Given the link between smoking and cancer, you might expect smoking to affect genes associated with cell division and DNA repair. A recent study by researchers from the BC Cancer Agency confirms this and also identifies some genes that might surprise you. One gene turned on in active smokers, CABYR, plays a role in helping sperm to swim. While defects in this gene have been associated with brain tumors, a link to lung cancer is relatively recent.
How did the researchers identify the affected genes? They took lung tissue samples from 24 current and former smokers and non-smokers and created SAGE libraries from the samples. The acronym “SAGE” stands for “Serial Analysis of Gene Expression, ” and SAGE libraries are collections of DNA copied from RNA (molecules in cells that are translated to become proteins) and tagged in a way that makes it easier to spot differences in gene expression between different samples.
The Canadian study suggests that while some changes can be reversed by stopping smoking, other changes are irreversible.
Reversibly affected genes include:
- genes involved in xenobiotic functions (e.g., expressing proteins involved in handling foreign substances, like chemicals, in the body);
- genes involved in nucleotide metabolism; and
- genes involved in mucus secretion.
Irreversibly affected genes include:
- genes involved in DNA repair; and
- genes that ordinarily safeguard against lung cancer development.
The results of the study suggest a reason why former smokers may still have a risk of developing lung cancer. However, the risk to former smokers is still much lower than for cur¬rent smok¬ers.
In a study using a different technique, researchers in North Carolina examined a larger pool of 75 subjects (34 current smokers, 18 former smokers, and 23 non-smokers). Rather than examining the expression of individual genes across different samples, the researchers looked for patterns in the expression of sets of related genes using microarray analysis. This technique called Gene Set Enrichment Analysis or GSEA allowed the researchers to come up with a “color map” illustrating global effects on cellular pathways.
By taking this global view, the researchers determined that one of the pathways significantly affected is the gamma-Hexachlorocyclohexane degradation pathway. This might seem unexpected since the pathway’s most well-known for its role in the degradation of a toxic insecticide called lindane. However, as pointed out by the researchers, several genes in the pathway are associated with the metabolism of nicotine. So like the researchers from Canada, this team identified genes involved in xenobiotic functions. Through pathway analysis, the researchers also confirmed that smoking affects genes involved in mucus production.
It’s not a trivial matter to make sense of the patterns of gene expression associated with a particular disease like cancer. Sometimes, genes expressed at low levels can have big effects on a physiological response. Because they’re expressed at such low levels, changes in these genes can be hard to detect. Through complementary techniques like SAGE and GSEA, our understanding of genes that matter can help us to generate more effective treatments.