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Cancer Study Finds Protein-Truncating Mutations Overrepresented in Specific Mutational Signatures

NEW YORK – Using a large collection of cancer genomes, a Toronto research team has linked truncating, "stop-gain" tumor mutations (SGMs) to environmental or lifestyle factors such as smoking as well as exposure to reactive oxygen species or enhanced APOBEC cytidine deaminase enzyme activity, demonstrating that SGMs are enhanced in related mutational signatures.

For a paper published in Science Advances on Friday, Reimand and his colleagues assessed whole-genome or exome sequences for 12,341 tumor samples originating in 18 tissue types. The collection included samples assessed through the Cancer Genome Atlas PanCanAtlas project, the Pan-Cancer Analysis of Whole Genomes, or the Hartwig Medical Foundation.

"[W]e demonstrate that the mutational processes of tobacco smoking, APOBEC, and reactive oxygen species are especially enriched in SGMs and therefore these processes generate loss-of-function mutations in cancer genomes," senior and corresponding author Jüri Reimand, a researcher affiliated with the Ontario Institute for Cancer Research and the University of Toronto, said in an email.

"This shows the direct role of tobacco/APOBEC/ROS mutations," he added, "and allows us to better understand the causes of mutagenesis, genetic cancer mechanisms, and positive selection."

Their results suggested that such stop-gain mutations (SGMs) tend to fall in tumor suppressor genes previously flagged in relevant cancer types — from truncating mutations affecting TP53 and more than a dozen other genes previously linked to lung cancer to SGMs in the head and neck cancer-associated gene FAT1 or the APC gene, known for its role in colorectal cancer and related precursor conditions.

"[W]e find that some SGMs are concentrated into established tumor suppressor genes and thus contribute to oncogenesis and progression," Reimand noted, "while others occur proteome-wide and likely contribute to tumor heterogeneity."

Likewise, the team linked the SGMs to cancer-related pathways involved in processes ranging from cell proliferation and development to cell motility, growth factor signaling, and apoptosis.

Such results may be particularly important when it comes to deterring related behaviors such as smoking, which appeared to introduce potentially preventable cancer-related alterations associated with mutational signatures found in primary lung cancers, metastatic lung cancers, and liver cancers.

"We found that lifetime smoking history of lung cancer patients correlated with the number of SGMs in cancer genomes, indicating a preventable cause and lifestyle choice of these harmful mutations," Reimand said.

When they focused on the SGMs stemming from reactive oxygen species, on the other hand, the investigators highlighted mutational signatures described in colorectal, stomach, and esophageal cancers, along with cancers of the breast, neuroendocrine system, or pancreas.

Based on the nucleotide motifs most often affected by the APOBEC-related SGMs, together with genomic and transcriptomic clues from breast cancers profiled for the Cancer Genome Atlas, meanwhile, the investigators linked higher-than-usual expression of APOBEC3A to truncating mutations and a mutational signature found in some breast, head and neck, uterine, and other cancers.

The results prompted a series of follow-up experiments in five breast cancer, bladder cancer, or B cell lymphoma cell lines, where the team saw reduced levels of SGMs in cells missing APOBEC3A but not in cell lines lacking the ABOBECB gene.

"These associations of APOBEC mutagenesis of SGMs with APOBEC3 gene expression and DNA motifs connect the mutational processes of SGMs in patient cancer genomes with the expected molecular pathways and functional evidence," the authors reported, adding that the "clinical and molecular associations of mutational processes and SGMs provide insights to tumor heterogeneity and patient outcomes and have potential implications for biomarker and therapy development."