Childhood Cancer Genomics (PDQ®)–Health Professional Version - National Cancer Institute

Childhood Cancer Genomics (PDQ®)–Health Professional Version

Retinoblastoma

Retinoblastoma is a tumor that occurs in heritable (25%–30%) and nonheritable (70%–75%) forms. Heritable disease is defined by the presence of a germline mutation of the RB1 gene. This germline mutation may have been inherited from an affected progenitor (25% of cases) or may have occurred in a germ cell before conception or in utero during early embryogenesis in patients with sporadic disease (75% of cases). The presence of positive family history or bilateral or multifocal disease is suggestive of heritable disease.

Heritable retinoblastoma may manifest as unilateral or bilateral disease. The penetrance of the RB1 mutation (laterality, age at diagnosis, and number of tumors) is probably dependent on concurrent genetic modifiers such as MDM2 and MDM4 polymorphisms.[1,2] All children with bilateral disease and approximately 15% of patients with unilateral disease are presumed to have the heritable form, even though only 25% have an affected parent.

Children with heritable retinoblastoma tend to be diagnosed at a younger age than are children with the nonheritable form of the disease. It was thought that unilateral retinoblastoma in children younger than 1 year raises concern for the presence of heritable disease, whereas older children with a unilateral tumor are more likely to have the nonheritable form of the disease.[3] However, in a retrospective single-institution report of 182 patients with unilateral retinoblastoma, patients with a positive genetic result (n = 32) were diagnosed at a mean age of 26 months, and patients without genetic results were diagnosed at a mean age of 22 months (P = .31).[4]

The genomic landscape of retinoblastoma is driven by alterations in RB1 that lead to biallelic inactivation.[5,6] A rare cause of RB1 inactivation is chromothripsis, which may be difficult to detect by conventional methods.[7] Other recurring genomic changes that occur in a small minority of tumors include BCOR mutation/deletion, MYCN amplification, and OTX2 amplification.[5-7] A study of 1,068 unilateral nonfamilial retinoblastoma tumors reported that a small percentage of cases (approximately 3%) lacked evidence of RB1 loss. Approximately one-half of these cases with no evidence of RB1 loss (representing approximately 1.5% of all unilateral nonfamilial retinoblastoma) showed MYCN amplification.[6] The functional status of the retinoblastoma protein (pRb) is inferred to be inactive in retinoblastoma with MYCN amplification. This suggests that inactivation of RB1 by mutation or inactive pRb is a requirement for the development of retinoblastoma, independent of MYCN amplification.[8]

(Refer to the PDQ summary on Retinoblastoma Treatment for information about the treatment of retinoblastoma.)

References

Castéra L, Sabbagh A, Dehainault C, et al.: MDM2 as a modifier gene in retinoblastoma. J Natl Cancer Inst 102 (23): 1805-8, 2010. [PUBMED Abstract]
de Oliveira Reis AH, de Carvalho IN, de Sousa Damasceno PB, et al.: Influence of MDM2 and MDM4 on development and survival in hereditary retinoblastoma. Pediatr Blood Cancer 59 (1): 39-43, 2012. [PUBMED Abstract]
Zajaczek S, Jakubowska A, Kurzawski G, et al.: Age at diagnosis to discriminate those patients for whom constitutional DNA sequencing is appropriate in sporadic unilateral retinoblastoma. Eur J Cancer 34 (12): 1919-21, 1998. [PUBMED Abstract]
Berry JL, Lewis L, Zolfaghari E, et al.: Lack of correlation between age at diagnosis and RB1 mutations for unilateral retinoblastoma: the importance of genetic testing. Ophthalmic Genet 39 (3): 407-409, 2018. [PUBMED Abstract]
Zhang J, Benavente CA, McEvoy J, et al.: A novel retinoblastoma therapy from genomic and epigenetic analyses. Nature 481 (7381): 329-34, 2012. [PUBMED Abstract]
Rushlow DE, Mol BM, Kennett JY, et al.: Characterisation of retinoblastomas without RB1 mutations: genomic, gene expression, and clinical studies. Lancet Oncol 14 (4): 327-34, 2013. [PUBMED Abstract]
McEvoy J, Nagahawatte P, Finkelstein D, et al.: RB1 gene inactivation by chromothripsis in human retinoblastoma. Oncotarget 5 (2): 438-50, 2014. [PUBMED Abstract]
Ewens KG, Bhatti TR, Moran KA, et al.: Phosphorylation of pRb: mechanism for RB pathway inactivation in MYCN-amplified retinoblastoma. Cancer Med 6 (3): 619-630, 2017. [PUBMED Abstract]

Kidney Tumors

Wilms Tumor

Wilms tumors, similar to other pediatric embryonal neoplasms, typically arise after a limited number of genetic aberrations. One study showed the following:[1]

Wilms tumors commonly arise through more than one genetic event.
Wilms tumors show differences in gene expression and methylation patterns with different genetic aberrations.
Wilms tumors have a large number of candidate driver genes, most of which are mutated in less than 5% of Wilms tumors.
Wilms tumors have recurrent mutations in genes with common functions, with most involved in either early renal development or epigenetic regulation (e.g., chromatin modifications, transcription elongation, and miRNA).

