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Research Highlight | December 14, 2023

Study finds smoking tobacco causes mutations that directly disable the genes protecting us from cancer

Toronto-based researchers funded by The Terry Fox Research Institute have discovered one way smoking tobacco weakens the body’s natural defences and leads to cancer, yielding important and actionable insights into cancer treatment and prevention.

“Using large-scale genomic analyses, we learned how mutational processes that alter DNA cause the loss of function of important genes that protect us from cancer,” says study lead Dr. Jüri Reimand, a Terry Fox New Investigator and researcher at the Ontario Institute for Cancer Research.

“We show that certain mutational processes generate stop-gain mutations (SGMs) that tend to accumulate in tumour-suppressor proteins that protect our cells from cancer, causing these proteins to be disabled. This provides a direct link on how mutations from tobacco smoking and APOBEC activity cause or contribute to cancer,” says Dr. Reimand.

To help explain the study’s findings, Dr. Reimand refers to the genome as a book. Within this book, genes are like sentences that hold the instructions needed to form proteins. Like any sentence, these genes need a period (called a stop codon in the genome) telling the reader when it ends.

In cancer genomes, mutational processes like tobacco smoking or the activity of APOBEC enzymes (which, when misregulated, are a source of mutation in cancers) can create additional stop codons, inserting periods where they shouldn’t be and cutting off the instructions early. This is known as a stop-gain mutation, and it results in incomplete or non-existent proteins.

And while we’ve long known that smoking causes DNA mutations that lead to cancer, Dr. Reimand hopes that the identification of these stop-gain mutations may make this concept easier to understand. That is, “smoking can cause mutations that directly disable the genes that protect you from cancer,” he says.

Their findings also help to explain the diversity, or heterogeneity, of cancers among patients. As these stop codons are inserted across genes, various proteins can become inactivated over time – contributing to why therapies that target specific genes are often inefficient.

In the future, the team hopes this knowledge can help predict and detect cancers earlier, leading individuals like frequent smokers who are at a higher risk of developing cancer to access treatment sooner.

“While the association between smoking and stop-gain mutations was strong, the comprehensive nature of this study led to the discovery of links between stop-gain mutations and several other mutational processes in cancer, such as reactive oxygen species and the activity of APOBEC enzymes in cells. These processes can be potentially altered by lifestyle changes or become targets for treatment, which opens the door to new opportunities for research in this area,” says Nina Adler, the PhD student who led the study.

“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,” says Dr. Reimand. “Today, we do not have enough evidence to directly verify all of these potential links by tying together lifestyle habits and the abundance of these harmful mutations, but as the community develops newer cancer genomic resources with more detailed profiles of cancer patients, we may find out more about how our environments, habits and genetic makeup can shape the genome and cellular logic in cancer.”

In the meantime, Dr. Reimand’s team will focus on other types of mutations that may play a role in cancer to identify how cancerous mutations are generated in DNA and identify other potential causes.

This study was funded by a Terry Fox New Investigator Award in Deciphering recurrence of glioblastoma for precision medicine using multi-omics data integration.