Mutational Characteristics of Chemotherapy-Treated Bladder Urothelial Neoplasms

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This study by Faltas et al was able to demonstrate that L1CAM/integrin- and APOBEC-induced mutations are potentially actionable genomic targets for future therapeutic agents.

— Juan J. Chipollini, MD, and Philippe E. Spiess, MD

Radical cystectomy with urinary diversion is the standard of care for muscle invasive bladder cancer.1 Meta-analyses of prospective data have shown a 5% overall survival benefit at 5 years for those receiving neoadjuvant systemic chemotherapy prior to cystectomy.2,3 We currently know of two distinct molecular pathways in the development of bladder cancer: Activation of the Ras receptor and FGRFR3 genes occurs in cases of low-grade bladder cancers, whereas mutations in the p53 and RB pathways have been implicated in high-grade bladder urothelial neoplasms.4 However, the literature is sparse in regard to molecular drivers of cancer progression as well as the key inciting events that occur during the transition from locally confined to widely disseminated, systemic disease.

Mutational Heterogeneity and Clonality

The meaningful contribution by Faltas et al in Nature Genetics, reviewed in this issue of The ASCO Post, brought to light the high mutational heterogeneity among bladder tumors from individual patients, as well as the clonal evolution of primary untreated tumors to those present in the postchemotherapy metastatic setting.5 Using whole-exome sequencing and clonality analysis, their results were consistent with those from The Cancer Genome Atlas data; only a low proportion of mutations were shared by both pre- and postchemotherapy samples (28% in this study), with some taking place in known driver genes such as TP53 and TSC1.6 

Juan J. Chipollini, MD

Juan J. Chipollini, MD

Philippe E. Spiess, MD

Philippe E. Spiess, MD

Remarkably, the authors were able to investigate the mutational evolution caused by systemic chemotherapy by examining 16 matched tumor pairs in the pre- and postchemotherapy settings. From one of the lymph nodes removed at the time of cystectomy, they were able to identify nonsilent mutation of the TSPAN8 gene, a proangiogenic and prometastatic gene, as well as APOBEC3-induced mutagenesis as significant events in the evolution of chemotherapy-treated tumors. 

Of interest was the increased clonality in the postchemotherapy tumor samples, specifically genes involved in the transmembrane proteins L1CAM (L1 cell adhesion molecule) and the integrins, which have been linked to multidrug chemotherapy resistance. Although this was a missense mutation that the authors believed could theoretically lead to a gain of function, this was not corroborated by looking at the expression of downstream signal effectors. 

Mechanisms Brought to Light

Notwithstanding, this nicely designed study brought to light some of the mechanisms involved in the evolution of chemotherapy-treated tumors. By evaluating the genetic profile of a given bladder urothelial neoplasm in a patient from the time of primary diagnosis, a change in the genetic makeup of tumors was appreciable with loss observed in genes involved with cisplatin response, including POLD2 and FOXP1. Also noted was the low frequency of ERCC2 mutations in this cohort of mostly chemoresistant patients, which correlates with previous studies identifying low expression of ERCC2 mutants in cisplatin-sensitive patients.7 

In conclusion, this study by Faltas et al was able to demonstrate that L1CAM/integrin- and APOBEC-induced mutations are potentially actionable genomic targets for future therapeutic agents. More translational research and collaboration are encouraged in order to identify relevant genomic alterations in bladder cancer patients. The era of precision medicine will also require the integration of molecular classification, based on whole-genome profiling, into current clinical guidelines for bladder and other malignancies. ■

Disclosure: Drs. Chipollini and Spiess reported no potential conflicts of interest.

Dr. Chipollini is a urologic oncology fellow, and Dr. Spiess is a urologic oncologist in the Department of Genitourinary Oncology, Moffitt Cancer Center, Tampa, Florida.


1. Clark PE, Spiess PE, Agarwal N, et al: NCCN Guidelines Insights: Bladder Cancer, version 2.2016. J Natl Compr Canc Netw 14:1213-1224, 2016.

2. Grossman HB, Natale RB, Tangen CM, et al: Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 349:859-866, 2003.

3. International Collaboration of Trialists, et al: International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: Long-term results of the BA06 30894 trial. J Clin Oncol 29:2171-2177, 2011.

4. Netto GJ: Molecular biomarkers in urothelial carcinoma of the bladder: Are we there yet? Nat Rev Urol 9:41-51, 2011.

5. Faltas BM, Prandi D, Tagawa ST, et al: Clonal evolution of chemotherapy-resistant urothelial carcinoma. Nat Genet 48:1490-1499, 2016.

6. Cancer Genome Atlas Research Network: Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 507:315-322, 2014.

7. Van Allen EM, Mouw KW, Kim P, et al: Somatic ERCC2 mutations correlate with cisplatin sensitivity in muscle-invasive urothelial carcinoma. Cancer Discov 4:1140-1153, 2014.

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