Approximately one-third of Wilms tumor cases involve mutations in WT1, CTNNB1, or WTX.[2,3] Another subset of Wilms tumor cases results from mutations in miRNA processing genes (miRNAPG), including DROSHA, DGCR8, DICER1, and XPO5.[4-7] Other genes critical for early renal development that are recurrently mutated in Wilms tumor include SIX1 and SIX2 (transcription factors that play key roles in early renal development),[4,5] EP300, CREBBP, and MYCN.[1] Of the mutations in Wilms tumors, 30% to 50% appear to converge on the process of transcriptional elongation in renal development and include the genes MLLT1, BCOR, MAP3K4, BRD7, and HDAC4.[1] Anaplastic Wilms tumor is characterized by the presence of TP53 mutations.

Elevated rates of Wilms tumor are observed in a number of genetic disorders, including WAGR (Wilms tumor, aniridia, genitourinary anomalies, and mental retardation) syndrome, Beckwith-Wiedemann syndrome, hemihypertrophy, Denys-Drash syndrome, and Perlman syndrome.[8] Other genetic causes that have been observed in familial Wilms tumor cases include germline mutations in REST and CTR9.[9,10]

The genomic and genetic characteristics of Wilms tumor are summarized below.

WT1 gene

The WT1 gene is located on the short arm of chromosome 11 (11p13). WT1 is a transcription factor that is required for normal genitourinary development and is important for differentiation of the renal blastema.[11] WT1 mutations are observed in 10% to 20% of cases of sporadic Wilms tumor.[2,11,12]

Wilms tumor with a WT1 mutation is characterized by the following:

Evidence of WNT pathway activation by activating mutations in the CTNNB1 gene is common.[12-14]
Loss of heterozygosity (LOH) at 11p15 is commonly observed, as paternal uniparental disomy for chromosome 11 represents a common mechanism for losing the remaining normal WT1 allele.[12,15]
Nephrogenic rests are benign foci of embryonal kidney cells that abnormally persist into postnatal life. Intralobar nephrogenic rests occur in approximately 20% of Wilms tumor cases. They are observed at high rates in cases with genetic syndromes that have WT1 mutations such as WAGR and Denys-Drash syndromes.[16] Intralobar nephrogenic rests are also observed in cases with sporadic WT1 and MLLT1 mutations.[17,18]
WT1 germline mutations are uncommon (2%–4%) in nonsyndromic Wilms tumor.[19,20]
WT1 mutations and 11p15 loss of heterozygosity were associated with relapse in patients with very low-risk Wilms tumor in one study of 56 patients who did not receive chemotherapy.[21] These findings need validation but may provide biomarkers for stratifying patients in the future.

Germline WT1 mutations are more common in children with Wilms tumor and one of the following:

WAGR syndrome, Denys-Drash syndrome,[22] or Frasier syndrome.[23]
Genitourinary anomalies, including hypospadias and cryptorchidism.
Bilateral Wilms tumor.
Unilateral Wilms tumor with nephrogenic rests in the contralateral kidney.
Stromal and rhabdomyomatous differentiation.

Syndromic conditions with germline WT1 mutations include WAGR syndrome, Denys-Drash syndrome,[22] and Frasier syndrome.[23]

WAGR syndrome. Children with WAGR syndrome are at high risk (approximately 50%) of developing Wilms tumor.[24] WAGR syndrome results from deletions at chromosome 11p13 that involve a set of contiguous genes that includes the WT1 and PAX6 genes.
Inactivating mutations or deletions in the PAX6 gene lead to aniridia, while deletion of WT1 confers the increased risk of Wilms tumor. Sporadic aniridia in which WT1 is not deleted is not associated with increased risk of Wilms tumor. Accordingly, children with familial aniridia, generally occurring for many generations, and without renal abnormalities, have a normal WT1 gene and are not at an increased risk of Wilms tumor.[25,26]
Wilms tumor in children with WAGR syndrome is characterized by an excess of bilateral disease, intralobar nephrogenic rests–associated favorable-histology (FH) tumors of mixed cell type, and early age at diagnosis.[27] The mental retardation in WAGR syndrome may be secondary to deletion of other genes, including SLC1A2 or BDNF.[28]

