Scientists know that tumors have mutations, and mutated genes allow the tumor cells to grow. What's not understood, however, is how tumors need additional genes to grow.Bacolla set out to learn about these supplemental genes that promote mutations in the genome. He used public data sets to make correlations from 11,000 patients, such as the number of mutations the patient had and the degree to which each gene in the human body was expressed in that patient.

“I expected that the type of genes that would show this correlation were genes that had to do with repairing the damage that occurs in the DNA,” he said. “In fact, I discovered the opposite. The genes that most strongly correlated with the number of mutations are genes that the tumor uses to replicate and invade other tissues. That was surprising.”

It became evident to Bacolla that tumors use these supplemental genes to grow very fast. “We found that it's the tumor cell that's pushed to replicate that causes many mutations — it's called replication stress.” Most of the cancer literature today focuses on what kind of mutations are in tumors and how they arise.

Instead, Bacolla's question centered on the iteration of mutated tumor cells, or the extent to which a tumor cell expresses one gene compared to its adjacent normal tissue. For genes used by the tumor to grow, such as one called CENPA, these genes are expressed up to 10 times more than in normal tissues.

“I suspect that these genes are protected by the tumor — they are the tumor's friends,” Bacolla said. “These friends are upregulated genes in the tumor cell and cause mutations that support disease. There are about 190 of these genes and the tumor relies on them – it needs the machinery that takes the chromosomes apart and distributes them to the dividing cells. Best friends for the tumor, but the worst enemies for us.”

The paper is called “Cancer mutational burden is shaped by G4 DNA, replication stress and mitochondrial dysfunction'. It appeared in Progress in Biophysics and Molecular Biology, October 2019. Authors: Albino Bacolla, Zu Ye, Zamal Ahmed and John A. Tainer, Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center. The researchers are grateful for funding by the National Institutes of Health and the Cancer Prevention and Research Institute of Texas for their efforts to understand DNA damage.

Source: TACC