Smoking is considered an important risk factor for bladder cancer (BC), yet molecular characterization of BC in nonsmokers has not been extensively studied. Here, we compare molecular differences between smokers and nonsmokers with BC. BC specimens (676) profiled at a Clinical Laboratory Improvement Amendments-certified laboratory from 2006 to 2014 were retrospectively evaluated for molecular differences between smokers and nonsmokers. Protein expression was determined with immunohistochemistry. In situ hybridization was used for ERBB2 (HER2/neu) and EGFR evaluation. Genes were evaluated using Sanger or next-generation sequencing. Thirty patients were confirmed lifetime nonsmokers (NS) and 39 were reformed or current smokers (RCS). There was a trend for increased PIK3CA mutations in NS versus RCS (43% vs 11%, p = 0.1760), whereas TP53 alterations were higher in RCS versus NS (63% vs 53%, p = 0.6699). EGFR amplification was observed more in NS versus RCS (22% vs 11%, p = 0.5815), while HER2 was amplified only in RCS (23% vs 0%, p = 0.05). The molecular differences between RCS and NS with BC suggest a different oncogenesis with potentially different treatment options. Patient summary: Bladder cancer patients with no history of smoking have different molecular characteristics than those with smoking history. We found that smokers tend to have higher incidence of HER2 amplification, whereas nonsmokers seemed to have higher PIK3CA mutation. This knowledge provides essential information, which can bear relevance to treatment options. Bladder cancer patients with no smoking history may have different molecular characteristics when compared with those with a smoking history. This could help develop a more precise therapeutic option for this select patient population.
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