Germline WT1 point mutations produce genetic syndromes that are characterized by nephropathy, 46XY disorder of sex development, and varying risks of Wilms tumor.[29,30]

Denys-Drash and Frasier syndromes. Denys-Drash syndrome is characterized by nephrotic syndrome caused by diffuse mesangial sclerosis, XY pseudohermaphroditism, and increased risk of Wilms tumor (>90%). Frasier syndrome is characterized by progressive nephropathy caused by focal segmental glomerulosclerosis, gonadoblastoma, and XY pseudohermaphroditism.
WT1 mutations in Denys-Drash syndrome are most often missense mutations in exons 8 and 9, which code for the DNA binding region of WT1.[22] By contrast, WT1 mutations in Frasier syndrome typically occur in intron 9 at the KTS site, and they affect an alternative splicing, thereby preventing production of the usually more abundant WT1 +KTS isoform.[31]

Studies evaluating genotype/phenotype correlations of WT1 mutations have shown that the risk of Wilms tumor is highest for truncating mutations (14 of 17 cases, 82%) and lower for missense mutations (27 of 67 cases, 42%). The risk is lowest for KTS splice site mutations (1 of 27 cases, 4%).[29,30] Bilateral Wilms tumor was more common in cases with WT1-truncating mutations (9 of 14 cases) than in cases with WT1 missense mutations (3 of 27 cases).[29,30] These genomic studies confirm previous estimates of elevated risk of Wilms tumor for children with Denys-Drash syndrome and low risk of Wilms tumor for children with Frasier syndrome.

Late effects associated with WAGR syndrome and Wilms tumor include the following:

Children with WAGR syndrome or other germline WT1 mutations are monitored throughout their lives because they are at increased risk of developing hypertension, nephropathy, and renal failure.[32]
Patients with Wilms tumor and aniridia without genitourinary abnormalities are at lower risk but are monitored for nephropathy or renal failure.[33]
Children with Wilms tumor and any genitourinary anomalies are also at increased risk of late renal failure and are monitored. Features associated with germline WT1 mutations that increase the risk of developing renal failure include the following:[32]
- Stromal predominant histology.
- Bilateral disease.
- Intralobar nephrogenic rests.
- Wilms tumor diagnosed before age 2 years.

(Refer to the Late effects after Wilms tumor therapy section of the PDQ summary on Wilms Tumor and Other Childhood Kidney Tumors Treatment for more information about the late effects associated with Wilms tumor.)

CTNNB1 gene

CTNNB1 is the most commonly mutated gene in Wilms tumor, reported to occur in 15% of patients with Wilms tumor.[1,3,12,14,34] These CTNNB1 mutations result in activation of the WNT pathway, which plays a prominent role in the developing kidney.[35] CTNNB1 mutations commonly occur with WT1 mutations, and most cases of Wilms tumor with WT1 mutations have a concurrent CTNNB1 mutation.[12,14,34] Activation of beta-catenin in the presence of intact WT1 protein appears to be inadequate to promote tumor development because CTNNB1 mutations are rarely found in the absence of a WT1 or WTX mutation, except when associated with a MLLT1 mutation.[3,36] CTNNB1 mutations appear to be late events in Wilms tumor development because they are found in tumors but not in nephrogenic rests.[17]

WTX gene on the X chromosome

WTX, which is also called AMER1, is located on the X chromosome at Xq11.1. It is altered in 15% to 20% of Wilms tumor cases.[2,3,12,37,38] Germline mutations in WTX cause an X-linked sclerosing bone dysplasia, osteopathia striata congenita with cranial sclerosis (MIM300373 ).[39] Despite having germline WTX mutations, individuals with osteopathia striata congenita are not predisposed to tumor development.[39] The WTX protein appears to be involved in both the degradation of beta-catenin and in the intracellular distribution of APC protein.[36,40] WTX is most commonly altered by deletions involving part or all of the WTX gene, with deleterious point mutations occurring less commonly.[2,12,37] Most Wilms tumor cases with WTX alterations have epigenetic 11p15 abnormalities.[12]

WTX alterations are equally distributed between males and females, and WTX inactivation has no apparent effect on clinical presentation or prognosis.[2]

Imprinting cluster regions (ICRs) on chromosome 11p15 (WT2) and Beckwith-Wiedemann syndrome

A second Wilms tumor locus, WT2, maps to an imprinted region of chromosome 11p15.5; when it is a germline mutation, it causes Beckwith-Wiedemann syndrome. About 3% of children with Wilms tumor have germline epigenetic or genetic changes at the 11p15.5 growth regulatory locus without any clinical manifestations of overgrowth. Like children with Beckwith-Wiedemann syndrome, these children have an increased incidence of bilateral Wilms tumor or familial Wilms tumor.[28]

