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Development of a custom next-generation sequencing panel for the determination of bladder cancer risk in a Tunisian cohort

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A Correction to this article was published on 02 January 2022

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Abstract

Backgound

Bladder cancer (BCa) is a heterogeneous disease caused by the interaction between environmental and genetic risk factors. The goal of this case–control study was to evaluate the implication of a selected SNP panel in the risk of BCa development in a Tunisian cohort. We were also interested in studying the interaction between this predictive panel and environmental risk factors.

Methods

The case/control cohort was composed with 249 BCa cases and 255 controls. The designed Bladder cancer hereditary panel (BCHP) was composed of 139 selected variants. These variants were genotyped by an amplification-based targeted Next-Generation Sequencing (NGS) on the Ion Torrent Proton sequencer (Life Technologies, Ion Torrent technology).

Results

We have found that rs162555, rs2228000, rs10936599, rs710521, rs3752645, rs804276, rs4639, rs4881400 and rs288980 were significantly associated with decreased risk of bladder cancer. However the homozygous genotypes for VPS37C (rs7104333, A/A), MPG (rs1013358, C/C) genes or the heterozygous genotype for ARNT gene (rs1889740, rs2228099, rs2256355, rs2864873), GSTA4 (rs17614751) and APOBR/IL27 (rs17855750) were significantly associated with increased risk of bladder cancer development compared to reference group (OR 2.53, 2.34, 1.99, 2.00, 2.00, 1.47, 1.96 and 2.27 respectively). We have also found that non–smokers patients harboring heterozygous genotypes for ARNT/rs2864873 (A > G), ARNT/ rs1889740 (C > T) or GSTA4/rs17614751 (G–A) were respectively at 2.775, 3.069 and 6.608-fold increased risk of Bca development compared to non-smokers controls with wild genotypes. Moreover the ARNT CT (rs1889740), ARNT CG (rs2228099), ARNT TC (rs2864873) and GSS GA genotypes were associated with an increased risk of BCa even in absence of professional risk factors. Finally the decision-tree analysis produced a three major BCa classes. These three classes were essentially characterized by an intensity of tobacco use more than 20 pack years (PY) and the CYP1A2 (rs762551) genotype.

Conclusions

The determined association between environmental factors, genetic variations and the risk of Bca development may provide additional information to urologists that may help them for clinical assessment and treatment decisions. Nevertheless, the underlying mechanisms through which these genes or SNPs affect the clinical behavior of BCas require further studies.

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Data availability

The dataset is available upon reasonable request to the corresponding author.

Change history

Abbreviations

ACTRT3:

Actin Related Protein T3; 3q26.2

APOBR:

Apolipoprotein B Receptor

ARNT:

Aryl hydrocarbon receptor nuclear translocator

BCa:

Bladder cancer

BER:

Base excision repair

BLNK:

B cell linker

COMT:

Catechol-O-methyltransferase

CYP1B1:

Cytochrome P450 family 1 subfamily B member 1

CYP3A4:

Cytochrome P450 3A4

dbSNP:

Database of single nucleotide polymorphisms

DNA:

Deoxyribonucleic acid

DRC:

DNA Repair Capacity

DSBR:

Double-strand break repair

EDTA:

Ethylene diamine tetra-acetic acid

ERCC4:

Excision Repair Cross-Complementation group 4

GSTM1:

Glutathione-s-transferase M1

GWAS:

Genome-Wide Association Study

GSS:

Glutathione Synthase

GSTA4:

Glutathione S-transferase Alpha 4

HG:

High-Grade

IARC:

International Agency for Research on Cancer

IL27:

Interleukin 27

KEGG:

Kyoto Encyclopedia of Genes and Genomes

LG:

Low-Grade

MIBC:

Muscle-invasive BCa

MMR:

Mismatch repair

MPG:

N-methylpurine DNA glycosylase

NEIL2:

Nei-like DNA glycosylase 2

NAT2:

N-acetyltransferase 2

NER:

