How Smoking Causes Cancer

How Does Smoking Cause Cancer?

New research shows that smoking harms tumor-suppressor genes, which keep abnormal cell growth under control.

Tobacco causes genetic changes known as “stop-gain mutations,” or SGMs. These mutations prevent the genes from functioning properly, allowing cancer cells to multiply uncontrollably.

DNA analysis of more than 12000 tumor samples across 18 cancer types found that tobacco smoking truncated these tumor-suppressor genes, substantially reducing their normal functions.

Science Advances published the study on 3 November 2023. Lead author Dr. Jüri Reimand, a specialist in computational biology and molecular genetics, explains: “Our research shows that the marks tobacco consumption leaves on DNA cause harmful protein-truncating mutations.”

The study also found that lifestyle factors such as diet and alcohol consumption may have similar harmful effects on DNA.

Reimand also said the team identified SGMs generated through APOBEC (apolipoprotein B mRNA editing catalytic polypeptide-like) enzymes and that these mutations “may help unravel the role of APOBEC enzymes in tumor formation and development”. APOBEC-driven SGMs have been associated with breast and other cancers.

More Smoking, More SGMs

Researchers examined 12341 cancer genomes across 18 cancer types, analyzing mutations affecting protein-coding properties. SGMs were frequently associated with factors such as tobacco smoking, APOBEC enzymes, and reactive oxygen species.

These SGMs were frequently found in tumor-suppressor genes such as TP53, FAT1, and APC, seriously impairing their ability to produce proteins that prevent abnormal cell growth.

The study suggests that environmental factors may contribute to SGM formation. For example, it identified a connection between tobacco-related SGMs and smoking habits in lung cancer, suggesting these mutations may be preventable.

Comparisons were made between smokers and people who had never smoked using their cancer-cell genomes. Lifelong nonsmokers had fewer tobacco-related SGMs. There was no marked difference between current smokers and recent quitters, but both groups had far more SGMs than lifelong nonsmokers and former smokers who had quit years earlier.

The Cancer Genome Atlas (TCGA) analysis found an average of 10.5 tobacco-smoking-related SGMs per genome in lung cancer samples: at least one protein-truncating mutation was found in 73% of cancers examined, and at least ten in 39%.

More detailed analyses showed that tobacco smoking was a major driver of SGMs not only in lung and head-and-neck cancers, but also in esophageal cancers directly exposed to smoke.

The team also identified APOBEC-driven SGMs in breast and head-and-neck cancers expressing APOBEC3A. APOBEC enzymes are generally key components of antiviral immune defense and somatic antibody diversification, inactivating viruses by generating SGMs in viral RNA.

Breast cancer samples with high APOBEC3A expression had significantly more APOBEC-driven SGMs than samples with low expression.

In breast cancers from The Cancer Genome Atlas, APOBEC processes were associated with an average of 1.1 SGMs per sample and occurred in a quarter of samples analyzed. The burden was higher in metastatic breast cancer: an average of 2.3 SGMs per sample, affecting 32% of samples. This suggests that APOBEC activity may persist longer or reach higher levels in advanced cancers.

It has long been known that smoking causes cancer-driving DNA mutations. These SGMs now make that relationship easier to understand. This may encourage frequent smokers with high cancer risk to seek earlier and more regular health checks.

As more detailed genetic data from cancer patients are collected alongside environmental and lifestyle information, we will better understand how mutations form and affect our cells. Although current information is insufficient to conclusively establish these relationships, new cancer-genetics research may reveal how our environment and everyday habits affect genes and cancer at the cellular level.

Conclusion

The study offers new insights into fundamental mechanisms of cancer development, including stop-gain mutations (SGMs) in critical genes such as TP53 and their role among cancer's causes.

The findings indicate that greater tobacco-smoke exposure increases the risk of acquiring SGMs. This strengthens existing evidence that tobacco exposure is a major cause of cancer and a foundational issue for science seeking to treat and combat it.

Public messages about tobacco's harms are the first and most important defense against tobacco-related cancers.

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