Approximately 80% of patients with Beckwith-Wiedemann syndrome have a molecular defect of the 11p15 domain.[41] Various molecular mechanisms underlying Beckwith-Wiedemann syndrome have been identified. Some of these abnormalities are genetic (germline mutations of the maternal allele of CDKN1C, paternal uniparental isodisomy of 11p15, or duplication of part of the 11p15 domain) but are more frequently epigenetic (loss of methylation of the maternal ICR2/KvDMR1 or gain of methylation of the maternal ICR1).[28,42]

Several candidate genes at the WT2 locus comprise the two independent imprinted domains IGF2/H19 and KIP2/LIT1.[42] Loss of heterozygosity, which exclusively affects the maternal chromosome, has the effect of upregulating paternally active genes and silencing maternally active ones. A loss or switch of the imprint for genes (change in methylation status) in this region has also been frequently observed and results in the same functional aberrations.[28,41,42]

A relationship between epigenotype and phenotype has been shown in Beckwith-Wiedemann syndrome, with a different rate of cancer in Beckwith-Wiedemann syndrome according to the type of alteration of the 11p15 region.[43] The overall tumor risk in patients with Beckwith-Wiedemann syndrome has been estimated to be between 5% and 10%, with a risk between 1% (loss of imprinting at ICR2) and 30% (gain of methylation at ICR1 and paternal 11p15 isodisomy). For patients with Beckwith-Wiedemann syndrome, the risk of developing Wilms tumor is 4.1%. Development of Wilms tumor has been reported in patients with only ICR1 gain of methylation, whereas other tumors such as neuroblastoma or hepatoblastoma were reported in patients with paternal 11p15 isodisomy.[44-46] For patients with Beckwith-Wiedemann syndrome, the relative risk of developing hepatoblastoma is 2,280 times that of the general population.[47]

Loss of imprinting or gene methylation is rarely found at other loci, supporting the specificity of loss of imprinting at 11p15.5.[48] Interestingly, Wilms tumor in Asian children is not associated with either nephrogenic rests or IGF2 loss of imprinting.[49]

Approximately one-fifth of patients with Beckwith-Wiedemann syndrome who develop Wilms tumor present with bilateral disease, and metachronous bilateral disease is also observed.[25,47,50] The prevalence of Beckwith-Wiedemann syndrome is about 1% among children with Wilms tumor reported to the National Wilms Tumor Study (NWTS).[47,51]

Other genes and chromosomal alterations

Additional genes and chromosomal alterations that have been implicated in the pathogenesis and biology of Wilms tumor include the following:

