NEW YORK (GenomeWeb News) – Colorectal cancer samples have fewer new mutations affecting mitochondrial DNA than do matched normal colon tissues, according to a study appearing online last night in PLoS Genetics.
Researchers from the US and Ireland tested matched tumor-normal samples from 20 individuals with colorectal carcinoma. Along with mitochondrial genome sequencing to look for clonally expanded mutations in the samples, they also relied on a random mutation assay to compare the frequency of non-clonal, random mutations in the mtDNA.
Rather than finding a cancer-related rise in genetic instability in the mitochondria — as is generally the case in genomic DNA — the investigators found a dip in de novo single base substitution rates in mtDNA from colon cancers compared to the corresponding normal colorectal tissues.
"This is completely opposite of what we see in nuclear DNA, which has an increased overall mutation burden in cancer," senior author Jason Bielas, a molecular diagnostics and pathology researcher affiliated with the Fred Hutchinson Cancer Research Center and the University of Washington, said in a statement.
"This work started with the idea that there would be a huge mutation burden in the mitochondrial DNA, but our findings were completely opposite of what we had expected," he added. "Hopefully our discovery will open up new avenues for treatment, early detection and monitoring treatment response of colon cancer and other malignancies."
Since the first cancer genome was sequenced in late 2008, a tide of information has been unleashed, providing new details about the nature and extent of the mutations to nuclear DNA that are associated with various cancer types during cancer development, progression, metastasis, and treatment.
But far less is known about the sorts of cancer-related changes that occur in DNA found in the mitochondria, if any. And because the energy-producing organelle is found in multiple copies per cell, Bielas and his colleagues were curious about whether they might be able to find telltale changes in mtDNA that could be used to predict the presence of cancer-associated alterations in the nuclear genome.
"Cells contain a thousand-fold more mitochondrial genetic material than nuclear DNA," according to Bielas, "so theoretically you'd need a thousand times less tissue to get the same genetic information to predict clinical outcomes such as how fast a tumor would progress or whether it would be resistant to therapy."
To look at this in more detail, the team used mitochondrial genome sequencing and "Random Mutation Capture," or RMC, assays to profile mtDNA mutation in surgically removed samples from 20 individuals with colorectal carcinoma.
Researchers had access to matched normal samples for all 20 individuals and benign adenoma samples for 11 of them. Matched benign adenoma and normal tissue from eight more individuals was also assessed in the study.
Though some clonally expanded mtDNA mutations were identified in cancer and benign adenoma samples, the team reported, the analysis did not uncover a statistically significant jump in the levels of clonally expanded mutations predicted to alter protein function in the carcinoma samples.
On the other hand, the random mutation rate was reduced in the mtDNA from colon carcinomas compared to normal colorectal tissues. And when they looked at the nature of the random mutations turning up in the normal cells, the researchers noticed that the excess substitutions were the same types that tend to occur when DNA is damaged oxidatively.
That, in turn, made them suspect that the lack of mutation in the mitochondria's genetic material might reflect cancer's decreased reliance on a glucose-related energy production process that uses oxygen and releases reactive oxygen species.
Indeed, in the team's follow-up experiments, the proteins and metabolites present in colorectal cancer cells indicated that these cells tend to rely more heavily on an oxygen-free energy production process called anaerobic glycolysis rather than glucose metabolism.
Based on these findings, the team reasoned that it may be that possible to combat cancer by jump starting oxygen-dependent energy production processes in the mitochondria or even introducing mutations to mtDNA that tip cancer cells towards aging rather than allowing their growth to continue unchecked.
"[T]his suggests, somewhat counter intuitively, that higher mitochondrial mutation rates may actually serve as a barrier to cancer development," Bielas speculated, "and drugs that focus directly on increasing mitochondrial DNA damage and mutation might swap cancer's immortality for accelerated aging and tumor-cell death."