transmission of mitochondrial DNA to the nuclear genome occurs in neoplastically transformed cells, but we do not exclude the possibility that some mitochondrial-nuclear DNA fusions observed in cancer occurred years earlier in normal somatic cells. ; This work was supported by the Wellcome Trust. Y.S.J is supported by a European Molecular Biology Organization long-term fellowship (LTF 1203_2012). J.M.C.T. is supported by Marie Curie Fellowship FP7 PEOPLE-2012-IEF (project number 328264). P.J.C. is a Wellcome Trust Senior Clinical Fellow. Support was provided to A.M.F. by the National Institute for Health Research (NIHR) UCLH Biomedical Research Centre. The ICGC Breast Cancer Consortium was supported by a grant from the European Union (BASIS) and the Wellcome Trust. The ICGC Prostate Cancer Consortium was funded by Cancer Research UK with a grant from the Dallaglio Foundation (grant number C5047/A14835). R.E. is supported by National Institute for Health Research support to the Biomedical Research Centre at The Institute of Cancer Research and Royal Marsden NHS Foundation Trust. We also thank the National Cancer Research Prostate Cancer Mechanisms of Progression and Treatment (PROMPT) collaborative (grant code G0500966/75466) which has funded tissue and urine collections in Cambridge. The authors also acknowledge financial support from the Department of Health via the National Institute for Health Research comprehensive Biomedical Research Centre award to Guy's and St. Thomas' NHS Foundation Trust and Breakthrough Breast Cancer Research (ICGC 08/09 and KCL) (A.T.).