1q. Gain of chromosome 1q is associated with an inferior outcome and is the single most powerful predictor of outcome. In the presence of 1q gain, neither 1p nor 16q loss is significant.[52,53] Gain of chromosome 1q is one of the most common cytogenetic abnormalities in Wilms tumor and is observed in approximately 30% of tumors.
In an analysis of FH Wilms tumor from 1,114 patients from NWTS-5 (COG-Q9401/NCT00002611), 28% of the tumors displayed 1q gain.[52]
- The 8-year event-free survival (EFS) rate was 77% for patients with 1q gain and 90% for those lacking 1q gain (P < .001). Within each disease stage, 1q gain was associated with inferior EFS.
- The 8-year overall survival (OS) rate was 88% for those with 1q gain and 96% for those lacking 1q gain (P < .001). OS was significantly inferior in cases with stage I disease (P < .0015) and stage IV disease (P = .011).
16q and 1p. Additional tumor-suppressor or tumor-progression genes may lie on chromosomes 16q and 1p, as evidenced by loss of heterozygosity for these regions in 17% and 11% of Wilms tumor cases, respectively.[54]
- In large NWTS studies, patients with tumor-specific loss of these loci had significantly worse relapse-free survival and OS rates. Combined loss of 1p and 16q are used to select FH Wilms tumor patients for more aggressive therapy in the current Children's Oncology Group (COG) study. However, a U.K. study of more than 400 patients found no significant association between 1p deletion and poor prognosis, but a poor prognosis was associated with 16q loss of heterozygosity.[55]
- An Italian study of 125 patients, using treatment quite similar to that in the COG study, found significantly worse prognosis in those with 1p deletions but not 16q deletions.[56]
These conflicting results may arise from the greater prognostic significance of 1q gain described above. Loss of heterozygosity of 16q and 1p loses significance as independent prognostic markers in the presence of 1q gain. However, in the absence of 1q gain, loss of heterozygosity of 16q and 1p retains their adverse prognostic impact.[52] The loss of heterozygosity of 16q and 1p appears to arise from complex chromosomal events that result in 1q loss of heterozygosity or 1q gain. The change in 1q appears to be the critical tumorigenic genetic event.[57]
miRNAPG. Mutations in selected miRNAPG are observed in approximately 20% of Wilms tumor cases and appear to perpetuate the progenitor state.[1,4-7] The products of these genes direct the maturation of miRNAs from the initial pri-miRNA transcripts to functional cytoplasmic miRNAs (refer to Figure 10).[58] The most commonly mutated miRNAPG is DROSHA, with a recurrent mutation (E1147K) affecting a metal-binding residue of the RNase IIIb domain, representing about 80% of DROSHA-mutated tumors. Other miRNAPG that are mutated in Wilms tumor include DGCR8, DICER1, TARBP2, DIS3L2, and XPO5. These mutations are generally mutually exclusive, and they appear to be deleterious and result in impaired expression of tumor-suppressing miRNAs. A striking sex bias was noted in mutations for DGCR8 (located on chromosome 22q11), with 38 of 43 cases (88%) arising in girls.[4,5]
Germline mutations in miRNAPG are observed for DICER1 and DIS3L2, with mutations in the former causing DICER1 syndrome and mutations in the latter causing Perlman syndrome.
- DICER1 syndrome is typically caused by inherited truncating mutations in DICER1, with tumor formation following acquisition of a missense mutation in a domain of the remaining allele of DICER1 (the RNase IIIb domain) responsible for processing miRNAs derived from the 5p arms of pre-miRNAs.[59] Tumors associated with DICER1 syndrome include pleuropulmonary blastoma, cystic nephroma, ovarian sex cord–stromal tumors, multinodular goiter, and embryonal rhabdomyosarcoma.[59] Wilms tumor is an uncommon presentation of the DICER1 syndrome. In one study, three families with DICER1 syndrome included children with Wilms tumor, with two of the Wilms tumor cases showing the typical second DICER1 mutation in the RNase IIIb domain.[60] Another study identified DICER1 mutations in 2 of 48 familial Wilms tumor families.[61] Large sequencing studies of Wilms tumor cohorts have also observed occasional cases with DICER1 mutations.[5,6]
- Perlman syndrome is a rare overgrowth disorder caused by mutations in DIS3L2, which encodes a ribonuclease that is responsible for degrading pre-let-7 miRNA.[62,63] The prognosis of Perlman syndrome is poor, with a high neonatal mortality rate. In a survey of published cases of Perlman syndrome (N = 28), in infants who survived beyond the neonatal period, approximately two-thirds developed Wilms tumor, and all patients showed developmental delay. Fetal macrosomia, ascites, and polyhydramnios are frequent manifestations.[64]
  ENLARGE
  Figure 10. The miRNA processing pathway is commonly mutated in Wilms tumor. Expression of mature miRNA is initiated by RNA polymerase–mediated transcription of DNA-encoded sequences into pri-miRNA, which form a long double-stranded hairpin. This structure is then cleaved by a complex of Drosha and DGCR8 into a smaller pre-miRNA hairpin, which is exported from the nucleus and then cleaved by Dicer (an RNase) and TRBP (with specificity for dsRNA) to remove the hairpin loop and leave two single-stranded miRNAs. The functional strand binds to Argonaute (Ago2) proteins into the RNA-induced silencing complex (RISC), where it guides the complex to its target mRNA, while the nonfunctional strand is degraded. Targeting of mRNAs by this method results in mRNA silencing by mRNA cleavage, translational repression, or deadenylation. Let-7 miRNAs are a family of miRNAs highly expressed in ESCs with tumor suppressor properties. In cases in which LIN28 is overexpressed, LIN28 binds to pre-Let-7 miRNA, preventing DICER from binding and resulting in LIN28-activated polyuridylation by TUT4 or TUT7, causing reciprocal DIS3L2-mediated degradation of Let-7 pre-miRNAs. Genes involved in miRNA processing that have been associated with Wilms’ tumor are highlighted in blue (inactivating) and green (activating) and include DROSHA, DGCR8, XPO5 (encoding exportin-5), DICER1, TARBP2, DIS3L2, and LIN28. Copyright © 2015 Hohenstein et al.; Published by Cold Spring Harbor Laboratory Press. Genes Dev. 2015 Mar 1; 29(5): 467–482. doi: 10.1101/gad.256396.114 Exit Disclaimer. This article is distributed exclusively by Cold Spring Harbor Laboratory Press under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/Exit Disclaimer.
