• Dr. Robert A. Nagourney, MD

DNA Signatures and Genomics

Scientists have long applied technological advances to unravel the complexities of human biology. Nowhere has this been more true than in cancer, where genomics, the study of human genes and mutations has virtually taken over the field.

A recent study now raises serious questions about whether DNA signatures can predict response or survival in one of the most important target diseases for this approach: Childhood leukemia. (Cahyadi, A. Asian Pac J Cancer Prev. 2022 May 1;23(5):1679-1685.)

It turns out that two opposing genes; BCL2 and BAX control the forces of life and death in leukemia cells. Leukemia cells that have a lot of BCL2 would be expected to stay alive and cause patients to suffer. While leukemia cells that have a lot of BAX should die and allow the patient to survive.

But when this BCL2/BAX gene signature was applied to the leukemia cells of children receiving chemotherapy for acute leukemia, it didn’t predict response or survival. Somehow the “genes didn’t fit.”

Why would this simple test of genetic medicine fail? The answer is both simple and profound.

First, cancer researchers cannot force cancers to do what they demand. Cancer cells are too complicated and heterogeneous to be corralled by scientists’ feeble attempts to measure and control them.

Second, biological processes are complex and redundant. Every cancer cell has numerous mechanisms to live or die. Measuring one or two of these is overly simplistic and should be a lesson to future scientists.

Finally, life on earth is the result of billions of years of evolution. Every cancer is the end product of years sometimes decades of cellular evolution. Our blunt instruments like BCL2 or BAX used to measure or treat cancer have proven largely ineffective. Scientists need humility when they approach the mysteries of human cancer biology.

When our group first approached this same disease, childhood leukemia, some years ago we did not use DNA measures or genes. Instead, we tested the drugs that are used in these children’s treatments right on their cells in the test tube and measured whether the cells died following exposure.

Unlike the current failed DNA approach, our lab's patient study was highly successful and accurately predicted the children who would survive going out for over 15 years as we published in a landmark paper.

Why did Nagourney Cancer Institute's study succeed while their study failed? The answer is that we used the single most important predictor of clinical response, cell death, while they measured an isolated and ultimately irrelevant feature of cell response.

Cancer patients have seen enough interesting science. They want answers and at our laboratory, we give them answers that matter