New Clues May Link Hereditary Cancer Genes to Increased Risk of Cancer From Alcohol
In laboratory experiments conducted on human cell lines at the Johns Hopkins Sidney Kimmel Cancer Center, scientists have shown that people carrying certain mutations in two hereditary cancer genes, BRCA2 and PALB2, may have a higher than usual susceptibility to DNA damage caused by acetaldehyde, a byproduct of alcohol. The findings by Ghosh et al were published in The American Journal of Pathology.
While the scientists cautioned that the research is preliminary, they said their findings suggest that studies on disease risk factors should take into account these particular genetic variations and the use of alcohol.
“We need to identify which behaviors in certain populations increase disease risk, and keep in mind that our genetic susceptibility plays a large role in cancer risk,” said study author Scott Kern, MD, the Everett and Marjorie Kovler Professor in Pancreas Cancer Research at Johns Hopkins.
Acetaldehyde, which is ubiquitous in nature, is produced during the metabolism of alcohol and is known to cause DNA damage. Alcohol use has long been linked to cancers of the upper aerodigestive tract, breast, pancreas, and stomach.
Study Details
Previous reports have linked acetaldehyde and a related chemical, formaldehyde, to a rare cancer-susceptibility disease called Fanconi anemia, which is characterized by mutations in BRCA2 and other genes. Dr. Kern and his team took a closer look at the growth response of cells exposed to acetaldehyde and other compounds and created human cell lines that lacked BRCA2 and PALB2 genes.
“You can add any chemical to a cell culture and growth of the cells will go down, so the significant responses are ones that differ by 10-fold or larger,” commented Dr. Kern.
The scientists found that BRCA2 and PALB2-mutant cell lines exposed to acetaldehyde had up to 25 times more growth reduction when compared with related cells lacking these mutations. The significant reduction in cell growth indicates that these cell lines, which lack the two genes, are more susceptible to the DNA damage caused by acetaldehyde, said the scientists. They suggest that the DNA-damaging effects of acetaldehyde exposure in people lacking these genes may accelerate cancer growth.
Findings Could Lead to Development of New Therapies
The investigators estimated that the BRCA2 and PALB2 genes, when they function normally, protect cells against up to 96% of the toxicity associated with acetaldehyde. The acetaldehyde model could, theoretically, be used to develop drugs that kill cancer cells, as well as to alter cancer risk, said Dr. Kern. They found that cell lines with mutations in PALB2 were up to 20% more sensitive to chemotherapy agents, such as cisplatin, that work by breaking down DNA, compared with anticancer drugs that work in other ways.
When the genes function correctly, BRCA2 and PALB2 bind to each other to repair DNA damage. Mutations in the genes disable their DNA-repairing capability and make carriers more susceptible to cancer, the researchers said.
“BRCA2 and PALB2 may have evolved over time to repair or protect us from acetaldehyde damage,” said Dr. Kern. “In most people, the genes function well and we're equipped to handle most of our exposure to acetaldehyde, but patients or carriers with mutations in these genes could face a higher risk of cancers with high exposure to alcohol or acetaldehyde-containing foods.”
Dr. Kern said that there is a possibility acetaldehyde leaves a signature of damage in cells, adding that scientists may have been overlooking the role of acetaldehyde in disease and aging.
Dr. Kern is the corresponding author for The American Journal of Pathology article.
Funding for the research was provided by the National Institutes of Health’s National Cancer Institute and The Everett and Marjorie Kovler Professorship in Pancreas Cancer Research.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