SIX1 and SIX2. SIX1 and SIX2 are highly homologous transcription factors that play key roles in early renal development and are expressed in the metanephric mesenchyme, where they maintain the mesenchymal progenitor population. The frequency of SIX1 mutations is 3% to 4% in Wilms tumor, and the frequency of SIX2 mutations in Wilms tumor is 1% to 3%.[4,5] Virtually all SIX1 and SIX2 mutations are in exon 1 and result in a glutamine-to-arginine mutation at position 177. Mutations in WT1, WTX, and CTNNB1 are infrequent in cases with SIX1/SIX2 or miRNAPG mutations. Conversely, SIX1/SIX2 mutations and miRNAPG mutations tend to occur together.
MLLT1. Approximately 4% of Wilms tumor cases have mutations in the highly conserved YEATS domain of MLLT1 (ENL), a gene known to be involved in transcriptional elongation by RNA polymerase II during early development.[18] The mutant MLLT1 protein shows altered binding to acetylated histone tails. Patients with MLLT1-mutant tumors present at a younger age and have a high prevalence of precursor intralobar nephrogenic rests, supporting a model whereby activating MLLT1 mutations early in renal development result in the development of Wilms tumor.
TP53 (tumor suppressor gene). Most anaplastic Wilms tumor cases show mutations in the TP53 tumor suppressor gene.[65-67] TP53 may be useful as an unfavorable prognostic marker.[65,66]
In a study of 118 prospectively identified patients with diffuse anaplastic Wilms tumor registered on the NWTS-5 trial, 57 patients (48%) demonstrated TP53 mutations, 13 patients (11%) demonstrated TP53 segmental copy number loss without mutation, and 48 patients (41%) lacked both (wild-type TP53 [wtTP53]). All TP53 mutations were detected by sequencing alone. Patients with stage III or stage IV disease with wtTP53 had a significantly lower relapse rate and mortality rate than did patients with TP53 abnormalities (P = .00006 and P = .00007, respectively). There was no effect of TP53 status on patients with stage I or stage II tumors. In-depth analysis of a subset of 39 patients with diffuse anaplastic Wilms tumor showed that 7 patients (18%) were wtTP53. These tumors demonstrated gene expression evidence of p53 pathway activation. Retrospective pathology review of wtTP53 revealed no or very low volume of anaplasia in six of seven tumors. These data support the key role of TP53 loss in the development of anaplasia in Wilms tumor and support its significant clinical influence in patients who have residual anaplastic disease after surgery.[68]
FBXW7. FBXW7, a ubiquitin ligase component, is a gene that has been identified as recurrently mutated at low rates in Wilms tumor. Mutations of this gene have been associated with epithelial-type tumor histology.[69]
9q22.3 microdeletion syndrome. Patients with 9q22.3 microdeletion syndrome have an increased risk of Wilms tumor.[70,71] The chromosomal region with germline deletion includes PTCH1, the gene that is mutated in Gorlin syndrome (nevoid basal cell carcinoma syndrome associated with osteosarcoma). 9q22.3 microdeletion syndrome is characterized by the clinical findings of Gorlin syndrome, as well as developmental delay and/or intellectual disability, metopic craniosynostosis, obstructive hydrocephalus, prenatal and postnatal macrosomia, and seizures.[70] Five patients who presented with Wilms tumor in the context of a constitutional 9q22.3 microdeletion have been reported.[71-73]
MYCN. MYCN copy number gain was observed in approximately 13% of Wilms tumor cases, and it was more common in anaplastic cases (7 of 23 cases, 30%) than in nonanaplastic cases (11.2%).[74] Activating mutations at codon 44 (p.P44L) were identified in approximately 4% of Wilms tumor cases.[74] Germline copy number gain at MYCN has been reported in a bilateral Wilms tumor case, and germline MYCN duplication was also reported for a child with prenatal bilateral nephroblastomatosis and a family history of nephroblastoma.[75]
CTR9. Inactivating CTR9 germline mutations were identified in 4 of 36 familial Wilms tumor pedigrees.[10,76] CTR9, which is located at chromosome 11p15.3, is a key component of the polymerase-associated factor 1 complex (PAF1c), which has multiple roles in RNA polymerase II regulation and is implicated in embryonic organogenesis and maintenance of embryonic stem cell pluripotency.
REST. Inactivating germline mutations in REST (encoding RE1-silencing transcription factor) were identified in four familial Wilms tumor pedigrees.[9] REST is a transcriptional repressor that functions in cellular differentiation and embryonic development. Most REST mutations clustered within the portion of REST encoding the DNA-binding domain, and functional analyses showed that these mutations compromise REST transcriptional repression. When screened for REST mutations, 9 of 519 individuals with Wilms tumor who had no history of relatives with the disease tested positive for the mutation; some had parents who also tested positive.[9] These observations indicate that REST is a Wilms tumor predisposition gene associated with approximately 2% of Wilms tumor.

