Genomic profiling of Chinese patients with urothelial carcinoma

Abstract

Backgrounds Urothelial carcinoma (UC) is the most common genitourinary malignancy in China. In this study, we surveyed the genomic features in Chinese UC patients and investigated the concordance of genetic alterations between circulating tumor DNA (ctDNA) in plasma and matched tumor tissue. Materials and methods A total of 112 UC patients were enrolled, of which 31 were upper tract UC (UTUC) and 81 were UC of bladder (UCB). Genomic alterations in 92 selected genes were analyzed by targeted next-generation sequencing. Results In the study cohort, 94.64, 86.61 and 62.50% of patients were identified as having valid somatic, oncogenic and actionable somatic alterations, respectively. The most frequently altered genes included TP53, KMT2D, KDM6A, FAT4, FAT1, CREBBP and ARID1A. The higher prevalence of HRAS (22.0% vs 3.7%) and KMT2D (59.26% vs 34.57%) was identified in UTUC than in UCB. Comparisons of somatic alterations of UCB and UTUC between the study cohort and western cohorts revealed significant differences in mutant prevalence. Notably, 28.57, 17.86 and 47.32% of the cases harbored alterations in FGFRs, ERBBs and DNA damage repair genes, respectively. Furthermore, 75% of the patients carried non-benign germline variants, but only two (1.79%) were pathogenic. The overall concordance for genomic alterations in ctDNA and matched tumor tissue was 42.97% (0–100%). Notably, 47.25% of alterations detected in ctDNA were not detected in the matched tissue, and 54.14% of which were oncogenic mutations. Conclusions We found a unique genomic feature of Chinese UC patients. A reasonably good concordance of genomic features between ctDNA and tissue samples were identified.

Comprehensive genomic profiling of upper tract urothelial carcinoma and urothelial carcinoma of the bladder identifies distinct molecular characterizations with potential implications for targeted therapy & immunotherapy

“…Epigenetic abnormality, such as alterations in chromatin remodeling, DNA methylation, and histone modification, were strongly associated with tumor development and progression (46), meanwhile, epigenetic regulation of chromatin function controlled gene expression pattern (47). Notably, our finding was in consistent with previous studies (37,48) that the alteration frequency of FGFR3 was significantly higher in western UTUC patients, which is the main actionable gene in UC. Therefore, Erdafitinib and pemigatinib as effective FGFR inhibitors approved by the FDA-US (49) might be clinically applicable for less patients in China.…”

“…The molecular characterizations of P/LP germline variants provided the preliminary evidence for the subsequent researches of hereditary UC, and would be of guiding significance to helping establish prevention and surveillance strategies to suppress the incidence of UC. Furthermore, a total of 122 (49.00%) UC patients harbored alterations in the DDR related signaling pathway, similar to the finding of another Chinese UC cohort (37). Of note, RECQL4 alterations were significantly more prevalent in Chinese UTUC; whereas, ERCC2 and PMS1 alterations were common in UCB.…”

Genomic features of Chinese small cell lung cancer

“…The FFPE samples and peripheral blood mononuclear cells were collected using DNeasy Blood &Tissue Kit (Qiagen, Inc.) to isolate gDNA following the manufacturer’s instruction [ 14 ]. cfDNA was extracted from blood was using the QIAamp Circulating Nucleic Acid Kit (Qiagen, Inc.) according to the protocol of the manufacturer.…”

“…cfDNA was extracted from blood was using the QIAamp Circulating Nucleic Acid Kit (Qiagen, Inc.) according to the protocol of the manufacturer. The purified gDNA and cfDNA were quantified using the Qubit 3.0 Fluorometer (Life Technologies, Inc.) and StepOnePlus System (Life Technologies, Inc.) [ 14 ].…”

“…For the tumor and blood samples, 100 ng gDNA was sheared to target 200 bp fragment sizes with the Covaris E210 system (Covaris, Inc.). Next-generation sequencing of gDNA and cfDNA was performed, in which Accel-NGS 2S DNA Library Kit (Swift Biosciences, Inc.) was used for library preparation and xGen Lockdown Probes kit (IDT, Inc.) for target enrichment [ 14 ]. The custom xGen Lockdown probe was synthesized by IDT, Inc. for the exons and selected intronic regions of 618 genes (Additional file 1 : Table S1).…”