Acquired Mitochondrial DNA Mutations in Metastatic Prostatic Adenocarcinoma
John A Petros, Rebecca S Arnold, Lawrence D True, Leland W Chung, Adeboye O Osunkoya. Emory University School of Medicine, Atlanta; Cedars-Sinai Medical Center, Los Angeles; University of Washington, Seattle
Background: Mitochondrial DNA (mtDNA) mutations are present in patients with prostatic adenocarcinoma both as modulators of inherited predisposition to disease, and as somatically acquired mutations in the primary tumors. In animal models, it has been suggested that additional mtDNA mutations can markedly influence metastatic capability of tumor cells. The presence of additional acquired mtDNA in metastatic prostatic adenocarcinoma in humans has not been studied.
Design: In order to determine whether additional mutations occur in the process of metastasis in humans, we performed mtDNA sequencing of bone metastasis from three patients with known mtDNA mutations (Patient 1: G9477A; Patient 2:C4458A, C8532T and Patient 3: G7521A, G8854A), that died of metastatic prostatic adenocarcinoma. All bone specimens were confirmed to contain cancer on routine histological analysis. Decalcified, fixed sections were subjected to laser capture microdissection to obtain pure metastatic cancer for sequencing of specific mitochondrially encoded genes. In order to determine which mutations were associated with malignant progression, control tissue (normal kidney) was also sequenced from each patient.
Results: Metastatic prostatic adenocarcinoma to bone contained multiple pathogenic mutations in key mitochondrial genes that were not present in corresponding normal tissues. These mutations include protein synthesis mutations (in both ribosomal RNA and tRNAs) as well as amino-acid altering missense mutations in respiratory complexes 1 and 4. Both homoplasmic and heteroplasmic alterations were seen. One alteration in particular appeared to be especially prevalent in metastatic prostatic adenocarcinoma in all patients; the A10398G (Thr114Ala) mutation of the NADH Dehydrogenase Subunit 3 (ND3) mitochondrial gene.
Conclusions: This is the first study to demonstrate that metastatic prostatic adenocarcinoma is characterized by a high level of acquired pathogenic mutations in the mitochondrial genome. A specific individual mutation (A10398G), appears to be particularly common as a somatic mutation in metastatic prostatic adenocarcinoma to bone. It is therefore conceivable that this mutation may be involved in cancer cell alteration in a manner that enhances the metastatic phenotype.
Category: Genitourinary (including renal tumors)
Tuesday, March 20, 2012 1:00 PM
Poster Session IV # 103, Tuesday Afternoon