Clinical and genetic characteristics of patients with nephroblastoma associated with REST gene mutation

Background. The introduction of molecular genetic studies has made it possible to more fully characterize the genetic events associated with an increased risk of developing nephroblastoma (NB). In recent years, new cancer predisposition genes have been identified, in particular, the REST gene, which acts as a tumor suppressor.

The purpose of the study – assessment of clinical and genetic characteristics of patients with NB associated with germinal mutations in the REST gene.

Materials and methods. The study included 3 patients with a histologically confirmed diagnosis of NB and with germinal pathogenic variants in the REST gene who received treatment or counseling at the N.N. Blokhin National Research Medical Center for Oncology from September 01, 2019 to June 01, 2024.

Results. The median age at the time of diagnosis of NB was 42.9 months, while the median age at the time of detection of the REST gene mutation was 85.5 months. All patients (n = 3) had phenotypic features and concomitant pathology. In the first case, facial dysmorphic disorder, autism spectrum disorders, as well as radiologically confirmed multiple metaphysical cortical defects of both tibia and right femur were observed. In the second case, gum hypertrophy and cerebral palsy were noted. The third patient was diagnosed with cryptorchidism with the concomitant obesity. In 2 patients, NB developed on the background of perilobar nephroblastomatosis, no correlation with the histological type of tumor was found. All patients are alive without signs of recurrence of the underlying disease, the median duration of follow-up was 2.4 years.

Conclusions. A mutation in the REST gene is a rare genetic event in the pathogenesis of NB. The analysis of the clinical and genetic characteristics of three patients with this mutation demonstrated a high variability of phenotypic manifestations, including facial dysmorphic disorder, neuropsychiatric disorders, skeletal abnormalities and malformations of the genitourinary system. It is noteworthy that in 2 out of 3 patients, the development of NB was noted against the background of perilobar nephroblastomatosis, which requires further study. Despite the heterogeneity of clinical manifestations, the presence of a mutation in the REST gene in patients with NB in this group is associated with a favorable prognosis, taking into account the duration of follow-up, which allows us to consider this genetic marker as a potential factor for a favorable prognosis. Given the rarity of this mutation, the presented observations make a significant contribution to understanding the clinical and genetic characteristics of this cohort of patients.

1. Balis F., Green D.M., Anderson C., Cook S., Dhillon J., Gow K., Hiniker S., Jasty-Rao R., Lin C., Lovvorn H., MacEwan I., Martinez-Agosto J., Mullen E., Murphy E.S., Ranalli M., Rhee D., Rokitka D., Tracy E.L., Vern-Gross T., Walsh M.F., Walz A., Wickiser J., Zapala M., Berardi R.A., Hughes M. Wilms Tumor (Nephroblastoma), Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2021;19(8):945–77. doi: 10.6004/jnccn.2021.0037. PMID: 34416707.

2. Steliarova-Foucher E., Colombet M., Ries L.A.G., Moreno F., Dolya A., Bray F., Hesseling P., Shin H.Y., Stiller C.A.; IICC-3 contributors. International incidence of childhood cancer, 2001–10: a population-based registry study. Lancet Oncol. 2017;18(6):719–31. doi: 10.1016/S1470-2045(17)30186-9. Epub 2017 Apr 11. Erratum in: Lancet Oncol. 2017;18(6):e301. PMID: 28410997; PMCID: PMC5461370.

3. Treger T.D., Chowdhury T., Pritchard-Jones K., Behjati S. The genetic changes of Wilms tumour. Nat Rev Nephrol. 2019;15(4):240–51. doi: 10.1038/s41581-019-0112-0. PMID: 30705419.

4. Turner J.T., Brzezinski J., Dome J.S. Wilms tumor predisposition. 2003 Dec 19 [Updated 2022 Mar 24]. In: Adam M.P., Bick S., Mirzaa G.M., Pagon R.A., Wallace S.E., Amemiya A. (eds.). GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2023.

5. Merks J.H., Caron H.N., Hennekam R.C. High incidence of malformation syndromes in a series of 1,073 children with cancer. Am J Med Genet A. 2005;134A(2):132–43. doi: 10.1002/ajmg.a.30603. PMID: 15712196.

6. Wegert J., Appenzeller S., Treger T.D., Streitenberger H., Ziegler B., Bausenwein S., Vokuhl C., Parks C., Jüttner E., Gramlich S., Ernestus K., Warman S.W., Fuchs J., Hubertus J., von Schweinitz D., Fröhlich B., Jorch N., Knöfl er R., Friedrich C., Corbacioglu S., Frühwald M.C., Pekrun A., Schneider D.T., Faber J., Stursberg J., Metzler M., Welter N., Pritchard-Jones K., Graf N., Furtwängler R., Behjati S., Gessler M. Distinct pathways for genetic and epigenetic predisposition in familial and bilateral Wilms tumor. Genome Med. 2025;17(1):49. doi: 10.1186/s13073-025-01482-0. PMID: 40340749; PMCID: PMC12060375.

