Multiregion human bladder cancer sequencing reveals tumour evolution, bladder cancer phenotypes and implications for targeted therapy

Heide, Timon; Maurer, Angela; Eipel, Monika; Knoll, Katrin; Geelvink, Mirja; Veeck, Jürgen; Knuechel, Ruth; Essen, J. van; Stoehr, Robert; Hartmann, Arndt; Altmueller, Janine; Graham, Trevor A.; Gaisa, Nadine T.

doi:10.1002/path.5250

Cited by 33 publications

(27 citation statements)

References 45 publications

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“…To our knowledge, no previously published studies on BC have focused on mutations in normal appearing bladder tissue without being restricted to mutations observed in the tumor. Heide et al [36] performed multiregional WES on samples from whole cystectomies and detected mutations in normal samples as well and characterized early disease drivers. However, in this work no driver mutations specific for normal appearing urothelium were reported, though alterations related to mutational signatures S1 and S5 were identified in normal urothelium from one patient.…”

Section: Discussionmentioning

confidence: 99%

Mutational Analysis of Field Cancerization in Bladder Cancer

Strandgaard

Nordentoft

Lamy

et al. 2020

BLC

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BACKGROUND: Morphologically normal tissue, adjacent to tumors, contains multiple molecular changes, the so-called field cancerization. The multifocal and recurrent nature of bladder cancer has been hypothesized to originate from this. However, further studies are required to explore the mutational composition of normal tissue adjacent to tumors. OBJECTIVE: To analyze field cancerization in bladder cancer patients using a non-tumor guided approach. METHODS: We investigated the mutational landscape of normal appearing urothelium and paired bladder tumors from four patients by applying deep-targeted sequencing. RESULTS: Sequencing of 509 cancer driver genes revealed the presence of 2– 13 mutations exclusively localized in normal tissue (average target read depth 634×). Furthermore, 6– 13 mutations were shared between tumor and normal samples and 8– 75 mutations were exclusively detected in tumor samples. More mutations were observed in normal samples from patients with multifocal disease compared to patients with unifocal disease. Mutations in normal samples had lower variant allele fractions (VAF) compared to tumor mutations (p < 2.2*10–16). Furthermore, significant differences in the type of nucleotide changes between tumor, normal and shared mutations (p = 2.2*10–5) were observed, and mutations in APOBEC context were observed primarily among tumor mutations (p = 0.02). No differences in functional impact between normal, shared and tumor mutations were observed (p = 0.61). CONCLUSION: Overall, these findings support the presence of more than one field in the bladder, and document non-tumor specific driver mutations to be present in normal appearing bladder tissue.

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Section: Discussionmentioning

confidence: 99%

Mutational Analysis of Field Cancerization in Bladder Cancer

Strandgaard

Nordentoft

Lamy

et al. 2020

BLC

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“…Improved technology has allowed scientists and clinicians to characterize the heterogeneity of tumor at multiple levels. Moreover, multi-region sequencing was performed in many cancer types, including lung [36], breast [37], kidney [38][39][40], rectal [41], colorectal [42], prostate cancers [43], and BC [44], which provides the opportunity to expose the etiologies of treatment failure and drug resistance. At the molecular level, MIBC is a heterogeneous disease that is characterized by genomic instability and a high somatic mutation rate (median, 5.5 per megabase), similar to non-small cell lung cancer and melanoma [45].…”

Section: Heterogeneity In Bcmentioning

confidence: 99%

“…Current strategies for the treatment of MIBC or other cancers are typically relied on the biopsy of a single primary or metastatic site. In some multifocal cancers, such as breast [37], kidney [38], rectal [41], prostate cancers [43], and BC [44], the majority of point mutations detected in different fragments are frequently unique to a single fragment. These findings indicate that gene mutations found in single biopsies will not necessarily be representative of mutations presented in the entire tumor and ITH has substantial obstacle to appropriate selection of precision therapies.…”

Section: Genomic Heterogeneitymentioning

confidence: 99%

“…These findings indicate that gene mutations found in single biopsies will not necessarily be representative of mutations presented in the entire tumor and ITH has substantial obstacle to appropriate selection of precision therapies. For example, in a recent study, Heide et al [44] used multiregional whole-exome sequencing of 10 whole cystectomy specimens from BC to show an uneven distribution of key molecular alterations across distinct areas within a tumor. It intends to support an evolutionary model whereby synchronous development and parallel evolution of important alterations are followed in a dynamic rather than static way.…”

Section: Genomic Heterogeneitymentioning

confidence: 99%

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Tumor heterogeneity and the potential role of liquid biopsy in bladder cancer

Huang

2020

Cancer Communications

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Bladder cancer (BC) is a heterogeneous disease that characterized by genomic instability and a high mutation rate. Heterogeneity in tumor may partially explain the diversity of responses to targeted therapies and the various clinical outcomes. A combination of cytology and cystoscopy is the standard methodology for BC diagnosis, prognosis, and disease surveillance. However, genomics analyses of single tumor-biopsy specimens may underestimate the mutational burden of heterogeneous tumors. Liquid biopsy, as a promising technology, enables analysis of tumor components in the bodily fluids, such as blood and urine, at multiple time points and provides a minimally invasive approach that can track the evolutionary dynamics and monitor tumor heterogeneity. In this review, we describe the multiple faces of BC heterogeneity at the genomic and transcriptional levels and how they affect clinical care and outcomes. We also summarize the outcomes of liquid biopsy in BC, which plays a potential role in revealing tumor heterogeneity. Finally, we discuss the challenges that must be addressed before liquid biopsy can be widely used in clinical treatment.

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“…Heide and colleagues performed multiregional whole exome sequencing of ten RC samples [28]. The authors found APOBEC mutational signatures active in CIS; these appeared to be a source of mutations that persisted as the tumor evolved into invasive cancer.…”

Section: Molecular Biology Of Cismentioning

confidence: 99%

CIS of the Bladder: Significance and Implications for Therapy

Mirabal

Taylor

Lerner

2019

BLC

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Purpose of the review: To review the most recent literature with regards to the pathogenesis, diagnostics, clinical implications and treatment strategies for Carcinoma in Situ (CIS) of the Bladder. Recent findings: There have been advancements in understanding the genetic composition and biochemical behavior of CIS. Technological advancements including Photodynamic Diagnosis (PDD) with Hexaminolevulinate (HVA) better detect CIS compared to traditional white light (WL) cystoscopy. Recently published single and multi-center studies have enabled better understanding of the impact of CIS on clinical and cancer related outcomes, including disease recurrence and patient survival. Alternative intravesical chemotherapeutic and immunotherapies for CIS have been investigated, especially in the setting of Bacillus Calmette-Guerin (BCG) unresponsive disease. While these demonstrate a great deal of promise, they have not garnered much success. Summary: The genetics of CIS is linked to aggressive, and at times resistant disease, with increased cancer progression and associated clinically worse cancer specific outcomes. New technologies have enabled a more effective diagnosis of CIS. The development of a standardized definition for clinical trials and greater disease understanding will enable us to develop better treatment options.

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Multiregion human bladder cancer sequencing reveals tumour evolution, bladder cancer phenotypes and implications for targeted therapy

Cited by 33 publications

References 45 publications

Mutational Analysis of Field Cancerization in Bladder Cancer

Mutational Analysis of Field Cancerization in Bladder Cancer

Tumor heterogeneity and the potential role of liquid biopsy in bladder cancer

CIS of the Bladder: Significance and Implications for Therapy

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