AGORA, a data‐ and biobank for birth defects and childhood cancer

Rooij, Iris A. L. M. van; Zanden, Loes F M van der; Bongers, Ernie M.H.F.; Renkema, Kirsten Y.; Wijers, Charlotte H. W.; Thonissen, Michelle; Dokter, E.M.J.; Marcelis, Carlo; Blaauw, Ivo de; Wijnen, Marc H. W. A.; Hoogerbrugge, Peter M.; Bökkerink, J.P.M.; Schreuder, Michiel F.; Koster-Kamphuis, Linda; Cornelissen, Elisabeth A.M.; Kapusta, Livia; Heijst, Arno van; Liem, Kian D.; Gier, R.P.E. de; Kuijpers-Jagtman, Anne Marie; Admiraal, R.J.C.; Bergé, Stefaan; Biezen, Jan Jaap van der; Verdonck, Anna; Poorten, Vincent Vander; Hens, Greet; Roosenboom, Jasmien; Lilien, Marc R.; Jong, Tom P.V.M. de; Broens, Paul M. A.; Wijnen, René; Brooks, Alice S.; Franke, Barbara; Brunner, Han G.; Carels, Carine; Knoers, Nine V A M; Feitz, W.F.J.; Roeleveld, Nel

doi:10.1002/bdra.23512

Cited by 39 publications

(24 citation statements)

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“…The first cohort consisted of 84 unrelated patients affected by Wilms tumors. Lymphocyte‐derived germline DNA was obtained from AGORA (Aetiologic research into Genetic and Occupational/environmental Risk factors for Anomalies in children), a large ongoing data‐ and biobank coordinated by the Radboud university medical center including children with childhood cancer or congenital malformations . The data collection protocol and this study were approved by the Regional Committee on Research involving Human Subjects Arnhem‐Nijmegen (No.…”

Section: Methodsmentioning

confidence: 99%

TRIM28 haploinsufficiency predisposes to Wilms tumor

Diets

Hoyer

Ekici

et al. 2019

Intl Journal of Cancer

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Two percent of patients with Wilms tumors have a positive family history. In many of these cases the genetic cause remains unresolved. By applying germline exome sequencing in two families with two affected individuals with Wilms tumors, we identified truncating mutations in TRIM28. Subsequent mutational screening of germline and tumor DNA of 269 children affected by Wilms tumor was performed, and revealed seven additional individuals with germline truncating mutations, and one individual with a somatic truncating mutation in TRIM28. TRIM28 encodes a complex scaffold protein involved in many different processes, including gene silencing, DNA repair and maintenance of genomic integrity. Expression studies on mRNA and protein level showed reduction of TRIM28, confirming a loss‐of‐function effect of the mutations identified. The tumors showed an epithelial‐type histology that stained negative for TRIM28 by immunohistochemistry. The tumors were bilateral in six patients, and 10/11 tumors are accompanied by perilobar nephrogenic rests. Exome sequencing on eight tumor DNA samples from six individuals showed loss‐of‐heterozygosity (LOH) of the TRIM28‐locus by mitotic recombination in seven tumors, suggesting that TRIM28 functions as a tumor suppressor gene in Wilms tumor development. Additionally, the tumors showed very few mutations in known Wilms tumor driver genes, suggesting that loss of TRIM28 is the main driver of tumorigenesis. In conclusion, we identified heterozygous germline truncating mutations in TRIM28 in 11 children with mainly epithelial‐type Wilms tumors, which become homozygous in tumor tissue. These data establish TRIM28 as a novel Wilms tumor predisposition gene, acting as a tumor suppressor gene by LOH.

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Section: Methodsmentioning

confidence: 99%

TRIM28 haploinsufficiency predisposes to Wilms tumor

Diets

Hoyer

Ekici

et al. 2019

Intl Journal of Cancer

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“…The success of research consortia relies heavily on patient numbers, diagnostic accuracy, and deep-phenotyping of patients. In KOUNCIL, we used the AGORA data- and biobank protocols to systematically recruit and include patients ( http://www.agoraproject.nl ) ( 7 ). Furthermore, we involved the professional Society for Dutch Pediatric Nephrologists and requested participation of pediatric nephrologists in recruiting patients for the renal ciliopathy database.…”

Section: Results Of Kouncilmentioning

confidence: 99%

The KOUNCIL Consortium: From Genetic Defects to Therapeutic Development for Nephronophthisis

Renkema¹,

Giles²,

Lilien³

et al. 2018

Front. Pediatr.

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Nephronophthisis (NPH) is the most common monogenic cause of renal failure in children. Treatment options are limited to dialysis and transplantation. Therapeutics to significantly delay or prevent end-stage renal disease (ESRD) in children are currently not available. In the Dutch-Anglo KOUNCIL (Kidney-Oriented UNderstanding of correcting CILiopathies) consortium, several groups and specialties united to perform scientific groundwork with the aim to develop genetic and therapeutic personalized care for NPH patients. At the start of this consortium, a genetic diagnosis for NPH was available for only 30–40% of patients, which improved to 50–60% during the course of the 4-year KOUNCIL project. Other major accomplishments of the consortium were (1) the establishment of a Dutch renal ciliopathy patient database with genotype and phenotype data; (2) composition of a proteomics-based integrated network of protein modules disrupted in NPH; (3) the development of non-invasive, urine-based assays that allow functional assessment of genomic variants in NPH and of therapeutic efficiency of drugs; and (4) chemical screening toward the identification of compounds that delay or prevent disease progression in NPH, which resulted in four potential medical interventions for NPH. In conclusion, the KOUNCIL consortium effectively channeled complementary approaches to broaden our understanding of NPH pathogenesis, resulted in 54 publications, improvement of genome diagnostics for NPH patients, awareness in the nephrology and clinical genetics communities for NPH, and new avenues for patient management.

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“…The data collection methods for AGORA were described in detail elsewhere. 27 For this study, we included all cases with any type of hypospadias with or without other congenital malformations and controls registered in the AGORA data-and biobank in the period 2004-2018. Cases were born in the period 1975-2016 and controls in 1990-2011.…”

Section: What This Study Addsmentioning

confidence: 99%