Mutations in the Transcriptional Repressor REST Predispose to Wilms Tumor

Overview

Journal Nat Genet

Specialty Genetics

Date 2015 Nov 10

PMID 26551668

Citations 35

Authors

Shazia S Mahamdallie

Sandra Hanks

Kristen L Karlin

Anna Zachariou

Elizabeth R Perdeaux

Elise Ruark

Chad A Shaw

Alexander Renwick

Emma Ramsay

Shawn Yost

Anna Elliott

Jillian Birch

Michael Capra

Juliet Gray

Juliet Hale

Judith Kingston

Gill Levitt

Thomas McLean

Eamonn Sheridan

Anthony Renwick

Sheila Seal

Charles Stiller

Neil Sebire

Thomas F Westbrook

Nazneen Rahman

Affiliations

Soon will be listed here.

Abstract

Wilms tumor is the most common childhood renal cancer. To identify mutations that predispose to Wilms tumor, we are conducting exome sequencing studies. Here we describe 11 different inactivating mutations in the REST gene (encoding RE1-silencing transcription factor) in four familial Wilms tumor pedigrees and nine non-familial cases. Notably, no similar mutations were identified in the ICR1000 control series (13/558 versus 0/993; P < 0.0001) or in the ExAC series (13/558 versus 0/61,312; P < 0.0001). We identified a second mutational event in two tumors, suggesting that REST may act as a tumor-suppressor gene in Wilms tumor pathogenesis. REST is a zinc-finger transcription factor that functions in cellular differentiation and embryonic development. Notably, ten of 11 mutations clustered within the portion of REST encoding the DNA-binding domain, and functional analyses showed that these mutations compromise REST transcriptional repression. These data establish REST as a Wilms tumor predisposition gene accounting for ∼2% of Wilms tumor.

Citing Articles

Long-term kidney outcomes in survivors of Wilms tumor: a single-center retrospective cohort study.

Reinert S, Benoit S, Nagarajan R Pediatr Nephrol. 2025; .

PMID: 39779510 DOI: 10.1007/s00467-024-06624-x.

Predisposition Footprints in the Somatic Genome of Wilms Tumors.

Treger T, Wegert J, Wenger A, Coorens T, Al-Saadi R, Kemps P Cancer Discov. 2024; 15(2):286-298.

PMID: 39665570 PMC: 7617291. DOI: 10.1158/2159-8290.CD-24-0878.

Re-envisioning genetic predisposition to childhood and adolescent cancers.

Kratz C Nat Rev Cancer. 2024; 25(2):109-128.

PMID: 39627375 DOI: 10.1038/s41568-024-00775-7.

Curating genomic disease-gene relationships with Gene2Phenotype (G2P).

Yates T, Ansari M, Thompson L, Hunt S, Uhalte E, Hobson R Genome Med. 2024; 16(1):127.

PMID: 39506859 PMC: 11539801. DOI: 10.1186/s13073-024-01398-1.

Nephroblastoma in Older Adult: Case Report and Review of Literature.

Fernandez-Ferreira R, Torres-Zazueta J, Martinez-Medrano C, Melendez-Mendoza A, Tavares-Garcia S, Munoz Rubiano M Case Rep Oncol. 2024; 17(1):818-830.

PMID: 39144242 PMC: 11324259. DOI: 10.1159/000540279.

References

Scott R, Walker L, Olsen O, Levitt G, Kenney I, Maher E . Surveillance for Wilms tumour in at-risk children: pragmatic recommendations for best practice. Arch Dis Child. 2006; 91(12):995-9. PMC: 2083016. DOI: 10.1136/adc.2006.101295. View

Kreisler A, Strissel P, Strick R, Neumann S, Schumacher U, Becker C . Regulation of the NRSF/REST gene by methylation and CREB affects the cellular phenotype of small-cell lung cancer. Oncogene. 2010; 29(43):5828-38. DOI: 10.1038/onc.2010.321. View

Ruark E, Munz M, Renwick A, Clarke M, Ramsay E, Hanks S . The ICR1000 UK exome series: a resource of gene variation in an outbred population. F1000Res. 2016; 4:883. PMC: 4706061. DOI: 10.12688/f1000research.7049.1. View

Hohenstein P, Pritchard-Jones K, Charlton J . The yin and yang of kidney development and Wilms' tumors. Genes Dev. 2015; 29(5):467-82. PMC: 4358399. DOI: 10.1101/gad.256396.114. View

