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A study by Mitchell and colleagues published in Clinical Cancer Research sought to understand how the genetic differences between African Americans and European Americans could be changing the way lung tumors behave. In order to answer this question, the researchers looked at seven different Baltimore hospitals that had about 40% African American patients. They looked at patients who had surgery that cured their non-small cell lung cancer. From these patients, they compared genetic material on multiple levels to understand how the differences in African Americans and European Americans predicted different characteristics of the tumor.
The genetic material that this group chose to look at is mRNA and miRNA. mRNA is short for messenger RNA. It is the intermediate genetic material between DNA and a protein. miRNA is short for microRNA, RNAs that do not code for proteins. These pieces, called “non-coding RNA”, can bind to mRNA molecules to keep them from being read by the cellular machinery that translate RNA into proteins. After studying the differences in the mRNA and miRNA patterns in African Americans and European Americans, tried to understand how they may be leading to different molecular pathways being activated, which drugs may work better, what cells from the body would enter the tumor, what proteins are expressed on the tumor that would help with immunotherapy, and which targets exist in the tumor to be treated by miRNAs delivered into the tumor.
They found that the genes that were expressed more highly in African American patient tumors were related to stem cell and invasion pathways. Conversely, European Americans had genes that were enriched in pathways related to cells multiplying. These differences were driven partly by the differences in the miRNAs, suggesting that there are specific differences in the parts of the DNA that do not code for protein which lead to silencing genes and creating these expression differences between African Americans and European Americans. When examining therapeutic differences, many African Americans developed resistance to drugs that European Americans responded well to. Some level of these differences could be attributed to the different expression profiles between the two populations. For example, European Americans have increased sensitivity to drugs like Irinotecan, which is a chemotherapy that targets DNA replication during cell division. Because European Americans have tumors with high levels of cell replication-related genes, it makes sense that European Americans respond well to this drug while African Americans are resistant to it. They also saw differences in some types of T cells and macrophages between the two populations. This suggests that the types of immune cells that enter the tumor are different between the two populations, which can guide prognosis and proper treatment methods.
Currently, one of the important proteins expressed in tumor cells that have led to game-changer treatment protocols is called PD-L1, a protein frequently found in high amounts on tumor cells. T cells use a receptor called PD-1 to bind to this protein and use the body’s own immune system to kill the tumor. It is important to note, since PD-1 checkpoint immunotherapy is an important part of lung cancer treatment, that there were no significant differences in PD-L1 expression between African Americans and European Americans.
The differences highlighted by Mitchell et al., in African Americans and European Americans begin uncovering a huge gap in medical research. With the development of genetic technology, personalized medicine is slowly becoming a reality where we tailor treatment to each patient’s tumor, to the best of our ability. But beginning to understand inherent biological differences in the way a tumor is composed and behaves between races will help doctors start closer to treatments that are more likely to work quickly, leading to better outcomes for all of the patients involved.
Edited by Sara Musetti
Comparative Transcriptome Profiling Reveals Coding and Noncoding RNA Differences in NSCLC from African Americans and European Americans. Khadijah A. Mitchell, Adriana Zingone, Leila Toulabi, Jacob Boeckelman and Bríd M. Ryan. Clin Cancer Res December 1 2017 (23) (23) 7412-7425; DOI: 10.1158/1078-0432.CCR-17-0527