Figure 11 summarizes the genomic landscape of a selected cohort of Wilms tumor patients selected because they experienced relapse despite showing FH.[18] The 75 FH Wilms tumor cases were clustered by unsupervised analysis of gene expression data, resulting in six clusters. Five of six MLLT1-mutant tumors with available gene expression data were in cluster 3, and two were accompanied by CTNNB1 mutations. This cluster also contained four tumors with a mutation or small segment deletion of WT1, all of which also had either a mutation of CTNNB1 or small segment deletion or mutation of WTX. It also contained a substantial number of tumors with retention of imprinting of 11p15 (including all MLLT1-mutant tumors). The miRNAPG-mutated cases clustered together and were mutually exclusive with both MLLT1 and with WT1/WTX/CTNNB1-mutated cases.

Chart showing unsupervised analysis of gene expression data for clinically distinctive favorable histology Wilms tumor. — Figure 11. Unsupervised analysis of gene expression data. Non-negative Matrix Factorization (NMF) analysis of 75 FH Wilms tumor resulted in six clusters. Five of six *MLLT1* mutant tumors with available gene expression data occurred in NMF cluster 3, and two were accompanied by *CTNNB1* mutations. This cluster also contained a substantial number of tumors with retention of imprinting of 11p15 (including all *MLLT1*-mutant tumors), in contrast to other clusters, where most cases showed 11p15 loss of heterozygosity or retention of imprinting. Almost all miRNAPG-mutated cases were in NMF cluster 2, and most *WT1*, *WTX*, and *CTNNB1* mutations were in NMF clusters 3 and 4. Copyright © 2015 Perlman, E. J. et al. MLLT1 YEATS domain mutations in clinically distinctive Favourable Histology wilms tumours. Nat. Commun. 6:10013 doi: 10.1038/ncomms10013 (2015).Exit Disclaimer This article is distributed by Nature Publishing Group, a division of Macmillan Publishers Limited under a Creative Commons Attribution 4.0 International License, as described at http://creativecommons.org/licenses/by/4.0/Exit Disclaimer.

Renal Cell Carcinoma

Translocation-positive carcinomas of the kidney are recognized as a distinct form of renal cell carcinoma (RCC) and may be the most common form of RCC in children, accounting for 40% to 50% of pediatric RCC.[77] In a Children's Oncology Group (COG) prospective clinical trial of 120 childhood and adolescent patients with RCC, nearly one-half of patients had translocation-positive RCC.[78] These carcinomas are characterized by translocations involving the transcription factor E3 gene (TFE3) located on Xp11.2. The TFE3 gene may partner with one of the following genes:

ASPSCR in t(X;17)(p11.2;q25).
PRCC in t(X;1)(p11.2;q21).
SFPQ in t(X;1)(p11.2;p34).
NONO in inv(X;p11.2;q12).
Clathrin heavy chain (CLTC) in t(X;17)(p11;q23).

Another less-common translocation subtype, t(6;11)(p21;q12), involving an Alpha–transcription factor EB (TFEB) gene fusion, induces overexpression of TFEB. The translocations involving TFE3 and TFEB induce overexpression of these proteins, which can be identified by immunohistochemistry.[79]

Previous exposure to chemotherapy is the only known risk factor for the development of Xp11 translocation RCCs. In one study, the postchemotherapy interval ranged from 4 to 13 years. All reported patients received either a DNA topoisomerase II inhibitor and/or an alkylating agent.[80,81]

Controversy exists as to the biological behavior of translocation RCC in children and young adults. Whereas some series have suggested a good prognosis when RCC is treated with surgery alone despite presenting at a more advanced stage (III/IV) than TFE-RCC, a meta-analysis reported that these patients have poorer outcomes.[82-84] The outcomes for these patients are being studied in the ongoing COG AREN03B2 (NCT00898365) biology and classification study. Vascular endothelial growth factor receptor–targeted therapies and mammalian target of rapamycin (mTOR) inhibitors seem to be active in Xp11 translocation metastatic RCC.[85] Recurrences have been reported 20 to 30 years after initial resection of the translocation-associated RCC.[86]

Diagnosis of Xp11 translocation RCC needs to be confirmed by a molecular genetic approach, rather than using TFE3 immunohistochemistry alone, because reported cases have lacked the translocation. There is a rare subset of RCC cases that is positive for TFE3 and lack a TFE3 translocation, showing an ALK translocation instead. This subset of cases represents a newly recognized subgroup within RCC that is estimated to involve 15% to 20% of unclassified pediatric RCC. In the eight reported cases in children aged 6 to 16 years, the following was observed:[87-90]

ALK was fused to VCL (vinculin) in a t(2;10)(p23;q22) translocation (n = 3). The VCL translocation cases all occurred in children with sickle cell trait, whereas none of the TMP3 translocation cases did.
ALK was fused to TPM3 (tropomyosin 3) (n = 3).
ALK was fused to HOOK-1 on 1p32 (n = 1).
t(1;2) translocation fusing ALK and TMP3 (n = 1).

