Next Article in Journal
Novel Treatment Strategies for Glioblastoma
Next Article in Special Issue
Screening for Early Gastric Cancer Using a Noninvasive Urine Metabolomics Approach
Previous Article in Journal
Radiomics of Liver Metastases: A Systematic Review
Previous Article in Special Issue
Nanoparticles in 472 Human Cerebrospinal Fluid: Changes in Extracellular Vesicle Concentration and miR-21 Expression as a Biomarker for Leptomeningeal Metastasis
Article

Genomic Instability Signature of Palindromic Non-Coding Somatic Mutations in Bladder Cancer

1
Unité de Pharmacogénomique, Service de Génétique, Institut Curie, F-75005 Paris, France
2
Plateforme de Bioinformatique, Centre de Recherche de l’Institut Curie, F-75005 Paris, France
3
INSERM U900 (Institut National de la Santé et de la Recherche Médicale), F-75005 Paris, France
4
Unité de Génétique Somatique, Service de Génétique, Institut Curie, F-75005 Paris, France
5
TRePCa, Université Paris Est Créteil, F-94010 Créteil, France
6
Plateforme de ressources biologiques, AP-HP, Hôpital Henri Mondor, F-94010 Créteil, France
7
Service d’Anatomopathologie, Hôpital Cochin, F-75014 Paris, France
8
INSERM U1138, Team Cancer, Immune Control, and Escape, Centre de Recherche des Cordeliers, F-75005 Paris, France
9
Département de Pathologie, Institut Curie, F-92210 Saint-Cloud, France
10
Institut Curie, Department of Drug Development and Innovation (D3i), Institut Curie Paris & Saint Cloud, F-75005 Paris, France
11
Département d’Urologie, Unité de Chirurgie Oncologique, Institut Paoli-Calmettes, F-13009 Marseille, France
12
INSERM U1016, Université Paris Descartes, F-75005 Paris, France
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2020, 12(10), 2882; https://doi.org/10.3390/cancers12102882
Received: 24 September 2020 / Revised: 1 October 2020 / Accepted: 3 October 2020 / Published: 8 October 2020
(This article belongs to the Collection Cancer Biomarkers)
Bladder cancer is the tenth most common cancer worldwide, and its incidence has increased markedly in recent decades. However, current prognostic factors are insufficient to predict outcome at the individual level whereas non-coding somatic alterations remain weakly explored. The goal of this study was to identify clinical biomarkers in non-coding regions for bladder cancer patients. We identified a new type of frequent non-coding somatic genomic instability, specific to bladder tumors. This mutational signature is a promising candidate clinical biomarker for the early detection of relapse and a major low-cost alternative to the TMB to monitor the response to immunotherapy for bladder cancer patients.
Numerous pan-genomic studies identified alterations in protein-coding genes and signaling pathways involved in bladder carcinogenesis, while non-coding somatic alterations remain weakly explored. The goal of this study was to identify clinical biomarkers in non-coding regions for bladder cancer patients. We have previously identified in bladder tumors two non-coding mutational hotspots occurring at high frequencies (≥30%). These mutations are located close to the GPR126 and PLEKHS1 genes, at the guanine or the cytosine of a TGAACA core motif flanked, on both sides, by a stretch of palindromic sequences. Here, we hypothesize that such a pattern of recurrent non-coding mutations could be a signature of somatic genomic instability specifically involved in bladder cancer. We analyzed 26 additional mutable non-coding sites with the same core motif in a cohort of 103 bladder cancers composed of 44 NMIBC cases and 59 MIBC cases using high-resolution melting (HRM) and Sanger sequencing. Five bladder cancers were additionally analyzed for protein-coding gene mutations using a targeted NGS panel composed of 571 genes. Expression levels of three members of the APOBEC3 family genes were assessed using real-time quantitative RT-PCR. Non-coding somatic mutations were observed for at least one TGAACA core motif locus in 62.1% (64/103) of bladder tumor samples. These non-coding mutations co-occurred in the bladder tumors but were absent in prostate tumor, HPV-positive Head and Neck Squamous Cell Carcinoma, and high microsatellite instability (MSI-H) colorectal tumor series. This signature of palindromic non-coding somatic mutations, specific to bladder tumors, was not associated with patients’ outcome and was more frequent in females. Interestingly, this signature was associated with high tumor mutational burden (TMB) and high expression levels of APOBEC3B and interferon inducible genes. We identified a new type of somatic genomic instability targeting the TGAACA core motif loci flanked by palindromic sequences in bladder cancer. This mutational signature is a promising candidate clinical biomarker for the early detection of relapse and a major low-cost alternative to the TMB to monitor the response to immunotherapy for bladder cancer patients. View Full-Text
Keywords: bladder cancer; genomic instability signature; non-coding mutation; clinical biomarkers bladder cancer; genomic instability signature; non-coding mutation; clinical biomarkers
Show Figures

Figure 1

MDPI and ACS Style

Vacher, S.; Suybeng, V.; Girard, E.; Masliah Planchon, J.; Thomson, G.; Le Goux, C.; Garinet, S.; Schnitzler, A.; Chemlali, W.; Firlej, V.; Damotte, D.; Allory, Y.; Kamal, M.; Pignot, G.; Bieche, I. Genomic Instability Signature of Palindromic Non-Coding Somatic Mutations in Bladder Cancer. Cancers 2020, 12, 2882. https://doi.org/10.3390/cancers12102882

AMA Style

Vacher S, Suybeng V, Girard E, Masliah Planchon J, Thomson G, Le Goux C, Garinet S, Schnitzler A, Chemlali W, Firlej V, Damotte D, Allory Y, Kamal M, Pignot G, Bieche I. Genomic Instability Signature of Palindromic Non-Coding Somatic Mutations in Bladder Cancer. Cancers. 2020; 12(10):2882. https://doi.org/10.3390/cancers12102882

Chicago/Turabian Style

Vacher, Sophie, Voreak Suybeng, Elodie Girard, Julien Masliah Planchon, Grégory Thomson, Constance Le Goux, Simon Garinet, Anne Schnitzler, Walid Chemlali, Virginie Firlej, Diane Damotte, Yves Allory, Maud Kamal, Géraldine Pignot, and Ivan Bieche. 2020. "Genomic Instability Signature of Palindromic Non-Coding Somatic Mutations in Bladder Cancer" Cancers 12, no. 10: 2882. https://doi.org/10.3390/cancers12102882

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop