BACKGROUND AND OBJECTIVE: The role of genetic variants in response to systemic therapy in muscle-invasive bladder cancer (MIBC) is still elusive. We assessed variations in genes involved in DNA damage repair (DDR) before and after cisplatin-based neoadjuvant chemotherapy (NAC) and correlation of alteration patterns with DNA damage and response to therapy. METHODS: Matched tissue from 46 patients with MIBC was investigated via Ion Torrent-based next-generation sequencing using a self-designed panel of 30 DDR genes. Phosphorylation of γ-histone 2A.X (H2AX) was analyzed via immunohistochemistry to evaluate DNA damage. Genetic variants were analyzed along with clinical data and quantitative phospho-H2AX data using the Kaplan-Meier method, Cox regression analysis, and factor analysis of mixed data. KEY FINDINGS AND LIMITATIONS: Twenty-five patients (54%) had a response (

Center for Cancer Research Comprehensive Cancer Center Medical University of Vienna Vienna Austria

Clinical Institute of Pathology Medical University of Vienna Vienna Austria

Department of Urology 2nd Faculty of Medicine Charles University Prague Czechia

Department of Urology Comprehensive Cancer Center Medical University of Vienna Vienna Austria

Department of Urology University of Texas Southwestern Medical Center Dallas TX USA

Department of Urology Weill Cornell Medical College New York NY USA

Hourani Center for Applied Scientific Research Al Ahliyya Amman University Amman Jordan

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Witjes J.A., Babjuk M., Bellmunt J., et al. EAU-ESMO consensus statements on the management of advanced and variant bladder cancer—an international collaborative multistakeholder effort. Eur Urol. 2020;77:223–250. doi: 10.1016/j.eururo.2019.09.035. PubMed DOI

Petrelli F., Coinu A., Cabiddu M., Ghilardi M., Vavassori I., Barni S. Correlation of pathologic complete response with survival after neoadjuvant chemotherapy in bladder cancer treated with cystectomy: a meta-analysis. Eur Urol. 2014;65:350–357. doi: 10.1016/j.eururo.2013.06.049. PubMed DOI

Ploussard G., Shariat S.F., Dragomir A., et al. Conditional survival after radical cystectomy for bladder cancer: evidence for a patient changing risk profile over time. Eur Urol. 2014;66:361–370. doi: 10.1016/j.eururo.2013.09.050. PubMed DOI

Powles T., Bellmunt J., Comperat E., et al. Bladder cancer: ESMO clinical practice guideline for diagnosis, treatment and follow-up. Ann Oncol. 2022;33:244–258. doi: 10.1016/j.annonc.2021.11.012. PubMed DOI

Shariat S.F., Lotan Y., Vickers A., et al. Statistical consideration for clinical biomarker research in bladder cancer. Urol Oncol. 2010;28:389–400. doi: 10.1016/j.urolonc.2010.02.011. PubMed DOI PMC

Taber A., Christensen E., Lamy P., et al. Molecular correlates of cisplatin-based chemotherapy response in muscle invasive bladder cancer by integrated multi-omics analysis. Nat Commun. 2020;11:4858. doi: 10.1038/s41467-020-18640-0. PubMed DOI PMC

Zargar H., Espiritu P.N., Fairey A.S., et al. Multicenter assessment of neoadjuvant chemotherapy for muscle-invasive bladder cancer. Eur Urol. 2015;67:241–249. doi: 10.1016/j.eururo.2014.09.007. PubMed DOI PMC

Desai N.B., Scott S.N., Zabor E.C., et al. Genomic characterization of response to chemoradiation in urothelial bladder cancer. Cancer. 2016;122:3715–3723. doi: 10.1002/cncr.30219. PubMed DOI PMC

Plimack E.R., Dunbrack R.L., Brennan T.A., et al. Defects in DNA repair genes predict response to neoadjuvant cisplatin-based chemotherapy in muscle-invasive bladder cancer. Eur Urol. 2015;68:959–967. doi: 10.1016/j.eururo.2015.07.009. PubMed DOI PMC

Eisenhauer E.A., Therasse P., Bogaerts J., et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer. 2009;45:228–247. doi: 10.1016/j.ejca.2008.10.026. PubMed DOI

Cancer Genome Atlas Research N Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. 2014;507:315–322. doi: 10.1038/nature12965. PubMed DOI PMC

Bannon S.A., Routbort M.J., Montalban-Bravo G., et al. Next-generation sequencing of DDX41 in myeloid neoplasms leads to increased detection of germline alterations. Front Oncol. 2020;10 doi: 10.3389/fonc.2020.582213. PubMed DOI PMC