7. Hol J.A., Kuiper R.P., van Dijk F., Waanders E., van Peer S.E., Koudijs M.J., Bladergroen R., van Reijmersdal S.V., Morgado L.M., Bliek J., Lombardi M.P., Hopman S., Drost J., de Krijger R.R., van den Heuvel-Eibrink M.M., Jongmans M.C.J. Prevalence of (Epi) genetic predisposing factors in a 5-year unselected national Wilms tumor cohort: a comprehensive clinical and genomic characterization. J Clin Oncol. 2022;40(17):1892–902. doi: 10.1200/JCO.21.02510. Epub 2022 Mar 1. PMID: 35230882; PMCID: PMC9177240.

8. Gessler M., Poustka A., Cavenee W., Neve R.L., Orkin S.H., Bruns G.A. Homozygous deletion in Wilms tumours of a zinc-finger gene identified by chromosome jumping. Nature. 1990;343(6260):774–8. doi: 10.1038/343774a0. PMID: 2154702.

9. Call K.M., Glaser T., Ito C.Y., Buckler A.J., Pelletier J., Haber D.A., Rose E.A., Kral A., Yeger H., Lewis W.H., et al. Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. Cell. 1990;60(3):509–20. doi: 10.1016/0092-8674(90)90601-a. PMID: 2154335.

10. Astuti D., Morris M.R., Cooper W.N., Staals R.H., Wake N.C., Fews G.A., Gill H., Gentle D., Shuib S., Ricketts C.J., Cole T., van Essen A.J., van Lingen R.A., Neri G., Opitz J.M., Rump P., Stolte-Dijkstra I., Müller F., Pruijn G.J., Latif F., Maher E.R. Germline mutations in DIS3L2 cause the Perlman syndrome of overgrowth and Wilms tumor susceptibility. Nat Genet. 2012;44(3):277–84. doi: 10.1038/ng.1071. PMID: 22306653.

11. Brioude F., Kalish J.M., Mussa A., Foster A.C., Bliek J., Ferrero G.B., Boonen S.E., Cole T., Baker R., Bertoletti M., Cocchi G., Coze C., De Pellegrin M., Hussain K., Ibrahim A., Kilby M.D., Krajewska-Walasek M., Kratz C.P., Ladusans E.J., Lapunzina P., Le Bouc Y., Maas S.M., Macdonald F., Õunap K., Peruzzi L., Rossignol S., Russo S., Shipster C., Skórka A., Tatton-Brown K., Tenorio J., Tortora C., Grønskov K., Netchine I., Hennekam R.C., Prawitt D., Tümer Z., Eggermann T., Mackay D.J.G., Riccio A., Maher E.R. Expert consensus document: clinical and molecular diagnosis, screening and management of Beckwith–Wiedemann syndrome: an international consensus statement. Nat Rev Endocrinol. 2018;14(4):229–49. doi: 10.1038/nrendo.2017.166. Epub 2018 Jan 29. PMID: 29377879; PMCID: PMC6022848.

12. Mahamdallie S., Yost S., Poyastro-Pearson E., Holt E., Zachariou A., Seal S., Elliott A., Clarke M., Warren-Perry M., Hanks S., Anderson J., Bomken S., Cole T., Farah R., Furtwaengler R., Glaser A., Grundy R., Hayden J., Lowis S., Millot F., Nicholson J., Ronghe M., Skeen J., Williams D., Yeomanson D., Ruark E., Rahman N. Identification of new Wilms tumour predisposition genes: an exome sequencing study. Lancet Child Adolesc Health. 2019;3(5):322–31. doi: 10.1016/S2352-4642(19)30018-5. Epub 2019 Mar 16. PMID: 30885698; PMCID: PMC6472290.

13. Mahamdallie S.S., Hanks S., Karlin K.L., Zachariou A., Perdeaux E.R., Ruark E., Shaw C.A., Renwick A., Ramsay E., Yost S., Elliott A., Birch J., Capra M., Gray J., Hale J., Kingston J., Levitt G., McLean T., Sheridan E., Renwick A., Seal S., Stiller C., Sebire N., Westbrook T.F., Rahman N. Mutations in the transcriptional repressor REST predispose to Wilms tumor. Nat Genet. 2015;47(12):1471–4. doi: 10.1038/ng.3440. Epub 2015 Nov 9. Erratum in: Nat Genet. 2016;48(4):473. PMID: 26551668.

14. Salomatina A.S., Yasko L.A., Kurnikova M.A., Mareeva Y.M., Abasov R.K., Gegeliya N.V., Mitrofanova A.M., Usman N.Y., Novichkova G.A., Druy A.E. Case report: two clinical cases of Wilms tumor comorbid to gingival fibromatosis in young children with constitutionally mutated REST. Front Oncol. 2023;13:1192489. doi: 10.3389/fonc.2023.1192489. PMID: 37427114; PMCID: PMC10326162.

15. Maciaszek J.L., Oak N., Nichols K.E. Recent advances in Wilms' tumor predisposition. Hum Mol Genet. 2020;29(R2):R138–49. doi: 10.1093/hmg/ddaa091. PMID: 32412586.