Identifying new Wilms' tumour predisposition genes

Wilms' tumour, the most common renal tumour in children, is associated with specific genetic predisposition syndromes in 10–15% of cases.1Dome JS Huff V Wilms tumor predisposition.in: Adam MP Ardinger HH Pagon RA GeneReviews. University of Washington, Seattle2016Google Scholar In the early 1980s, microdeletions of 11p13 were linked to the WAGR syndrome, characterised by early-onset Wilms' tumour in the context of aniridia and developmental delays. By 1991, the WT1 gene at this locus had been identified and single-nucleotide variants in the gene were found to also predispose to Wilms' tumour, genitourinary malformations, and renal dysfunction. An estimated 2–4% of children with Wilms' tumour have a constitutional WT1 alteration.2Diller L Ghahremani M Morgan J et al.Constitutional WT1 mutations in Wilms' tumor patients.J Clin Oncol. 1998; 16: 3634-3640Crossref PubMed Scopus (49) Google Scholar, 3Little SE Hanks SP King-Underwood L et al.Frequency and heritability of WT1 mutations in nonsyndromic Wilms' tumor patients: a UK Children's Cancer Study Group study.J Clin Oncol. 2004; 22: 4140-4146Crossref PubMed Scopus (74) Google Scholar In 1968, a second Wilms' tumour predisposition syndrome—Beckwith-Wiedemann syndrome—was described and then linked to chromosome 11p15 in 1989. The complex genetic and epigenetic features that cause this syndrome were elaborated over many years. At least 4% of Wilms' tumour cases occur in children with Beckwith-Wiedemann syndrome.4Scott RH Douglas J Baskcomb L et al.Constitutional 11p15 abnormalities, including heritable imprinting center mutations, cause nonsyndromic Wilms tumor.Nat Genet. 2008; 40: 1329-1334Crossref PubMed Scopus (117) Google Scholar Although most paediatricians are aware of the risk of Wilms' tumour associated with WT1-related disorders and Beckwith-Wiedemann syndrome, many other constitutional genomic changes can predispose to the tumour in rare cases. The disorders caused by these constitutional changes include Li-Fraumeni syndrome (TP53), Fanconi anaemia (BRCA2), CLOVES syndrome (PIK3CA), and Perlman syndrome (DIS3L2). In total, children with these syndromes probably account for 1% or less of Wilms' tumour cases, although the prevalence has not been formally studied. However, pathogenic variants at these loci do not explain several families with multiple members affected by Wilms' tumour. Next-generation sequencing studies detected several new predisposition genes, including CTR9 and REST, in familial cases,5Hanks S Perdeaux ER Seal S et al.Germline mutations in the PAF1 complex gene CTR9 predispose to Wilms tumour.Nat Commun. 2014; 5: 4398Crossref PubMed Scopus (59) Google Scholar, 6Mahamdallie SS Hanks S Karlin KL et al.Mutations in the transcriptional repressor REST predispose to Wilms tumor.Nat Genet. 2015; 47: 1471-1474Crossref PubMed Scopus (44) Google Scholar but most of these cases remain unexplained, suggesting predisposition variants at other genomic loci. Furthermore, the more frequent genomic alterations had already been described, making rarer genomic findings increasingly difficult to discover. In The Lancet Child & Adolescent Health, Shazia Mahamdallie and colleagues7Mahamdallie S Yost S Poyastro-Pearson E et al.Identification of new Wilms tumour predisposition genes: an exome sequencing study.Lancet Child Adolesc Health. 2019; (published online March 15.)http://dx.doi.org/10.1016/S2352-4642(19)30018-5Summary Full Text Full Text PDF PubMed Scopus (49) Google Scholar reported the largest series to date of constitutional tissue from 890 patients with Wilms' tumour (91 whom are from 49 families), in which the investigators comprehensively analysed whole-exome sequencing data from this cohort to uncover five new genes that are likely to predispose to Wilms' tumour: TRIM28, FBXW7, NYNRIN, KDM3B, and CDC73. These results stem from the remarkable effort of the UK Wilms' Tumour Study to collect samples from children with renal tumours and their family members over several decades. A striking finding of this study is that, although pathogenic variants in TRIM28, FBXW7, and NYNRIN were described first in families, all of them can also be found as de novo events in children with sporadic tumours—mirroring the pattern seen with alterations in the REST gene previously described by this group.6Mahamdallie SS Hanks S Karlin KL et al.Mutations in the transcriptional repressor REST predispose to Wilms tumor.Nat Genet. 2015; 47: 1471-1474Crossref PubMed Scopus (44) Google Scholar In fact, Mahamdallie and colleagues estimated that 10% of sporadic tumours arise in children with pathogenic variants in described predisposition genes; 2–3% of these occur in the genes that they identified in this most recent study. Two contemporaneous studies8Halliday BJ Fukuzawa R Markie DM et al.Germline mutations and somatic inactivation of TRIM28 in Wilms tumour.PLoS Genet. 2018; 14: e1007399Crossref PubMed Scopus (30) Google Scholar, 9Armstrong AE Gadd S Huff V Gerhard DS Dome JS Perlman EJ A unique subset of low-risk Wilms tumors is characterized by loss of function of TRIM28 (KAP1), a gene critical in early renal development: a Children's Oncology Group study.PLoS One. 2018; 13: e0208936Crossref PubMed Scopus (23) Google Scholar have replicated the finding of recurrent constitutional TRIM28 variants in children with Wilms' tumours, and all three studies have shown that these pathogenic variants are much more common in children with epithelial tumours, suggesting a pathological association that could be used in the clinical setting to identify these patients. Mahamdallie and colleagues' novel description of constitutional genomic alterations in children with Wilms' tumours is highly relevant to the families for whom the molecular basis of their tumour predisposition was previously unexplained. Such data will undoubtedly not only be useful for genetic counselling, but also underscore the translational dilemmas facing clinicians in this era of next-generation sequencing. Until a few years ago, most practitioners would offer clinical genetic testing to children with Wilms' tumours and syndromic features of WT1-related disorders or Beckwith-Wiedemann syndrome. This approach became more complicated when pathogenic alterations at these loci were found to have very subtle syndromic features or, occasionally, none at all.3Little SE Hanks SP King-Underwood L et al.Frequency and heritability of WT1 mutations in nonsyndromic Wilms' tumor patients: a UK Children's Cancer Study Group study.J Clin Oncol. 2004; 22: 4140-4146Crossref PubMed Scopus (74) Google Scholar, 4Scott RH Douglas J Baskcomb L et al.Constitutional 11p15 abnormalities, including heritable imprinting center mutations, cause nonsyndromic Wilms tumor.Nat Genet. 2008; 40: 1329-1334Crossref PubMed Scopus (117) Google Scholar Clinical guidelines have been created to assist with identifying children for whom molecular testing is appropriate. These guidelines strive to reach a sensitivity of greater than 90% for detecting alterations at WT1 or chromosome 11p15.5 through selection of patients with particular clinical or pathologic features, such as bilateral disease or nephrogenic rests.10Goudie C Cullinan N Coltin H et al.Identifying children at increased risk for a cancer predisposition syndrome: the McGill Interactive Pediatric Oncogenetic Guidelines (MIPOGG).Pediatr Blood Cancer. 2017; 64: e26772Google Scholar However, by contrast with WT1 or chromosome 11p15.5, of the predisposition genes described by Mahamdallie and colleagues, so far only TRIM28 pathogenic variants are associated with identifiable pathological features, and none of the genes have a consistent clinical phenotype other than Wilms' tumour predisposition. Therefore, outside the rare familial cases, the identification of which patients are most likely to have a pathogenic variant in one of these genes would be difficult, making it hard to use targeted approaches for genetic testing. This problem will be compounded if and when further Wilms' tumour-associated variants are reported. With the increasing number of predisposition genes and the current absence of hotspot variants in these genes, targeted techniques, such as Sanger sequencing, become unwieldy. As in other fields, clinical practice in paediatric cancer genetics is evolving to include the use of next-generation sequencing. These techniques raise the potential for finding variants of unknown significance or, with non-targeted panels, finding pathogenic variants in incidental unrelated genes. Along with the added uncertainty for patients and clinicians, counselling families about these findings requires significant expertise and resources. The data reported by Mahamdallie and colleagues will help to elucidate the basic biology of Wilms' tumour, but their translational usefulness is unclear. The penetrance of Wilms' tumour in families with pathogenic variants in these genes is not complete, and it is also unclear whether screening for primary or recurrent tumours by ultrasonography will be necessary or beneficial for patients with these alterations. The benefits of screening for children with Beckwith-Wiedemann syndrome are generally accepted, although with a small evidence base, and important controversies exist about the use of molecular data to select children for tumour surveillance. Extrapolating from this experience, clinicians might choose to offer screening every 3 months until at least age 8 years to all patients with variants in these newly described genes, but this intervention would necessarily be made in the absence of any evidence of benefit, would be costly, and might increase parental anxiety at the time of each screening. Mahamdallie and colleagues' findings have opened the door to new opportunities to capitalise on clinical genetics for children with Wilms' tumour. Through their comprehensive and important work, we now have a more complete description of Wilms' tumour predisposition. Further research, experience, and development of evidence-based clinical guidelines will be needed to untangle the clinical implications of their findings. Where resources allow, all children with Wilms' tumour should be assessed by clinicians with expertise in cancer genetics. Different regions and institutions will probably develop their own practices on which patients should be offered further genetic testing. While these practices develop and further evidence is generated, the clinical genetics and paediatric oncology community should continue to evaluate the costs and benefits of testing. I declare no competing interests. Identification of new Wilms tumour predisposition genes: an exome sequencing studyThe four new Wilms tumour predisposition genes identified—TRIM28, FBXW7, NYNRIN, and KDM3B—are involved in diverse biological processes and, together with the other 17 known Wilms tumour predisposition genes, account for about 10% of Wilms tumour cases. The overlap between these 21 constitutionally mutated predisposition genes and 20 genes somatically mutated in Wilms tumour is limited, consisting of only four genes. We recommend that all individuals with Wilms tumour should be offered genetic testing and particularly, those with epithelial Wilms tumour should be offered TRIM28 genetic testing. Full-Text PDF Open Access

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