MP87-01 RECURRENT MITOCHONDRIAL DNA MUTATION FOUND IN BONE METASTASES

You have accessJournal of UrologyProstate Cancer: Advanced (including Drug Therapy) IV1 Apr 2018MP87-01 RECURRENT MITOCHONDRIAL DNA MUTATION FOUND IN BONE METASTASES Carrie Sun, Colm Morrissey, John Petros, and Rebecca Arnold Carrie SunCarrie Sun More articles by this author , Colm MorrisseyColm Morrissey More articles by this author , John PetrosJohn Petros More articles by this author , and Rebecca ArnoldRebecca Arnold More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.2901AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES We have previously described a single DNA base alteration in the mitochondrially encoded ND3 gene (A10398G; Thr114Ala) that occurs as a bone metastasis-specific alteration in the majority of 13 prostate cancer patients with bone metastasis (Bone 78 (2015) 81-86). The objective of this study was to define the incidence of this single base alteration in an expanded series of patients and to determine whether the prostate primary also harbored this mutation or if it occurred de-novo in the bone using an ultra-sensitive assay. METHODS We developed a digital drop PCR (ddPCR) fluorescent assay using the RainDance platform designed to quantitatively interrogate the mitochondrial DNA (mtDNA) nucleotide position 10398 missense mutation. Clinical specimens from a rapid autopsy program included 39 patients with multiple tissues available including the prostate primary, soft tissue metastases, bone metastases and normal tissue controls. The number of DNA molecules with the wild type and mutant base were counted and mutation levels compared between normal tissue, primary tumor and metastatic sites. RESULTS Of 39 patients with bone metastasis that were evaluated, 20 (51%) had significantly increased levels of the 10398 missense mutation in the mitochondrially encoded ND3 gene compared to normal uninvolved tissue. The increase ranged from 2.5-59 fold in the bone. On average, 200,000 DNA molecules were counted from each tissue examined. Because of the ultra-sensitive nature of the ddPCR assay used, we also identified the same base alteration in 2 lymph node metastases and one adrenal metastasis. Of the 3 primary prostate tissues examined that gave adequate results, 2 did not have an increased alteration at the 10398 position compared to normal tissue and one did. Of the two prostate primaries without the mutation, neither bone metastasis had the mutation. In the patient whose prostate primary tumor had mutation (2.2=fold increase over normal tissue), the bone metastasis also had the mutation (36-fold increase over normal tissue). CONCLUSIONS In this expanded cohort of 39 patients with prostate cancer bone metastases, the majority (51%) had a substantially increased level of missense mutation at the 10398 nucleotide position of the mitochondrial genome in the bone metastasis. This mutational hot-spot is unprecedented in frequency in prostate cancer and implies a strong selective pressure for bone metastatic cells that had acquired this mutation in the ND3 gene of respiratory complex 1. A smaller number of soft-tissue metastases also demonstrated enrichment of this mutation. While the small number of primary prostate cancers available for analysis preclude any firm conclusions, the two cases without the mutation also did not have the mutation in the bone metastasis while the one with the mutation in the prostate primary demonstrated a 36-fold increase of the mutation in the bone metastasis. It is therefore possible that the mutation arises in the prostate and is selected for in the bone metastasis. This finding that the exact same missense mutation is present in over 50% of patients prostate cancer bone metastases far exceeds any somatic mutation previously reported in prostate cancer suggesting functional importance. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e1187 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Carrie Sun More articles by this author Colm Morrissey More articles by this author John Petros More articles by this author Rebecca Arnold More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...