Hiding in Plain Sight: Mitochondrial DNA May Hold Overlooked Cancer Clues

Memorial Sloan Kettering computational biologist Ed Reznik.

Ed Reznik says mitochondrial DNA has mutational patterns similar to those found in well-known cancer genes.

Most human DNA is packaged in the chromosomes within a cell’s nucleus. But our cells also have what is called mitochondrial DNA (mtDNA). The mitochondria are small structures located in the fluid surrounding the nucleus that help cells produce energy from nutrients.

Scientists have long been interested in the idea that the dysfunction of mitochondria plays an important role in cancer. This connection is being actively pursued by researchers interested in cancer metabolism, including at Memorial Sloan Kettering. But when scientists have looked at how genetic mutations contribute to cancer, they have largely focused on the genome — the complete set of DNA — inside the nucleus. The mitochondrial genome has largely been ignored.

“The cancer-genomics community has avoided doing a really deep dive into the mutations that arise in mitochondrial DNA,” says MSK computational oncologist Ed Reznik. “One reason may be that human mtDNA contains only 13 genes that make proteins, compared with the 20,000 in the nuclear genome. But the mtDNA proteins are essential for basic cell functions needed for life. You can’t just break mtDNA without consequences.”

Now Dr. Reznik, in collaboration with Payam Gammage, a specialist in mitochondrial biology at the Beatson Institute for Cancer Research in the United Kingdom, has discovered that mutations are quite common in the mtDNA of tumors.

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Our investigators are creating tools to analyze the vast amount of information about the genomes of both normal and cancerous cells that has been made available because of next-generation sequencing.

“We have shown that the mitochondrial genome, which is critical to the cell’s energy-making machinery, is quite often broken in cancers.” Dr. Reznik says. “In fact, the mitochondrial genome is among the most mutated DNA regions in the entire cancer genome.”

What’s more, these mutations lead to very interesting characteristics in cancer cells, suggesting that a clearer understanding of mtDNA could be useful for sorting cancer patients into different risk groups, making more accurate prognoses, and developing new treatments. The researchers reported their findings on April 8, 2021, in Nature Metabolism.

A Long-Neglected Resource

“I like to say all the data leading to these discoveries was really hiding in plain sight because that’s often the case for mtDNA,” Dr. Reznik says. “Most genetic sequencing that MSK and other institutions do is focused on regions of the genome that we think are important for cancer, and mtDNA is often ignored. You can screen it out of your analysis with one click. But we realized it was this incredible resource we could use to study genetic variation that has a huge impact on metabolism.”

The team led by Drs. Reznik and Gammage analyzed vast amounts of genomic data from tumors that has become available in recent years. Some was obtained through MSK-IMPACTTM, a test that helps match people with cancer to the best treatment based on the genetic changes in their tumors. Other data came from The Cancer Genome Atlas, a landmark cancer genomics program led by the National Institutes of Health that provided information on more than 10,000 primary tumor samples spanning 33 cancer types.

The researchers found that mtDNA mutations were present in almost six out of 10 tumor samples. With the help of Sloan Kettering Institute graduate student Alex Gorelick, Dr. Reznik’s team was also able to formulate basic rules that describe the pattern by which mtDNA mutations arise. They detected types of mutations in the mtDNA that are similar to those found in many well-known cancer genes in nuclear DNA.

“A lot of genes that normally prevent cancer but end up promoting it when mutated [called tumor suppressor genes] have what are called truncating mutations,” Dr. Gorelick says. “These are mutations that can shorten the protein the gene codes for, which impairs its normal function. We found many of these truncating mutations in the mitochondrial genome.”

We have shown that the mitochondrial genome, which is critical to the cell's energy-making machinery, is quite often broken in cancers.
Ed Reznik computational biologist

This lends weight to the idea that mtDNA mutations play a significant role in many cancers. But how do the cancer cells keep living and functioning if they have mtDNA mutations? The researchers think the answer may lie in the large number of mitochondria that exist in each cell, which can number in the thousands. Only a fraction of the mitochondrial DNA in a given cell may contain disruptive mutations. The other mitochondria in the cells are normal enough to continue carrying out essential cell functions.  

Genetic mutations don’t always increase cancer risk. Intriguingly, the researchers found that one specific mtDNA mutational pattern in colorectal cancer tumors was linked to longer survival in patients.

“We think the mutations might promote a less malignant form of the disease,” Dr. Gorelick says. “This would be an example where the mtDNA mutation pattern gives someone a more favorable prognosis.”

Dr. Reznik says that the team wants to get even more data to validate their findings and explore the possibility of modeling the effect of these mtDNA mutations in mice, including zeroing in on mutations they think are especially disruptive to see how they may affect tumor development.

“This should redefine our understanding of cancer as a disease not of the genome, but of the genomes,” he says.

Drs. Reznik and Gorelick received support from the National Cancer Institute (NCI) Cancer Center Support (grant no. P30 CA008748). Dr. Reznik also was supported by the Geoffrey Beene Cancer Research Center Grant Award, Department of Defense Kidney Cancer Research Program (no. W81XWH-18-1-0318), and a Kidney Cancer Association Young Investigator Award.