- Cancer is an interwoven group of diseases that arise from diverse causes
- Carcinogens are known to cause cancer by disrupting gene expression
- Epigenetics is the study of changes in DNA from external stressors like carcinogens
- Researchers are developing epigenetic profiles to improve cancer treatment
From wood dust to diesel exhaust to acrylamides—nasty chemicals that form when meat burns on the BBQ—scientists have identified a long list of carcinogens, substances that trigger carcinogenesis or the formation of cancer.
Carcinogens are external stressors that can turn certain genes on and off and change traits. These changing characteristics aren’t hereditary; they’re epigenetic, meaning they are a product of the environment.
Nicotine, one of the most well-known carcinogens, correlates with the most common type of lung cancer, non-small cell lung cancer (NSCLC). Because many lung cancer cases have few known hereditary ties (most result from inhalation of tobacco smoke and air pollutants), researchers have targeted NSCLC specifically to study epigenetic mechanisms.
Researchers first discovered epigenetic mechanisms upon noting that some genes were never expressed. Typically, polymerase, a protein involved in the production of genes, acts like a train as it travels along a DNA strand, reading it for information. During an epigenetic mechanism called methylation, a carcinogen causes methyl groups to bind to the backbone of DNA. These methyl groups act like roadblocks that impede polymerase and inhibit the expression of genes.
Dr. Manel Esteller, a University of Barcelona molecular geneticist who researched the effect of methylation on carcinogenesis, commented, “We have found many genes undergoing the same [process] in many tumor types.” Carcinogens can inhibit traits related to tumor suppression (the prevention of cancerous tumors), cell replication, and DNA repair, eventually leading to tumors that divide out of control.
Implications and Applications
Scientists have found many different ways in which methyl groups affect expression. In smokers’ lungs, a dozen cancer-associated genes are abnormally methylated, most playing a role in cancer growth. For example p16, a tumor suppressor gene that helps regulate cell division and keep cancer in check is methylated and essentially turned off in NSCLC. Just how methylated genes come to be is still not fully understood. Are these methylated genes just a product of other cancer mechanisms at work? Or did gene methylation itself contribute to carcinogenesis?
Through scores of studies, scientists are constructing epigenetic profiles, categories typifying different stages of cancer, each category with an identifying set of epigenetic quirks. The hope is that these profiles can predict how patients may respond to certain treatments. Dr. Karl T. Kelsey, a professor of laboratory medicine at Brown University, thinks that if we can identify and target epigenetic changes that drive lung cancer, they would be ideal candidates to detect cancers early-on. “Unfortunately,” he says, “it seems that there are a wide variety of early changes and no one lesion [epigenetic change] that is common enough to serve as a biomarker.”
For now there’s no smoking gun. But, scientists still hope that constructing profiles can better categorize and treat cancer. Recently, Dr. Esteller and his colleagues constructed a profile they dub EPIMMUNE which can predict the clinical response to cancer therapies.
Such a wide array of potential profiles is clinically challenging. Some researchers seek more catch-all epigenetic solutions to combat tumors. “Much of the work now is aimed at understanding [epigenetic] patterns and devising drugs that target multiple altered gene loci,” writes Dr. Kelsey. In one study, for example, two drugs, when taken together, decreased abnormal gene methylation across the board in NSCLC tumors.
In the future, Dr. Kelsey says, “I have no doubt that the pattern of epigenetic alterations…will provide better classification [of cancer] and better prognostic information.” Even then, epigenetics is one piece in cancer’s complex jigsaw. But scientists are hopeful. As Dr. Kelsey says, when it comes to research, “Persistence (and sweat) always pay off.”
Dr. Manel Esteller is the director of the Cancer Epigenetics and Biology Program at the Bellvitge Biomedical Research Institute in Catalonia, Spain. He received his undergraduate degree in Medicine then his doctorate in Molecular Genetics of Endometrial Carcinoma from the University of Barcelona in 1996 where he is now a professor. His research interests include the molecular genetics of hereditary breast cancer and DNA methylation and its relationship with cancer in humans. His research helped establish that the hypermethylation of tumor suppressor genes is a characteristic trait of cancer tumors. In addition to his research, he serves as the editor-in-chief of the peer-reviewed journal Epigenetics.
Dr. Karl T. Kelsey is a Professor Epidemiology & Pathology and Laboratory Medicine at Brown University. He received his undergraduate and doctoral degrees from the University of Minnesota and later his Masters of Occupational Health from Harvard University in 1984 where he would teach at Harvard’s School of Public Health (now T. H. Chan). His research interests include biomarkers in environmental disease, chronic disease epidemiology, and tumor biology with the goal of understanding individual susceptibility to certain cancers. His work uses an epidemiologic approach to characterize genetic alterations of genes in the causal pathway for malignant tumors. Currently, he serves as an Ad Hoc Advisor for the Massachusetts Department of Environmental Protection, a reviewer for the Cancer Research Campaign in the UK, and is on the editorial board for three peer-reviewed journals.
- Duruisseaux, Michaël, and Manel Esteller. “Lung cancer epigenetics: From knowledge to applications.” Seminars in Cancer Biology. Academic Press, 2017.
- Huang, C. I., et al. “p16 protein expression is associated with a poor prognosis in squamous cell carcinoma of the lung.” British Journal of Cancer 82.2 (2000): 374.
- Juergens, Rosalyn A., et al. “Combination epigenetic therapy has efficacy in patients with refractory advanced non–small cell lung cancer.” Cancer Discovery (2011).
- Marsit, Carmen J., et al. “PTEN expression in non–small-cell lung cancer: evaluating its relation to tumor characteristics, allelic loss, and epigenetic alteration.” Human Pathology 36.7 (2005): 768–776.
- Sandoval, Juan, et al. “A prognostic DNA methylation signature for stage I non-small cell lung cancer.” Journal of Clinical Oncology 31 (2013): 4140–4147.
- Sarkar, Sibaji, et al. “Demethylation and re-expression of epigenetically silenced tumor suppressor genes: sensitization of cancer cells by combination therapy.” Epigenomics 5.1 (2013): 87–94.
- Toyooka, Shinichi, et al. “Smoke exposure, histologic type and geography‐related differences in the methylation profiles of non‐small cell lung cancer.” International Journal of Cancer 103.2 (2003): 153–160.
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