Bone metastasis in prostate cancer: Recurring mitochondrial DNA mutation reveals selective pressure exerted by the bone microenvironment

Abstract

Background Cancer progression and metastasis occurs such that cells with acquired mutations enhancing growth and survival (or inhibiting cell death) increase in number, a concept that has been recognized as analogous to Darwinian evolution of species since Peter C. Nowell’s description in 1976. Selective forces include those intrinsic to the host (including metastatic site) as well as those resulting from anti-cancer therapies. By examining the mutational status of multiple tumor sites within an individual patient some insight may be gained into those genetic variants that enhance site-specific metastasis. By comparing these data across multiple individuals, recurrent patterns may identify alterations that are fundamental to successful site-specific metastasis. Methods We sequenced the mitochondrial genome in 10 prostate cancer patients with bone metastases enrolled in a rapid autopsy program. Patients had late stage disease and received androgen ablation and frequently other systemic therapies. For each of 9 patients, 4 separate tissues were sequenced: the primary prostate cancer, a soft tissue metastasis, a bone metastasis and an uninvolved normal tissue that served as the non-cancerous control. An additional (10th) patient had no primary prostate available for sequencing but had both metastatic sites (and control DNA) sequenced. We then examined the number and location of somatically acquired mitochondrial DNA (mtDNA) mutations in the primary and two metastatic sites in each individual patient. Finally, we compared patients with each other to determine any common patterns of somatic mutation. Results Somatic mutations were significantly more numerous in bone compared to either the primary tumor or soft tissue metastases. A missense mutation at nucleotide position (np) 10398 (A10398G; Thr114Ala) in the respiratory complex I gene ND3 was the most common (7 of 10 patients) and was detected only in bone. Other notable somatic mutations that occurred in more than one patient include a tRNA Arg mutation at np 10436 and a tRNA Thr mutation at np 15928. The tRNA Arg mutation was restricted to bone metastases and occurred in three of 10 patients (30%). Somatic mutation at 15928 was not restricted to bone and also occurred in three patients. Conclusions Mitochondrial genomic variation was greater in metastatic sites than the primary tumor and bone metastases had statistically significantly greater numbers of somatic mutations than either the primary or the soft tissue metastases. The genome was not mutated randomly. At least one mutational “hot-spot” was identified at the individual base level (nucleotide position 10398 in bone metastases) indicating a pervasive selective pressure for bone metastatic cells that had acquired the 10398 mtDNA mutation. Two additional recurrent mutations (tRNA Arg and tRNA Thr) support the concept of bone site-specific “survival of the fittest” as revealed by variation in the mitochondrial genome and selective pressure exerted by the metastatic site.

Complex‐I Alteration and Enhanced Mitochondrial Fusion Are Associated With Prostate Cancer Progression

“…Complex-I regulates mt apoptosis and its loss may prevent cell death and promote progression (Gasparre et al, 2008;Mayr et al, 2008). Previous reports of RCI targeting mtDNA mutations in PCa (Jer onimo et al, 2001;Kloss-Brandst€ atter et al, 2010;Arnold et al, 2015) did not report on the corresponding protein expression in PCa. Interestingly, a study from the Sidransky laboratory (Jer onimo et al, 2001) reported a delA mutation at the nucleotide position 11032 spanning ND4 region, which is very closely located (6 nucleotides upstream) to the region that we have identified in the present study (11038delA).…”

“…A cybrid cell line generated from a breast cancer patient harboring A10398G variant was shown to induce an abnormal mt function, increased tumorigenic growth, and metastasis in mice (Arnold et al, ). Other studies also linked A10398G polymorphism with breast cancer susceptibility and increased risk (Arnold et al, ). In our study, we observed A10398G as a germ line sequence variant in 2 PCa patients (#5437 and #5359).…”

Roles of the mitochondrial genetics in cancer metastasis: not to be ignored any longer

“…Arnold and colleagues [91] compared mtDNA sequences from 10 prostate tumors with distant metastases. The tissues analyzed included the primary prostate, soft tissue and bone metastases, and adjacent normal tissues.…”

Understanding Mitochondrial Polymorphisms in Cancer

“…Interestingly, Kenny and colleagues found that there was no one specific mtDNA mutation that drove metastasis in the cancer cells, but rather the composition of the mtDNA genome [i.e., presence or absence of reactive oxygen species (ROS); activation of the SIRT/FOXO/SOD2 axis of the UPR mt ] dictated either promotion or repression of cancer cell metastasis (25). In comparison with Kenny and colleagues, Arnold and colleagues sequenced the mitochondrial genome of 10 prostate cancer patients with bone metastases (26). They found that there was a single recurring mtDNA mutation in 77% of the patients' bone metastases.…”