Ooi L, Wood I . Chromatin crosstalk in development and disease: lessons from REST. Nat Rev Genet. 2007; 8(7):544-54. DOI: 10.1038/nrg2100. View

Rapley E, Barfoot R, Bonaiti-Pellie C, Chompret A, Foulkes W, Perusinghe N . Evidence for susceptibility genes to familial Wilms tumour in addition to WT1, FWT1 and FWT2. Br J Cancer. 2000; 83(2):177-83. PMC: 2363495. DOI: 10.1054/bjoc.2000.1283. View

Rahman N, Arbour L, Tonin P, Renshaw J, Pelletier J, Baruchel S . Evidence for a familial Wilms' tumour gene (FWT1) on chromosome 17q12-q21. Nat Genet. 1996; 13(4):461-3. DOI: 10.1038/ng0896-461. View

Forbes S, Bindal N, Bamford S, Cole C, Kok C, Beare D . COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer. Nucleic Acids Res. 2010; 39(Database issue):D945-50. PMC: 3013785. DOI: 10.1093/nar/gkq929. View

Rimmer A, Phan H, Mathieson I, Iqbal Z, Twigg S, Wilkie A . Integrating mapping-, assembly- and haplotype-based approaches for calling variants in clinical sequencing applications. Nat Genet. 2014; 46(8):912-918. PMC: 4753679. DOI: 10.1038/ng.3036. View

10.

Scott R, Stiller C, Walker L, Rahman N . Syndromes and constitutional chromosomal abnormalities associated with Wilms tumour. J Med Genet. 2006; 43(9):705-15. PMC: 2564568. DOI: 10.1136/jmg.2006.041723. View

11.

McDonald J, Douglass E, Fisher R, GEISER C, KRILL C, Strong L . Linkage of familial Wilms' tumor predisposition to chromosome 19 and a two-locus model for the etiology of familial tumors. Cancer Res. 1998; 58(7):1387-90. View

12.

Lunter G, Goodson M . Stampy: a statistical algorithm for sensitive and fast mapping of Illumina sequence reads. Genome Res. 2010; 21(6):936-9. PMC: 3106326. DOI: 10.1101/gr.111120.110. View

13.

Gurrola-Diaz C, Lacroix J, Dihlmann S, Becker C, von Knebel Doeberitz M . Reduced expression of the neuron restrictive silencer factor permits transcription of glycine receptor alpha1 subunit in small-cell lung cancer cells. Oncogene. 2003; 22(36):5636-45. DOI: 10.1038/sj.onc.1206790. View

14.

Canzonetta C, Mulligan C, Deutsch S, Ruf S, ODoherty A, Lyle R . DYRK1A-dosage imbalance perturbs NRSF/REST levels, deregulating pluripotency and embryonic stem cell fate in Down syndrome. Am J Hum Genet. 2008; 83(3):388-400. PMC: 2556438. DOI: 10.1016/j.ajhg.2008.08.012. View

15.

Little S, Hanks S, King-Underwood L, Jones C, Rapley E, Rahman N . Frequency and heritability of WT1 mutations in nonsyndromic Wilms' tumor patients: a UK Children's Cancer Study Group Study. J Clin Oncol. 2004; 22(20):4140-6. DOI: 10.1200/JCO.2004.02.136. View

16.

Karlin K, Mondal G, Hartman J, Tyagi S, Kurley S, Bland C . The oncogenic STP axis promotes triple-negative breast cancer via degradation of the REST tumor suppressor. Cell Rep. 2014; 9(4):1318-32. PMC: 4427000. DOI: 10.1016/j.celrep.2014.10.011. View

17.

Ruark E, Snape K, Humburg P, Loveday C, Bajrami I, Brough R . Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancer. Nature. 2012; 493(7432):406-10. PMC: 3759028. DOI: 10.1038/nature11725. View

18.

Lu T, Aron L, Zullo J, Pan Y, Kim H, Chen Y . REST and stress resistance in ageing and Alzheimer's disease. Nature. 2014; 507(7493):448-54. PMC: 4110979. DOI: 10.1038/nature13163. View

19.

Tawadros T, Martin D, Abderrahmani A, Leisinger H, Waeber G, Haefliger J . IB1/JIP-1 controls JNK activation and increased during prostatic LNCaP cells neuroendocrine differentiation. Cell Signal. 2005; 17(8):929-39. DOI: 10.1016/j.cellsig.2004.11.013. View

20.

Bithell A . REST: transcriptional and epigenetic regulator. Epigenomics. 2011; 3(1):47-58. DOI: 10.2217/epi.10.76. View