Simultaneous generation of multiple mitochondrial DNA mutations in human prostate tumors suggests mitochondrial hyper-mutagenesis

Abstract

Multiple somatic mitochondrial DNA mutations are frequently reported in human tumors, but the process leading to homoplasmic transformation and accumulation of multiple mutations in the same tumor cell lineage remains a mystery. We address possible mechanisms responsible for the generation of multiple mitochondrial (mt)DNA mutations observed in a high frequency of prostate tumors using sensitive mutant-specific PCR coupled with laser capture microdissection. Analysis of prostate tumors with multiple mtDNA mutations in the control region indicates that the mutations are locally confined, that the multiple mutations exist on the same molecules and that more than one mtDNA mutant species co-exists in the same neoplastic lesion. These results suggest an unusually rapid process in mtDNA mutagenesis during tumor progression. On the basis of prostate tumor cell kinetics, we propose a unique process of mitochondrial hyper-mutagenesis, probably mediated by cellular oxidative stress, to account for a burst of multiple mtDNA mutations in human prostate tumors.

Mitochondrial mutations in cancer

“…However, thyroid tumors had a relatively low frequency of control region mutants, particularly in the hypervariable homopolymeric C region between nt 303 and 315 (Tong et al, 2003). Ovarian tumors harbored both control region (3/15) and coding region variants in 60% (6/10) of cases (Liu et al, 2001), breast cancer samples contained control region and coding region mutations in 61% (11/18) of samples (Parrella et al, 2001) and prostate cancer tumors had somatic control region mutations in 88% of cases (14/16) (Chen et al, 2002(Chen et al, , 2003 and control region and coding region mutations in 19% (3/16) of cases (Jeronimo et al, 2001). The functional relevance of tumor-specific polypeptide gene missense mutations was demonstrated by three heteroplasmic COI mutations reported in prostate tumors: G5949 (G16X, Stop), T6124C (M74T, CI ¼ 95%) and C6924T (A341S, CI ¼ 100%) (Petros et al, 2005).…”

Mitochondria and Cancer: Warburg Addressed

“…Forty-seven functionally relevant somatic mtDNA polypeptide mutations have been reported for ovarian (Liu et al 2001), glioblastoma (Kirches et al 2001), bladder, head and neck (Fliss et al 2000), colon (Polyak et al 1998), thyroid (Yeh et al 2000;Maximo et al 2002), breast (Parrella et al 2001), and prostate (Jeronimo et al 2001;Chen et al 2003) tumors. Five of these are rearrangements and can be excluded from the comparison.…”

Changes in Serum Proteomic Patterns by Presurgical α-Tocopherol andl-Selenomethionine Supplementation in Prostate Cancer

“…Prostate cancer tumor progression from microscopic to metastatic disease is poorly understood. Oxidative stress -induced genomic and mitochondrial DNA mutations have been implicated as tumor promotion factors in recent population studies (16,17). Offering a viable option in this setting is primary prevention, especially given that prostate cancer has as long latency period (18).…”