Study sheds new light on role of genetic mutations in colon cancer development

June 7, 2012

In exploring the genetics of mitochondria – the powerhouse of the cell – researchers at Fred Hutchinson Cancer Research Center have stumbled upon a finding that challenges previously held beliefs about the role of mutations in cancer development.

For the first time, researchers have found that the number of new mutations are significantly lower in cancers than in normal cells.

"This is completely opposite of what we see in nuclear DNA, which has an increased overall mutation burden in cancer," said cancer geneticist Jason Bielas, Ph.D., whose findings are published in the June 7 issue of PLoS Genetics.

Mutations are changes in the sequence of a cell's genome and can occur as a result of environmental exposure to viruses, radiation and certain chemicals, or due to spontaneous errors during cell division or DNA replication.

Mitochondria, which are primarily responsible for the cell's energy production, are semi-autonomous; similar to the nucleus, they have their own set of DNA, which encodes genes critical for the functioning of the cell. While the role of genomic instability has been well characterized in nuclear DNA, this is the first attempt to determine whether instability in mitochondrial DNA may play a similar role in cancer growth and metastasis.

"We were surprised to find that the frequency of new mutations in mitochondrial DNA from tumor cells is decreased compared to that of normal cells," said Bielas, an assistant member of the Public Health Sciences and Human Biology divisions at the Hutchinson Center. "By extension, this suggests, somewhat counterintuitively, that higher mitcochondrial mutation rates may actually serve as a barrier to , and drugs that focus directly on increasing mitochondrial DNA damage and mutation might swap cancer's immortality for accelerated aging and tumor-cell death."

For the study, the researchers used using an ultra-sensitive test to detect mutations in mitochondrial DNA from normal and cancerous colon tissue resected from 20 patients prior to chemotherapy.

Bielas and colleagues first set out to analyze mutation rates in mitochondrial DNA because they wanted to see if it could act as a surrogate for nuclear DNA as a cancer biomarker. "Cells contain a thousandfold more mitochondrial genetic material than nuclear DNA, 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," Bielas said.

While mitochondrial DNA proved to be an unreliable stand-in for nuclear DNA as a cancer biomarker, it offers promise as a new drug target.

"If we could increase DNA damage and mutation within the mitochondrial genome, theoretically we could decrease cancer," Bielas said. "That's what we're testing now. This is a whole new hypothesis."

The way mitochondria maintain genetic stability in the face of cancer, Bielas suggests, may be because unlike normal cells, cancer cells do not need oxygen to survive. In fact, cancer cells decrease the process by which they get energy from the and rely instead on a process called glycolysis, which is a form of energy production in the absence of oxygen.

"We believe less damage occurs to mitochondrial DNA of cancer cells because they no longer need oxygen," he said. "If we could program a cancer cell to once again need oxygen, we expect it would die – with minimal side effects."

Bielas and colleagues are now testing this theory in the laboratory, seeing whether that are reprogrammed to utilize oxygen and/or are targeted for mitochondrial DNA damage respond better to certain therapeutic agents.

"This finding is a game-changer because it challenges previous notions about the role of mutations in cancer development," said Bielas, who is also an affiliate assistant professor of pathology at the University of Washington, where the ultra-sensitive mutation-detection technology, called Random Mutation Capture, was developed. The test is so sensitive that it can detect the mutational equivalent of one misprinted letter in a library of a thousand 1,000-page books.

"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. Hopefully our discovery will open up new avenues for treatment, early detection and monitoring treatment response of colon and other malignancies," he said.

Explore further: How mitochondrial DNA defects cause inherited deafness

More information: “Decreased Mitochondrial DNA Mutagenesis in Human Colorectal Cancer,” PLoS Genetics.

Related Stories

How mitochondrial DNA defects cause inherited deafness

February 17, 2012
(Medical Xpress) -- Yale scientists have discovered the molecular pathway by which maternally inherited deafness appears to occur: Mitochondrial DNA mutations trigger a signaling cascade, resulting in programmed cell death. ...

New 'Achilles' heel' in breast cancer: tumor cell mitochondria

December 1, 2011
Researchers at the Kimmel Cancer Center at Jefferson have identified cancer cell mitochondria as the unsuspecting powerhouse and "Achilles' heel" of tumor growth, opening up the door for new therapeutic targets in breast ...

Recommended for you

Newly revealed autism-related genes include genes involved in cancer

September 25, 2017
The identification of genes related to autism spectrum disorder (ASD) could help to better understand the disorder and develop new treatments. While scientists have found many genetic differences in different people with ...

Scientists first to use genetic engineering technique to investigate Tourette's

September 25, 2017
Scientists at Rutgers University-New Brunswick are the first to use a genetic engineering technique to create brain cells from the blood cells of individuals in a three-generation family with Tourette syndrome to help determine ...

Study reveals an ancient Achilles heel in the human genome

September 21, 2017
In a major study published today, researchers at deCODE genetics use whole-genome data from 14,000 people from across the population of Iceland, including 1500 sets of parents and children, to provide the most detailed portrait ...

Forgotten strands of DNA initiate the development of immune cells

September 21, 2017
Intricate human physiological features such as the immune system require exquisite formation and timing to develop properly. Genetic elements must be activated at just the right moment, across vast distances of genomic space.

Genome editing reveals role of gene important for human embryo development

September 20, 2017
Researchers have used genome editing technology to reveal the role of a key gene in human embryos in the first few days of development. This is the first time that genome editing has been used to study gene function in human ...

A piece of the puzzle: Eight autism-related mutations in one gene

September 19, 2017
Scientists have identified a hotspot for autism-related mutations in a single gene.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.