Identification of Driver Mitochondrial Genome Mutations in Urothelial Carcinoma of Bladder
Abstract
Urothelial carcinoma of bladder (UCB) constitutes over 90% of bladder cancers. Non-muscle invasive UCB (NMIUCB) is the most common at presentation (around 70%-75%) and is treated by trans-urethral resection of bladder tumor (TURBT) with or without Bacille Calmette-Guerin (BCG). With this approach, 20% of patients will be cured, 70% will recur at least once every 5 years, and the remaining will progress to muscle-invasive disease, which carries a poor prognosis. Currently, it is unpredictable which tumor will progress and those that will not progress at the time of diagnosis. Moreover, conventional approaches (computed tomography [CT], urine cytology, histopathology, or tumor-node-metastasis classification) do not robustly predict risk of progression. Although previous studies underscore that accumulation of mtDNA alterations may be a critical factor in eliciting persistent mitochondrial defects and consequently contributing to tumor initiation and progression, the role of these mtDNA mutations in the progression of early lesions remain unknown. Therefore, dissecting the alterations in mtDNA that are causal to progression of NMIUCB to muscle invasive (MIUCB) will be critical for identifying molecular features related to aggressive tumor phenotypes. Very limited mitochondrial genome (MG) studies have been performed in UCB. In this proposal, the Fiscal Year 2020 Peer Reviewed Cancer Research Program Topic Areas of emphasis include understanding the clinical application (risk assessment of disease progression) of mitochondrial mutation that occur in bladder cancer and to functionally characterize certain mutational events that will help to develop a precision medicine approach in future. UCB is an environmental exposure-associated disease, and military personnel are more vulnerable to this kind of exposure due their deployment in different war situations. Population studies show that Veterans are smoking at higher rates as compared to non-Veterans, and smoking is associated with UCB. UCB is extremely heterogeneous, and understanding the MG alteration in NMIUCB and MIUCB will allow us to manage the Veteran patients who are usually exposed to numerous carcinogens in war situations and need life-long follow up for bladder cancer based on exposure history. Due to limited DNA repair mechanisms, mtDNA is susceptible to damage by environmental carcinogens (such as smoking and arsenic) as well as endogenous reactive oxygen species. As a result, the mutation rate in mtDNA is approximately 10 times higher than in nuclear genomic DNA. Mitochondrial dysfunction caused by mutations of the mtDNA has been implicated in a wide range of age-related pathologies, including cancers. Indeed, numerous somatic mutations in both the coding and control regions of mtDNA have been examined in a broad range of primary human cancers, albeit with small sample sizes and older technologies. Furthermore, the now-commonplace advanced nuclear sequencing studies (such as The Cancer Genome Atlas) usually ignore the MG. In particular to this proposal, while certain mtDNA mutations have been shown to be directly regulate (and not merely a consequence of) tumorigenesis in UCB, no study has yet been performed to delineate the role of MG alteration in the transition of NMIUCB to MIUCB. Novel mtDNA alterations detection strategies described in this proposal offer a new hope for improved risk assessment of NMIUCB and identify targets for further biological studies that may facilitate future therapeutic intervention. While advancements in next generation sequencing (NGS) techniques enable detection and analysis of mtDNA mutations as part of the whole-genome nuclear DNA sequencing, most current methods for mtDNA library preparation have limitations and are not focusing on mtDNA. Therefore, current approaches are not suitable for detection of all variants and heteroplasmy with high depth of coverage, especially in very small and highly degraded samples such as form
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110657
Entities
People
- Mohammad Hoque
Organizations
- Johns Hopkins University
- United States Army