Nucleotide excision repair

NGS:

Next-Generation Sequencing

NMIBC:

Non-muscle-invasive BCa

PRKAR2B:

Protein Kinase cAMP-dependent type II regulatory subunit beta

ROCK1:

Rho associated coiled-coil containing protein kinase 1

SNP:

Nucleotide polymorphisms

TCR:

Transcription-coupled repair

TP63:

Tumor Protein p63

VPS37C:

Vacuolar protein sorting-associated protein 37C

WHO:

World Health Organization

XPC:

Xeroderma Pigmentosum, Complementation group C

XPF:

Excision repair cross-complementing rodent repair deficiency, complementation group 4

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Acknowledgements

The authors thank all patients for participating in this study. We greatly thank also the Urology department, Charles Nicolle hospital, Tunis, Tunisia, Biochemistry Department, Charles Nicolle Hospital, Tunis and the International Agency for Research on Cancer IARC; Lyon, France.

Funding

No funding was obtained for this study.

Author information

Authors and Affiliations

  1. Laboratory of Proteins Engineering and Bioactive Molecules (LIP-MB), INSAT, National Institute of Applied Sciences and Technology of Tunis, University of Carthage, Tunis, Tunisia

    Imen Hemissi & Slah Ouerhani

  2. Laboratory of Genetics, Immunology and Human Pathology, Faculty of Sciences of Tunis, Tunis, Tunisia

    Sami Boussetta

  3. Pasteur Institute of Tunis, Tunis, Tunisia

    Hamza Dallali

  4. National Institute of Applied Sciences and Technology of Tunis, University of Carthage, Tunis, Tunisia

    Faycel Hellal

  5. Centre International de Recherche sur le Cancer CIRC/International Agency for Research on Cancer IARC, Lyon, France

    Geoffroy Durand, Catherine Voegele, James Mckay & Florence Le Calvez-Kelm

  6. Urology Department, Charles Nicolle Hospital, Tunis, Tunisia

    Haroun Ayed, Selim Zaghbib & Mohamed Chebil

  7. Medical Oncology Department, Saleh Azaiez Institute, Tunis, Tunisia

    Zeineb Naimi & Mouna Ayadi

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  1. Imen Hemissi
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Contributions

IH: Collecting clinical samples and data, designed the panel, molecular analysis, drafted the manuscript and bioinformatics analyzes. SB, HD and FH: Help in Bioinformatics and statistical analyzes. GD and CV: Technical assistance for NGS analyzes. HA: Clinical characterization of the studied population. ZN and MA: Help in collecting samples. MC and JM: Designed the study and revised the manuscript. FL: Drafted and revised the manuscript. SO: Designed the study, performed the statistical analysis and drafted and revised the manuscript. All authors read and approved the final version of the manuscript.

Corresponding author

Correspondence to Slah Ouerhani.

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Conflict of interest

The authors declare that they have no competing interests.

Ethical approval

This trial protocol and recruitment were approved and carried out after the agreement of the ethics committee of the Charles Nicolle Hospital and approved by an Ethics Committee (IEC Project No. 17-35) and an MTA [MATERIAL TRANSFER AGREEMENT MTA/2017/IMP/GCS)/0356] from IARC.

Consent to participate

Informed consent was obtained from all participants (in both languages: Arabic/French) prior to enrollment and participation in this study. All samples are coded and no patient names appear in the study. All data whether clinical or personal remains anonymous and secret.

Consent for publication

Not applicable. This study did not use identifying images and any clinical and personal details despite written informed consent for publication of their clinical details and/or clinical.

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The original online version of this article was revised due to one of the co-authors′ last names, Florence Le CalvezKelm, was misspelled.

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Hemissi, I., Boussetta, S., Dallali, H. et al. Development of a custom next-generation sequencing panel for the determination of bladder cancer risk in a Tunisian cohort. Mol Biol Rep 49, 1233–1258 (2022). https://doi.org/10.1007/s11033-021-06951-4

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