Platinum Priority – Bladder CancerEditorial by Cyrill A. Rentsch, David C. Müller, Christian Ruiz and Lukas Bubendorf on pp. 960–961 of this issueNext-generation Sequencing of Nonmuscle Invasive Bladder Cancer Reveals Potential Biomarkers and Rational Therapeutic Targets
Introduction
Of the estimated 429 000 people to be diagnosed with bladder cancer in the industrialized world each year, 70–80% will have nonmuscle invasive bladder cancer (NMIBC) [1], [2]. Half of all NMIBC patients will experience tumor recurrence within 5 yr, and 20–30% will progress to secondary MIBC [3]. Ultimately, as many as 10–15% of patients presenting with NMIBC will die of bladder cancer [4].
Previous investigations into NMIBC genetics have been limited by their inability to comprehensively profile tumors for multiple cancer-associated genes [5]. More recently, MIBC were comprehensively investigated by The Cancer Genome Atlas (TCGA) and other groups using next-generation sequencing (NGS), leading to the identification of potential biomarkers and targets for therapeutic intervention [6], [7]. However, very few NMIBC tumors have been examined with NGS methods to date, and these investigations have been limited by a lack of clinical annotation, the absence of restaging transurethral resection (TUR) to ensure appropriate tumor staging, or a failure to differentiate between primary and recurrent tumors [8], [9], [10], [11].
In this study, we examined primary treatment-naive index tumors from a cohort of patients with NMIBC using a massively parallel, targeted, exon capture-based NGS platform to define the prevalence of genetic alterations and their potential clinical implications.
Section snippets
Patients and samples
Targeted NGS with a 341 or updated 410 cancer-associated gene panel was performed on formalin-fixed paraffin embedded sections of treatment-naive index tumors along with matched germline DNA for 105 patients with NMIBC as part of an Institutional Review Board-approved protocol (Supplementary Fig. 1, Supplementary Table 1, Supplementary data) [12]. A board-certified genitourinary pathologist reviewed representative hematoxylin and eosin slides to confirm grade, stage, and urothelial histology.
Patient demographics and treatment
To characterize the genomic landscape of NMIBC, we analyzed 105 tumors across the disease spectrum comprising low-grade Ta (LGTa; n = 23), high-grade Tis (HGTis; n = 12), high-grade Ta (HGTa; n = 32), and HGT1 (n = 38) for alterations in 341 cancer-associated genes. Information on patient demographics and treatments are listed in Table 1, Supplementary Table 2, and Supplementary Table 3. The median follow-up for the NMIBC cohort managed by TUR with or without adjuvant intravesical therapy (n = 100) was
Discussion
Most sequencing efforts in bladder cancer have focused on MIBC. Yet the majority of bladder cancer patients are diagnosed with NMIBC, the treatment of which imposes substantial burden to patients and the global health care system [3]. To our knowledge, our study is the largest NGS effort to focus on NMIBC to date. Our objective was to identify genetic alterations with potential clinical implications in addressing the many unmet needs of NMIBC patients.
One major unmet need is reliable screening
Conclusions
NGS of treatment-naive index tumors from patients with NIMBC identified that the majority of tumors had at least one potentially actionable alteration that could serve as a drug target in clinical trials of novel intravesical or systemic therapy. High rates of DDR gene alterations were identified in high-grade NMIBC tumors, which might have implications for BCG immunotherapy and systemic checkpoint inhibition in NMIBC patients. ARID1A mutations may be associated with earlier recurrence after
References (30)
- et al.
Long-term cancer-specific survival in patients with high-risk, non-muscle-invasive bladder cancer and tumour progression: a systematic review
Eur Urol
(2011) - et al.
Genomic predictors of survival in patients with high-grade urothelial carcinoma of the bladder
Eur Urol
(2015) - et al.
Mutational context and diverse clonal development in early and late bladder cancer
Cell Rep
(2014) - et al.
Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT): a hybridization capture-based next-generation sequencing clinical assay for solid tumor molecular oncology
J Mol Diagn
(2015) - et al.
Genomic characterization of upper tract urothelial carcinoma
Eur Urol
(2015) - et al.
Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial
Lancet
(2016) - et al.
Telomerase reverse transcriptase promoter mutations in bladder cancer: high frequency across stages, detection in urine, and lack of association with outcome
Eur Urol
(2014) - et al.
Comprehensive mutation analysis of the TERT promoter in bladder cancer and detection of mutations in voided urine
Eur Urol
(2014) - et al.
Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012
Int J Cancer
(2015) - et al.
Histological classification and stage of newly diagnosed bladder cancer in a population-based study from the Northeastern United States
Scand J Urol Nephrol
(2008)
Recurrence of high-risk bladder cancer: a population-based analysis
Cancer
Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity
Nat Rev Cancer
Comprehensive molecular characterization of urothelial bladder carcinoma
Nature
Whole-genome sequencing of bladder cancers reveals somatic CDKN1A mutations and clinicopathological associations with mutation burden
Nat Commun
Recurrent inactivation of STAG2 in bladder cancer is not associated with aneuploidy
Nat Genet
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