(Refer to the PDQ summary on Wilms Tumor and Other Childhood Kidney Tumors Treatment for information about the treatment of renal cell carcinoma.)

Rhabdoid Tumors of the Kidney

Rhabdoid tumors in all anatomical locations have a common genetic abnormality—loss of function of the SMARCB1/INI1/SNF5/BAF47 gene located at chromosome 22q11.2. The following text refers to rhabdoid tumors without regard to their primary site. SMARCB1 encodes a component of the SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex that has an important role in controlling gene transcription.[91,92] Loss of function occurs by deletions that lead to loss of part or all of the SMARCB1 gene and by mutations that are commonly frameshift or nonsense mutations that lead to premature truncation of the SMARCB1 protein.[92,93] A small percentage of rhabdoid tumors are caused by alterations in SMARCA4, which is the primary ATPase in the SWI/SNF complex.[94,95] Exome sequencing of 35 cases of rhabdoid tumor identified a very low mutation rate, with no genes having recurring mutations other than SMARCB1, which appeared to contribute to tumorigenesis.[96]

Germline mutations of SMARCB1 have been documented in patients with one or more primary tumors of the brain and/or kidney, consistent with a genetic predisposition to the development of rhabdoid tumors.[97,98] Approximately one-third of patients with rhabdoid tumors have germline SMARCB1 alterations.[92,99] In most cases, the mutations are de novo and not inherited. The median age at diagnosis of children with rhabdoid tumors and a germline mutation or deletion is younger (6 months) than that of children with apparently sporadic disease (18 months).[100] Germline mosaicism has been suggested for several families with multiple affected siblings. It appears that patients with germline mutations may have the worst prognosis.[101,102] Germline mutations in SMARCA4 have also been reported in patients with rhabdoid tumors.[94,103]

(Refer to the PDQ summary on Wilms Tumor and Other Childhood Kidney Tumors Treatment for information about the treatment of rhabdoid tumor of the kidney.)

Clear Cell Sarcoma of the Kidney

Clear cell sarcoma of the kidney is an uncommon renal tumor that comprises approximately 5% of all primary renal malignancies in children, and it is observed most often before age 3 years. The molecular background of clear cell sarcoma of the kidney is poorly understood because of its rarity and lack of experimental models.

Several biological features of clear cell sarcoma of the kidney have been described, including the following:

Internal tandem duplications in exon 15 of the BCOR gene (BCL6 corepressor) were reported in 100% (20 of 20 cases) of clear cell sarcoma of the kidney cases but in none of the other pediatric renal tumors evaluated.[104] Other reports have confirmed the finding of BCOR internal tandem duplications in clear cell sarcoma of the kidney.[105-108] Hence, BCOR internal tandem duplications appear to play a key role in the tumorigenesis of clear cell sarcoma of the kidney, and their identification should aid in the differential diagnosis of renal tumors.[104]
The YWHAE-NUTM2 fusion (involving either NUTM2B or NUTM2E) resulting from t(10;17) was reported in 12% of cases of clear cell sarcoma of the kidney.[109] The presence of the YWHAE-NUTM2 fusion appears to be mutually exclusive with the presence of BCOR internal tandem duplications; this observation is based on a study of 22 cases of clear cell sarcoma of the kidney that included two cases with the YWHAE-NUTM2 fusion and 20 cases with BCOR internal tandem duplications.[105] The gene expression profiles for cases with the YWHAE-NUTM2 fusion were distinctive from those with BCOR internal tandem duplications.
Evaluation of 13 clear cell sarcoma of the kidney tumors for changes in chromosome copy number, mutations, and rearrangements found a single case with the YWHAE-NUTM2 fusion and 12 cases with BCOR internal tandem duplications.[107,110] No other recurrent segmental chromosomal copy number changes or somatic variants (single nucleotide or small insertion/deletion) were identified, providing further support for the role of BCOR internal tandem duplication as the primary oncogenic driver for clear cell sarcoma of the kidney.[110]

(Refer to the PDQ summary on Wilms Tumor and Other Childhood Kidney Tumors Treatment for information about the treatment of clear cell tumor of the kidney.)

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