Clonal evolution of chemotherapy-resistant urothelial carcinoma

Abstract

Chemotherapy-resistant urothelial carcinoma (UC) has no uniformly curative therapy. Understanding how selective pressure from chemotherapy directs UC’s evolution and shapes its clonal architecture is a central biological question with clinical implications. To address this question, we performed whole-exome sequencing and clonality analysis of 72 UCs including 16 matched sets of primary and advanced tumors prospectively collected before and after chemotherapy. Our analysis provided several insights: (i) chemotherapy-treated UC is characterized by intra-patient mutational heterogeneity and the majority of mutations are not shared, (ii) both branching evolution and metastatic spread are very early events in the natural history of UC; (iii) chemotherapy-treated UC is enriched with clonal mutations involving L1-cell adhesion molecule (L1CAM) and integrin signaling pathways; (iv) APOBEC induced-mutagenesis is clonally-enriched in chemotherapy-treated UC and continues to shape UC’s evolution throughout its lifetime.

Circulating Tumor DNA Reveals Clinically Actionable Somatic Genome of Metastatic Bladder Cancer

“…An added advantage of ctDNA profiling is the theoretical potential to survey intrapatient tumor heterogeneity, and the effect of the therapy on clonal dynamics. Advanced bladder cancer was recently shown to be characterized by high levels of intrapatient heterogeneity (51), but the comprehensive dissection of longitudinal heterogeneity in ctDNA samples will likely require broader genome-wide approaches and more matched metastatic tissue, than used in the current study.…”

Immune Checkpoint Human Endogenous Retrovirus-H Long Terminal Repeat-Associating Protein 2 is Upregulated and Independently Predicts Unfavorable Prognosis in Bladder Urothelial Carcinoma

“…Cystoscopy is a highly specific invasive procedure [10]. Although urine cytology is noninvasive and highly specific for detecting cancer cells, it lacks sensitivity, especially for low-grade malignancy [8]. Therefore, it is necessary to explore a noninvasive method with high specificity and sensitivity to improve the diagnosis and monitoring of BUC [11].…”

“…Nevertheless, 50-70% of patients with non-muscle invasive BUC recur after the transurethral resection of the bladder tumor, and 15-25% of the recurrent patients progress into a higher cancer grade and stage [7]. Early diagnosis and monitoring of the disease are important for obtaining better clinical outcomes for BUC patients [8]. Current standard methods for detecting BCa are cystoscopy and urine cytology [9].…”

Cancer evolution and heterogeneity

“…Treatment of cancer might be one of the selective pressures on clones, and recurrence might be derived from surviving clones 7, 33. As depicted in Figure 2, we implemented the simulation study to prove the presence of ITH with selective mutations in driver genes by exposing four environmental pressures, such as chemotherapy and other treatment modalities.…”

“…1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 This multiregional analysis (MRA) sequencing approach enabled us not only to observe spatial heterogeneity, but also to calculate temporal alterations and eventually disclose the evolution of tumors. There are two types of somatic aberration in a tumor: ubiquitous aberrations (founder mutations, trunk mutations, or clonal mutations) and scattered aberrations (progressor mutations, branch/leaf mutations, or subclonal mutations).…”