Scientists from the University of York say they have recreated how toxins from smoking cause unique patterns of DNA damage. The discovery could help researchers better understand the cause of bladder cancer and the link to smoking, according to the university team. The causes of bladder cancer remain largely unknown, but smoking is seen as the main risk factor for the disease.

Simon Baker, PhD, from the department of biology, and his colleagues grew human bladder tissues in the laboratory and exposed them to a common toxin from cigarette smoke. After the tissues were damaged by the smoke toxin, the team, which published its study “Procarcinogen Activation and Mutational Signatures Model the Initiation of Carcinogenesis in Human Urothelial Tissues In Vitro” in European Urology, analyzed all three billion letters of the genetic code to find a pattern of changes called a “mutational signature.”

“Disparity between genome-wide mutations in bladder and other cancers where smoking is a risk factor raises questions about carcinogenesis in different epithelia. To develop an experimental model of bladder carcinogenesis, we clonally expanded in vitro differentiated normal human urothelial (NHU) cells following exposure to an exemplar procarcinogen and used whole-genome DNA sequencing to derive mutational signatures. Benzo[a]pyrene (BaP) was activated by endogenous cytochrome P450 (cytochrome P450 family 1 subfamily A member 1 [CYP1A1]) to create genomically modified NHU cells. Comparison with the Catalogue of Somatic Mutations in Cancer (COSMIC) showed that mutations induced by BaP in NHU cells were similar to smoking-associated signatures in bladder and other cancers, including single- and doublet-base substitution signatures characterized by C > A transversions (COSMIC_SBS4 and COSMIC_DBS2, respectively), and an insertion/deletion signature of C deletions in homopolymer regions (ID3),” write the investigators.

“Our study provides the first direct evidence that BaP is activated locally in the urothelium, initiating the well-described smoking-associated mutational signatures. An absence of other common bladder cancer (BLCA)-associated genomic signatures points strongly to other primary causes of BLCA, which the new experimental approach described here is well placed to investigate. Mutational signatures ignore whether a gene is affected, but tissue-specific drivers (KMT2DKMT2C, and CDKN1A) were significantly over-mutated in this model, providing insight on the emergent selection pressures.”

“Mutational signatures can be used like fingerprints at a crime scene. When we look at the DNA in a cancer, we can see the fingerprints of all the criminals involved in causing the damage that led to cancer,” said Baker. “The DNA damaging event might be exposure to cigarette smoke or UV from the sun, but it might also be an unknown event that causes cancer. Our study found that the smoke toxin left its distinctive fingerprints on the DNA of bladder tissues grown in the laboratory. However, when we looked at the DNA of patients’ bladder cancers the mutational signature, of the smoke toxin, was only responsible for a small amount of the damage. So despite smoking being the key risk factor for bladder cancer, direct damage of the DNA by smoke toxins is unlikely to be the main reason for these cancers forming.”

It may be that the smoke toxins accelerate other DNA damaging events, and attention is now focusing on a family of enzymes called “APOBEC,” which destroy viruses by mutating their DNA as part of the body’s natural defenses against infection. However, recent studies suggest they might mistakenly target our own DNA in a number of cancer types. The next stage of the study will be to try and understand how and why APOBEC enzymes become activated in the cells of the bladder.

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