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An Epigenomic Approach to Improving Response to Neoadjuvant Cisplatin Chemotherapy in Bladder Cancer.

ABSTRACT: Bladder cancer is among the five most common cancers diagnosed in the Western world and causes significant mortality and morbidity rates in affected patients. Therapeutic options to treat the disease in advanced muscle-invasive bladder cancer (MIBC) include cystectomy and chemotherapy. Neoadjuvant cisplatin-based combination chemotherapy is effective in MIBC; however, it has not been widely adopted by the community. One reason is that many patients do not respond to neoadjuvant chemotherapy, and no biomarker currently exists to identify these patients. It is also not clear whether a strategy to sensitize chemoresistant patients may exist. We sought to identify cisplatin-resistance patterns in preclinical models of bladder cancer, and test whether treatment with the epigenetic modifier decitabine is able to sensitize cisplatin-resistant bladder cancer cell lines. Using a screening approach in cisplatin-resistant bladder cancer cell lines, we identified dysregulated genes by RNA sequencing (RNAseq) and DNA methylation assays. DNA methylation analysis of tumors from 18 patients receiving cisplatin-based chemotherapy was used to confirm in vitro results. Cisplatin-resistant bladder cancer cells were treated with decitabine to investigate epigenetic sensitization of resistant cell lines. Our results show that HOXA9 promoter methylation status is associated with response to cisplatin-based chemotherapy in bladder cancer cell lines and in metastatic bladder cancer. Bladder cancer cells resistant to cisplatin chemotherapy can be sensitized to cisplatin by the DNA methylation inhibitor decitabine. Our data suggest that HOXA9 promoter methylation could serve as potential predictive biomarker and decitabine might sensitize resistant tumors in patients receiving cisplatin-based chemotherapy.

SUBMITTER: Xylinas E

PROVIDER: S-EPMC5039423 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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An Epigenomic Approach to Improving Response to Neoadjuvant Cisplatin Chemotherapy in Bladder Cancer.

Xylinas Evanguelos E Hassler Melanie R MR Zhuang Dazhong D Krzywinski Martin M Erdem Zeynep Z Robinson Brian D BD Elemento Olivier O Clozel Thomas T Shariat Shahrokh F SF

Biomolecules 20160902 3

Bladder cancer is among the five most common cancers diagnosed in the Western world and causes significant mortality and morbidity rates in affected patients. Therapeutic options to treat the disease in advanced muscle-invasive bladder cancer (MIBC) include cystectomy and chemotherapy. Neoadjuvant cisplatin-based combination chemotherapy is effective in MIBC; however, it has not been widely adopted by the community. One reason is that many patients do not respond to neoadjuvant chemotherapy, and ...[more]

PMID: 27598218

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Project description:BACKGROUND:Cisplatin-based neoadjuvant chemotherapy (NAC) before cystectomy is the standard of care for muscle-invasive bladder cancer (MIBC), with 25-50% of patients expected to achieve a pathologic response. Validated biomarkers predictive of response are currently lacking. OBJECTIVE:To discover and validate biomarkers predictive of response to NAC for MIBC. DESIGN, SETTING, AND PARTICIPANTS:Pretreatment MIBC samples prospectively collected from patients treated in two separate clinical trials of cisplatin-based NAC provided the discovery and validation sets. DNA from pretreatment tumor tissue was sequenced for all coding exons of 287 cancer-related genes and was analyzed for base substitutions, indels, copy number alterations, and selected rearrangements in a Clinical Laboratory Improvements Amendments-certified laboratory. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:The mean number of variants and variant status for each gene were correlated with response. Variant data from the discovery cohort were used to create a classification tree to discriminate responders from nonresponders. The resulting decision rule was then tested in the independent validation set. RESULTS AND LIMITATIONS:Patients with a pathologic complete response had more alterations than those with residual tumor in both the discovery (p=0.024) and validation (p=0.018) sets. In the discovery set, alteration in one or more of the three DNA repair genes ATM, RB1, and FANCC predicted pathologic response (p<0.001; 87% sensitivity, 100% specificity) and better overall survival (p=0.007). This test remained predictive for pathologic response in the validation set (p=0.033), with a trend towards better overall survival (p=0.055). These results require further validation in additional sample sets. CONCLUSIONS:Genomic alterations in the DNA repair-associated genes ATM, RB1, and FANCC predict response and clinical benefit after cisplatin-based chemotherapy for MIBC. The results suggest that defective DNA repair renders tumors sensitive to cisplatin. PATIENT SUMMARY:Chemotherapy given before bladder removal (cystectomy) improves the chance of cure for some but not all patients with muscle-invasive bladder cancer. We found a set of genetic mutations that when present in tumor tissue predict benefit from neoadjuvant chemotherapy, suggesting that testing before chemotherapy may help in selecting patients for whom this approach is recommended.

Project description:Background and aimNeoadjuvant chemotherapy (NAC) followed by radical cystectomy is the current gold standard treatment for muscle-invasive urothelial bladder cancer (MIBC). Nonetheless, some MIBC patients showed limited pathological response after NAC. Herein, we used whole-exome sequencing (WES) to identify genetic mutations in MIBC that can predict NAC response.MethodsForty MIBC patients were enrolled in this study, in which 33 were successfully examined by WES and Sanger sequencing in the discovery cohort (n=13) and the validation cohort (n=20), respectively. ANNOVAR software was used to identify the potential mutations based on the data of WES. In addition, tumor-specific somatic mutations including single nucleotide variants and indels were called with the muTECT and Strelka software. The mutational analysis of specific genes was carried out based on the data from cBioPortal for Cancer Genomics.ResultsIn the discovery cohort, the mutation frequencies of TP53, MED16, DRC7, CEND1, ATAD5, SETD8, and PIK3CA were significantly higher in 13 MIBC patients. Specifically, the presence of somatic mutations of APC, ATM, CDH9, CTNNB1, METTL3, NBEAL1, PTPRH, RNASEL, and FBXW7 in NAC responder signifies that these mutations were potential predictors of pathological response to NAC. Furthermore, somatic mutations of CCDC141, PIK3CA, CHD5, GPR149, MUC20, TSC1, and USP54 were exclusively identified in NAC nonresponders, suggesting that these mutations may participate in the process of NAC resistance. In the validation cohort, the somatic mutations of CDH9, METTL3, and PTPRH were significantly enriched in NAC responders while the somatic mutation of CCDC141 was significantly enriched in NAC nonresponders. Furthermore, survival analysis revealed that the patients expressing mutated METTL3 have a longer overall survival and disease- or progression-free survival than the patients acquiring wild-type METTL3.ConclusionThe somatic mutation of METTL3 can be a potential predictive biomarker of NAC response in MIBC patients.Relevance for patientsMIBC patients bearing mutated METTL3 display a pathological response to NAC and have a significantly longer overall survival or disease/progression-free survival as compared to the patients bearing wild-type METTL3. Thus, the somatic mutation of METTL3 is a potential biomarker for predicting response to NAC in MIBC patients, assisting doctors in making the clinical decision.

Dataset Information

An Epigenomic Approach to Improving Response to Neoadjuvant Cisplatin Chemotherapy in Bladder Cancer.

Publications

An Epigenomic Approach to Improving Response to Neoadjuvant Cisplatin Chemotherapy in Bladder Cancer.

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