How Does Smoking Cause Cancer?

Tobacco smoking is linked to “stop-gain mutations” (SGMs) that interfere with the formation of tumor suppressor genes, which help keep abnormal cells in check, new research suggests.

An analysis of DNA from more than 12,000 tumor samples across 18 different cancer types showed how tobacco smoking truncates tumor suppressors, effectively deactivating them.

Dr Jüri Reimand

“Our study shows that tobacco smoking signatures in DNA generate these harmful protein-truncating mutations that contribute to the development of cancer and its increasing complexity over time,” senior author Jüri Reimand, PhD, Ontario Institute for Cancer Research, Toronto, Canada, told Medscape Medical News.

The study also pinpointed lifestyle factors, such as diet and alcohol consumption, that may have similar damaging effects on DNA.

Furthermore, Reimand said, the team identified APOBEC (apolipoprotein B mRNA editing catalytic polypeptide-like) enzyme-driven SGMs, “which may help decipher the role of APOBECs in tumorigenesis and progression.” APOBEC SGMs have been linked to breast and other cancer types.

The study was published online November 3 in Science Advances.

More Smoking, More SGMs

The investigators analyzed the protein-coding impact of mutations in 12,341 cancer genomes of patients with 18 cancer types. They found that SGMs were strongly enriched in DNA signatures of tobacco smoking, APOBEC enzymes, and reactive oxygen species.

These SGM mutations frequently affect cancer tumor suppressor genes such as TP53, FAT1, and APC, keeping them from fully forming to produce proteins that prevent abnormal cells from growing and causing cancer.

Environmental factors may play a role in SGM mutations, according to the new research. For example, tobacco-driven SGMs in lung cancer correlate with smoking history, meaning these mutations are potentially preventable.

Compared with patients with a smoking history, the cancer genomes of lifelong nonsmokers had fewer tobacco-associated SGMs. And, although no significant differences in the SGM burden were found between current smokers and those who quit smoking recently, both groups had significantly more SGMs than lifelong nonsmokers and former smokers who quit years earlier.

In The Cancer Genome Atlas (TCGA), lung cancer samples included 10.5 tobacco smoking–associated SGMs per genome on average: 73% of cancers had at least one, and 39% had at least 10 of these protein-truncating mutations.

Further analyses revealed that tobacco smoking seems to be the strongest driver of SGMs, not only in lung cancer and head and neck cancers, but also in esophageal cancers, all of which involve direct exposure to smoke.

Notably, increased tobacco smoking was associated with a higher SGM burden, indicating that the more an individual is exposed to tobacco smoke, the more likely they are to acquire SGMs that disrupt gene function in tobacco-exposed cells. Therefore, these mutations “appear to be influenced by lifestyle and environment factors, such as tobacco smoking or passive exposure to second-hand smoke,” the authors write.

The team also found that APOBEC-driven SGMs associated specifically with APOBEC3A gene expression were seen in both breast and head and neck cancers. Normally, APOBEC enzymes are core components of antiviral immune defense and somatic antibody diversification. They disable viruses by inducing SGMs in the viral RNA.

Breast cancer samples with higher APOBEC3A expression were found to have significantly more APOBEC-driven SGMs compared with cancers that had lower expression.

In primary breast cancers in The Cancer Genome Atlas, APOBEC processes were associated with an average of 1.1 SGMs per sample and affected a quarter of samples. In metastatic breast cancers, the burden was higher (mean, 2.3 SGMs per sample; 32% of samples), which is consistent with longer or higher levels of APOBEC activity in advanced cancers.

Clinical Implications

“For clinicians, prevention is an important and actionable message,” Reimand said. “We have known for decades that smoking causes DNA mutations that in turn cause cancer.  But through these SGMs, the idea might be now even easier to understand for everyone. This may enable earlier detection as individuals at higher cancer risk, such as frequent smokers, could come for checkups sooner and more frequently.

“As we start to have more detailed environmental and lifestyle profiles of the patients in large cancer genomics datasets, we will be able to learn more about how mutations arise and how exactly these alter cells,” he added. “Today, we do not have good evidence to verify these potential links, but as the community develops newer cancer genomic resources, we may find out more about how our environments and habits shape the genome and cellular logic in cancer.”

Dr Christine Ambrosone

Commenting on the study for Medscape, Christine Ambrosone, PhD, senior vice president of population sciences and chair of cancer prevention & control at Roswell Park Comprehensive Cancer Center in Buffalo, New York, said, “This research provides new insight into underlying mechanisms of carcinogenesis and the role that SGMs and truncating mutations can play in cancer etiology, particularly when they occur in important genes, such as TP53.”

“Of interest are the findings that the more an individual is exposed to tobacco smoke, the more likely they are to acquire these SGMs,” said Ambrosone, who was not involved in the study. “This research adds to the overwhelming evidence that tobacco exposure is a major cause of cancer [and] is one more piece of the puzzle that research needs to build upon to treat and cure cancer.”

“However,” she added, “messages to populations about the harms of tobacco use are the first armament for prevention of tobacco-related cancers.”

This work was supported by the following grants to Reimand: the Project Grant of Canadian Institutes of Health Research, the Operating Grant of the Cancer Research Society, and the Investigator Award from the Ontario Institute for Cancer Research. Reimand was also supported by the New Investigator Award of the Terry Fox Research Institute. The authors and Ambrosone report no relevant financial relationships.

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