Background: Next generation sequencing (NGS) to identify genomic alterations (GAs) in tumor samples are increasingly used in clinical practice. Targeted sequencing (TS) or whole exome sequencing (WES) are used by various commercially available platforms. Differing methods often result in poor inter-reproducibility, even when testing the same tissue. Bladder cancer has substantial genetic heterogeneity as compared to many other malignancies. The purpose of this study is to compare WES and TS in bladder cancer. Methods: Patients with advanced bladder cancer who had undergone tissue WES (GEM ExTra®) or TS (FoundationOne CDx® [FMI]) in the course of routine clinical care were assessed. Genes with at least one detected GA were selected, with others excluded. All detected GAs were classified as being detected on TS only, WES only, concordant (detected on both platforms), or partially concordant (different GAs detected within the same gene). Variants of uncertain significance were excluded for this study. Results: In our series, 25 patients had WES and 42 patients had TS - 14 patients (21%) had both tests performed. A total of 88 genes were detected to have at least one GA across all samples. Of all detected GAs, 66/162 (41%) were concordant, with 45/162 (28%) and 51/162 (31%) of GAs detected exclusively by WES and TS, respectively. The genes with the highest proportion of concordance when detected, were TERT (70%), TP53 (85%) and ARIDA1A (50%). SOX4 and E2F3 were detected on WES only, while RBM and CHEK2 were detected on TS only. Notably, six TP53 GAs were detected exclusively on TS. TP53, TERT, MLL2/KMT2D, ERBB2 were each partially concordant on one occasion. The difference in the rate of concordant GAs in samples from the same collection site and date (41%), as compared to those in which both differed (35%) were not statistically significant (p=0.54). Conclusions: Although the majority of GAs identified were concordant, each platform exclusively identified GAs with varying clinical significance. SOX4 and E2F3 mutation, shown to correlate with invasive potential in bladder cancer, were detected exclusively on WES. In contrast, RBM and CHEK2 (of known significance in melanoma and breast cancer) were found exclusively on TS. Larger series are needed to further establish the concordance of these approaches.
Citation Format: Neal Shiv Chawla, Zeynep Zengin, Ameish Govindarajan, Sumanta K. Pal. Comparison of whole exome sequencing and targeted sequencing in patients with advanced bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB196.