Molecular Footprints of Muscle-Invasive Bladder Cancer in Smoking and Nonsmoking Patients - Beyond the Abstract

Bladder cancer is considered smoking-related cancer, yet unlike lung cancer in which almost 90% have a strong smoking history, half of those with bladder cancer are non-smokers. We were very interested in this dichotomy between smoking and the development of bladder cancer and specifically wanted to know if the tumors from smokers were the same or different from non-smokers. This question goes back to the origin of bladder cancer. In smokers- we think we have an idea about the cause of their cancer- but what about non-smokers? Specifically, why do patients get bladder cancer? I struggle with this real-world question when I meet every patient with bladder cancer- I simply have no explanation for those that do not smoke or quit decades ago. The ultimate goal of our research is to identify these causes of bladder cancer because we could then identify cancers at an earlier stage and provide better treatments for patients. If the cancers were caused by an environmental carcinogen, perhaps we could prevent bladder cancer.

We started by identifying patients in the Cancer Genome Atlas that were non-smokers (n=98), reformed smokers (n=177) or smokers (n=83). When we evaluated the gene expression profiles of their tumors, we found only one gene, GPR15 was elevated in smokers. Our research has previously evaluated a mouse model of bladder cancer that has many genomic characteristics of smokers, and also identified an increase in expression of Gpr15 in mice exposed to this carcinogen. There was no difference in the rate of tumor subtypes by smoking and GPR15 expression was increased across bladder cancer subtypes. Unlike patients with lung cancer, we saw no difference in the total mutation burden between smokers and non-smokers. This data suggests that perhaps the carcinogenesis caused by smoking causes a direct impact on lung cancer, but perhaps this carcinogenesis occurred by a different mechanism in bladder cancer.

When we looked among the genes with differential mutations, we found six genes had differential mutation profiles, with five gene mutations more common in non-smokers and only one gene found to be mutated more frequently in smokers (SPTA1). None of these genes have been identified to play a role in cancer, and our research group is currently involved in determining their role in bladder cancer. Our most promising finding relates to the COSMIC signatures identified as the cause of each mutation. When we compared the COSMIC signatures of smokers to non-smokers, we found an inverse correlation between two signatures- COSMIC5, enriched in smokers, and COSMIC 13 found in non-smokers. This suggests that COSMIC13, which is an APOBEC signature marks the mutations found in non-smokers. Thus, if we can identify the initiator of APOBEC mutagenesis in non-smokers, we may identify the cause of bladder cancer. We don’t know at this time if APOBEC is responding to single-stranded DNA from genomic stress or even perhaps viral DNA. We are hoping this will lead to identifying the cause of non-smoking related bladder cancer. 

Written by: Joshua J Meeks, MD, Ph.D., Assistant Professor of Urology at the Northwestern University Feinberg School of Medicine, Section Chief of Robotic Surgery at the Jesse Brown VA Medical Center

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