Somatic Mitochondrial DNA Mutations in Prostate Cancer and Normal Appearing Adjacent Glands in Comparison to Age-Matched Prostate Samples without Malignant Histology

Abstract

Studies of somatic mitochondrial DNA mutations have become an important aspect of cancer research because these mutations might have functional significance and/or serve as a biosensor for tumor detection. Here we report somatic mitochondrial DNA mutations from three specific tissue types (tumor, adjacent benign, and distant benign) recovered from 24 prostatectomy samples. Needle biopsy tissue from 12 individuals referred for prostate biopsy, yet histologically benign (symptomatic benign), were used as among individual control samples. We also sampled blood (germplasm tissue) from each patient to serve as within individual controls relative to the somatic tissues sampled (malignant, adjacent, and distant benign). Complete mitochondrial genome sequencing was attempted on each sample. In contrast to both control groups [within patient (blood) and among patient (symptomatic benign)], all of the tissue types recovered from the malignant group harbored significantly different mitochondrial DNA (mtDNA) mutations. We conclude that mitochondrial genome mutations are an early indicator of malignant transformation in prostate tissue. These mutations occur well before changes in tissue histo-pathology, indicative of prostate cancer, are evident to the pathologist.

The awakening of an advanced malignant cancer: An insult to the mitochondrial genome

“…It is postulated that the D-loop of the mitochondrial genome is a mutational hotspot that bears the burden of mutations in the ageing and carcinogenesis of human cells, often before the morphological indications of malignant transformation are visible [60, 66, 96–99]. For example, Tan et al reported that tissues from smokers accumulate mutations more than those from nonsmokers and those tissues from nonsmokers accumulate mutations predominately in the D-loop, whereas mutations of smokers were observed in the D-loop and coding regions [73].…”

Mitochondrial DNA depletion in prostate epithelial cells promotes anoikis resistance and invasion through activation of PI3K/Akt2

“…Growing evidence suggests that mtDNA mutations may be associated with tumor development and progression in a variety of cancers, including prostate carcinoma. 2,3 For instance, it has been reported that introduction of a pathogenic mtDNA ATPase6 mutation into the PC-3 prostate cell line results in increased tumor growth, 2 and that the inheritance of mitochondrial haplotype U is associated with increased risk of prostate cancer in white Americans, 4 thus implicating mtDNA in prostate cancer etiology. However, despite all this new evidence, the molecular mechanisms linking mtDNA mutations and prostate cancer remain largely obscure.…”

Mitochondrial DNA Repair

“…Significantly, all of these mutations were present in the majority of the tumour cells and 90% of them were detectable in all of the mitochondrial DNA present in cells, strongly suggesting that all mitochondrial DNA molecules in the mitochondrion contain the same mutation. Breast cancer also exhibit somatic mitochondrial DNA mutations (Parrella et al, 2001;Radpour et al, 2009), in addition to kidney (Meierhofer et al, 2006) (Nagy et al, 2003), stomach (Hung et al, 2010;Jeong et al, 2010), prostate (Moro et al, 2009) (Parr et al, 2006) liver (Vivekanandan et al, 2010;Zhang et al, 2010), bladder (Dasgupta et al, 2008, head and neck (Allegra et al, 2006;Dasgupta et al, 2010;Mithani et al, 2007) and lung (Dai et al, 2006;Jin et al, 2007;Suzuki et al, 2003). Furthermore increased mitochondrial DNA mutation frequencies were associated with hereditary paraganglioma (Muller et al, 2005;Taschner et al, 2001) and thyroid cancers (Abu-Amero et al, 2005;Rogounovitch et al, 2004).…”