EAU 2018: The Impact of Smoking on Genomic Alterations in Muscle-invasive Bladder Cancer

Copenhagen, Denmark (UroToday.com) Smoking is an established risk factor for urothelial carcinoma of the bladder, amongst other malignancies. However, little is know about the specific genetic impact of smoking in the setting of bladder cancer, though it has been previously assessed in lung cancer, another cancer highly associated with cigarette smoking.

Using the TCGA dataset and the MSK-IMPACT dataset (Memorial Sloan Ketterings multi-malignancy genetic analysis study), the authors identified clinical and genomic data from MIBC and lung adenocarcinoma (LAC). The TCGA dataset contained genomic DNA sequencing, mutation count in Signature 5*, total mutational burden, RNA sequencing, follow-up, pack years and smoking history (current/former/never). From the MSK-IMPACT dataset, mutational burden and smoking history were used.

Mutation count by dataset

1) TCGA 382 patients: No difference between lifelong smokers, former smoker >= 15 years, former smoker < 15 years, or current smokers
2) MSK Impact 283 patients: No difference between former/current smoker vs. lifelong non-smoker
3) Lung Cancer TCGA: Significant (p<0.001) difference between lifelong smokers, former smoker >= 15 years, former smoker < 15 years, or current smokers

There was no association of smoking history (p=0.8) or pack years (p=0.9) to mutational burden in either the bladder TCGA or the MSK-IMPACT datasets. Mutation count in Signature 5* was higher in former or current smokers, but this did not reach significance (p=0.051) – unlike in lung cancer, where it was significantly higher.

Mutational burden was higher in patients with more pack-years of smoking history though (p=.005). Moreover, current and former smokers had a higher mutational burden when compared to never smokers.

In the bladder TCGA, smoking history, as well as pack years, were not related to disease-free (p=0.4) or to overall survival (p=0.2).

Although others have reported that carcinogen-induced MIBC in rodents has almost exclusively a basal-like phenotype (Kim PloS one 2011; Bivalacqua J Urol 2017), a similar association between smoking history and molecular subtypes of MIBC in TCGA patients was not apparent. We generated subtype calls using other published methods for molecular subtyping (Sjödahl Clin Cancer Res 2012, Choi Cancer Cell 2014, TCGA Nature 2014) but also found that there was no enrichment of one molecular subtype in current and/or former smokers.

Therefore, in this interesting study, while smoking is recognized as a major risk factor for developing MIBC, they could not identify any specific impact on genomic alterations in MIBC. This may be due to the fact that cigarette smoke contains over 4000 compounds, which may make it difficult to pinpoint specific mutational changes.

Speaker: R. Seiler

Co-Authors: Caridis A., Di Maio A., Knowles P., Gorman B., Jones R., Ward D., Oppermann U., Bountra C., Khanim F., Bryan R.

Written by: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, Twitter: @tchandra_uromd, at the 2018 European Association of Urology Meeting EAU18, 16-20 March, 2018 Copenhagen, Denmark