Stout L.A., Kassem N., Hunter C., Philips S., Radovich M., Schneider B.P. Identification of germline cancer predisposition variants during clinical ctDNA testing. Sci Rep. 2021;11:13624. doi: 10.1038/s41598-021-93084-0. PubMed DOI PMC

Yang L., Ghosh R.P., Franklin J.M., et al. NuSeT: a deep learning tool for reliably separating and analyzing crowded cells. PLoS Comput Biol. 2020;16 doi: 10.1371/journal.pcbi.1008193. PubMed DOI PMC

Mayakonda A., Lin D.C., Assenov Y., Plass C., Koeffler H.P. Maftools: efficient and comprehensive analysis of somatic variants in cancer. Genome Res. 2018;28:1747–1756. doi: 10.1101/gr.239244.118. PubMed DOI PMC

Flanagan S.E., Patch A.M., Ellard S. Using SIFT and PolyPhen to predict loss-of-function and gain-of-function mutations. Genet Test Mol Biomarkers. 2010;14:533–537. doi: 10.1089/gtmb.2010.0036. PubMed DOI

Tsongalis G.J., Peterson J.D., de Abreu F.B., et al. Routine use of the Ion Torrent AmpliSeq cancer hotspot panel for identification of clinically actionable somatic mutations. Clin Chem Lab Med. 2014;52:707–714. doi: 10.1515/cclm-2013-0883. PubMed DOI

Heeke A.L., Pishvaian M.J., Lynce F., et al. Prevalence of homologous recombination-related gene mutations across multiple cancer types. JCO Precis Oncol. 2018;2018 doi: 10.1200/PO.17.00286. PubMed DOI PMC

Teo M.Y., Seier K., Ostrovnaya I., et al. Alterations in DNA damage response and repair genes as potential marker of clinical benefit from PD-1/PD-L1 blockade in advanced urothelial cancers. J Clin Oncol. 2018;36:1685–1694. doi: 10.1200/JCO.2017.75.7740. PubMed DOI PMC

Robertson A.G., Kim J., Al-Ahmadie H., et al. Comprehensive molecular characterization of muscle-invasive bladder cancer. Cell. 2017;171:540–556.e25. doi: 10.1016/j.cell.2017.09.007. PubMed DOI PMC

Nassar A.H., Umeton R., Kim J., et al. Mutational analysis of 472 urothelial carcinoma across grades and anatomic sites. Clin Cancer Res. 2019;25:2458–2470. doi: 10.1158/1078-0432.CCR-18-3147. PubMed DOI

Van Allen E.M., Mouw K.W., Kim P., et al. Somatic ERCC2 mutations correlate with cisplatin sensitivity in muscle-invasive urothelial carcinoma. Cancer Discov. 2014;4:1140–1153. doi: 10.1158/2159-8290.CD-14-0623. PubMed DOI PMC

Liu D., Abbosh P., Keliher D., et al. Mutational patterns in chemotherapy resistant muscle-invasive bladder cancer. Nat Commun. 2017;8:2193. doi: 10.1038/s41467-017-02320-7. PubMed DOI PMC

Liu D., Plimack E.R., Hoffman-Censits J., et al. Clinical validation of chemotherapy response biomarker ERCC2 in muscle-invasive urothelial bladder carcinoma. JAMA Oncol. 2016;2:1094–1096. doi: 10.1001/jamaoncol.2016.1056. PubMed DOI PMC

Lin P.C., Yeh Y.M., Wu P.Y., Hsu K.F., Chang J.Y., Shen M.R. Germline susceptibility variants impact clinical outcome and therapeutic strategies for stage III colorectal cancer. Sci Rep. 2019;9:3931. doi: 10.1038/s41598-019-40571-0. PubMed DOI PMC

Richards S., Aziz N., Bale S., et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–424. doi: 10.1038/gim.2015.30. PubMed DOI PMC

Carlo M.I., Mukherjee S., Mandelker D., et al. Prevalence of germline mutations in cancer susceptibility genes in patients with advanced renal cell carcinoma. JAMA Oncol. 2018;4:1228–1235. doi: 10.1001/jamaoncol.2018.1986. PubMed DOI PMC

Tripathi A., Grivas P. The utility of next generation sequencing in advanced urothelial carcinoma. Eur Urol Focus. 2020;6:41–44. doi: 10.1016/j.euf.2019.08.016. PubMed DOI