Seminars article
Mutational landscape of non-muscle-invasive bladder cancer

https://doi.org/10.1016/j.urolonc.2018.10.015Get rights and content

Abstract

Non-muscle-invasive bladder cancer (NMIBC) includes stage Ta and stage T1 tumors and carcinoma in situ (CIS). Grading of Ta tumors subdivides these lesions into papillary urothelial neoplasms of low malignant potential and low- and high-grade noninvasive papillary urothelial carcinoma. CIS is by definition high-grade and the majority of stage T1 tumors are of high-grade. This pathologic heterogeneity is associated with divergent clinical outcome, with significantly worse prognosis for patients with T1 tumors or CIS. A wealth of molecular information has accumulated on NMIBC including mutational data that ranges from the whole chromosome level to next generation sequence data at nucleotide level. This has not only identified key genes that are mutated in NMIBC, but also provides insight into the processes that shape their mutational landscape. Although molecular analyses cannot yet provide definitive personal prognostic information, many differences between these entities promise improved disease management in the future. Most information is available for Ta and T1 samples and this is the focus of this review.

Section snippets

Gross chromosomal alterations

Since chromosomal banding techniques were developed, it has been clear that non-muscle-invasive bladder cancers (NMIBC) often have near-diploid karyotypes in contrast to the high level of aneuploidy found in muscle-invasive bladder cancers (MIBC) [1]. Comparative genomic hybridization (CGH) and/or loss of heterozygosity (LOH) analyses later confirmed these early findings. Major differences between Ta and T1 tumors were revealed [2], with loss of 9q and Y identified as common events in Ta

Candidates in regions of copy number alteration

The implication of copy number alterations is that tumor suppressor genes reside in regions of loss and oncogenes in regions of gain. Identification of the genes targeted by these alterations led to many studies during the 1980s and 1990s aimed at refining the candidate chromosomal regions and assessing candidate genes as valid contributors to bladder cancer development. Several key genes implicated in NMIBC were identified by candidate gene analysis during this period.

Chromosome 9 deletions

Mutations identified by whole exome sequence analysis

Several recent exome sequencing and/or targeted resequencing studies include or have focused entirely on NMIBC [7], [23], [37], [39], [40], [41]. Findings reveal significant differences from MIBC and provide a comprehensive view of the mutation spectrum of NMIBC at nucleotide level.

Tumor evolution and intratumor heterogeneity

Sequencing of synchronous multifocal NMIBC, metachronous tumors from the same patient, and samples before and following disease progression has been reported [40], [41], [43], [52]. Initial tumors that later progressed, have been reported to show higher levels of intratumor heterogeneity in mutational profile and more APOBEC-related mutations than those that did not progress, implying that APOBEC mutagenesis contributed later in tumor progression. Phylogenetic analysis showed that these tumors

Future outlook

Treatment options for NMIBC are currently limited to transurethral resection and localized intravesical chemotherapy or BCG, and are guided primarily by the tumor stage and histopathology. The efficacy of these treatments is relatively poor and until recently little progress has been made in identifying new therapeutic approaches. Knowledge of the molecular landscape of bladder cancer has been greatly enhanced by the use of whole-genome technologies. These studies are revealing clinically

Conflict of Interest

The authors have no conflicts of interest to disclose.

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