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Childhood Cancer Genomics (PDQ®) 5/8 –Health Professional Version - National Cancer Institute

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

National Cancer Institute

Childhood Cancer Genomics (PDQ®)–Health Professional Version

Hepatoblastoma and Hepatocellular Carcinoma

Genomic abnormalities related to hepatoblastoma include the following:
  • Hepatoblastoma mutation frequency, as determined by three groups using whole-exome sequencing, was very low (approximately three variants per tumor) in children younger than 5 years.[1-3]
  • Hepatoblastoma is primarily a disease of WNT pathway activation. The primary mechanism for WNT pathway activation is CTNNB1 activating mutations/deletions involving exon 3. CTNNB1 mutations have been reported in 70% of cases.[1] Rare causes of WNT pathway activation include mutations in AXIN1AXIN2, and APC (APC seen only in cases associated with familial adenomatosis polyposis coli).[4]
  • The frequency of NFE2L2 mutations in hepatoblastoma specimens was reported to be 4 of 62 tumors (7%) in one study [2] and 5 of 51 specimens (10%) in another study.[1]
    Similar mutations have been found in many types of cancer, including hepatocellular carcinoma. These mutations render NFE2L2 insensitive to KEAP1-mediated degradation, leading to activation of the NFE2L2-KEAP1 pathway, which activates resistance to oxidative stress and is believed to confer resistance to chemotherapy.
  • Somatic mutations were identified in other genes related to regulation of oxidative stress, including inactivating mutations in the thioredoxin-domain containing genes, TXNDC15 and TXNDC16.[2]
  • Figure 5 shows the distribution of CTNNB1NFE2L2, and TERT mutations in hepatoblastoma.[1]
    ENLARGEChart showing the distribution of CTNNB1, APC, NFE2L2, and TERT mutations for hepatoblastoma.
    Figure 5. Mutational status and functional relevance of NFE2L2 in hepatoblastoma. Clinicopathological characteristics and the mutational status of the CTNNB1APC, and NFE2L2 genes, as well as the TERT promoter region are color-coded and depicted in rows for each tumor of our cohort of 43 hepatoblastoma (HB) patients and four transitional liver cell tumour (TLCT) patients and 4 HB cell lines. Reprinted from Journal of HepatologyExit Disclaimer, Volume 61 (Issue 6), Melanie Eichenmüller, Franziska Trippel, Michaela Kreuder, Alexander Beck, Thomas Schwarzmayr, Beate Häberle, Stefano Cairo, Ivo Leuschner, Dietrich von Schweinitz, Tim M. Strom, Roland Kappler, The genomic landscape of hepatoblastoma and their progenies with HCC-like features, Pages 1312–1320, Copyright 2014, with permission from Elsevier.
To date, these genetic mutations have not been used to select therapeutic agents for investigation in clinical trials.
Genomic abnormalities related to hepatocellular carcinoma include the following:
  • A first case of pediatric hepatocellular carcinoma was analyzed by whole-exome sequencing, which showed a higher mutation rate (53 variants) and the coexistence of CTNNB1 and NFE2L2 mutations.[5]
  • One study investigated pediatric nonfibrolamellar hepatocellular carcinoma tumors (N = 15) using multiple analytic tools. These tumors were found to frequently carry alterations in a subset of genes that are commonly mutated in adult hepatocellular carcinoma, including CTNNB1 and TERT, but the molecular mechanisms of the mutations are different; the TP53 mutation was rare in this pediatric hepatocellular carcinoma cohort. Pediatric hepatocellular carcinoma that arose in the background of underlying metabolic disease had fewer mutations and a distinct molecular profile; typical driver mutations were lacking in this group of patients.[6]
  • Fibrolamellar hepatocellular carcinoma is a rare subtype of hepatocellular carcinoma observed in older children. It is characterized by an approximately 400 kB deletion on chromosome 19 that results in production of a chimeric RNA coding for a protein containing the amino-terminal domain of DNAJB1, a homolog of the molecular chaperone DNAJ, fused in frame with PRKACA, the catalytic domain of protein kinase A.[7]
  • A rare, more aggressive subtype of childhood liver cancer (hepatocellular neoplasm, not otherwise specified, also termed transitional liver cell tumor) occurs in older children, and it has clinical and histopathological findings of both hepatoblastoma and hepatocellular carcinoma.
    TERT mutations were observed in two of four cases tested.[1TERT mutations are also commonly observed in adults with hepatocellular carcinoma.[8]
To date, these genetic mutations have not been used to select therapeutic agents for investigation in clinical trials.
(Refer to the PDQ summary on Childhood Liver Cancer Treatment for information about the treatment of liver cancer.)
  1. Eichenmüller M, Trippel F, Kreuder M, et al.: The genomic landscape of hepatoblastoma and their progenies with HCC-like features. J Hepatol 61 (6): 1312-20, 2014. [PUBMED Abstract]
  2. Trevino LR, Wheeler DA, Finegold MJ, et al.: Exome sequencing of hepatoblastoma reveals recurrent mutations in NFE2L2. [Abstract] Cancer Res 73 (8 Suppl): A-4592, 2013. Also available onlineExit Disclaimer. Last accessed October 25, 2019.
  3. Jia D, Dong R, Jing Y, et al.: Exome sequencing of hepatoblastoma reveals novel mutations and cancer genes in the Wnt pathway and ubiquitin ligase complex. Hepatology 60 (5): 1686-96, 2014. [PUBMED Abstract]
  4. Hiyama E, Kurihara S, Onitake Y: Integrated exome analysis in childhood hepatoblastoma: Biological approach for next clinical trial designs. [Abstract] Cancer Res 74 (19 Suppl): A-5188, 2014.
  5. Vilarinho S, Erson-Omay EZ, Harmanci AS, et al.: Paediatric hepatocellular carcinoma due to somatic CTNNB1 and NFE2L2 mutations in the setting of inherited bi-allelic ABCB11 mutations. J Hepatol 61 (5): 1178-83, 2014. [PUBMED Abstract]
  6. Haines K, Sarabia SF, Alvarez KR, et al.: Characterization of pediatric hepatocellular carcinoma reveals genomic heterogeneity and diverse signaling pathway activation. Pediatr Blood Cancer 66 (7): e27745, 2019. [PUBMED Abstract]
  7. Honeyman JN, Simon EP, Robine N, et al.: Detection of a recurrent DNAJB1-PRKACA chimeric transcript in fibrolamellar hepatocellular carcinoma. Science 343 (6174): 1010-4, 2014. [PUBMED Abstract]
  8. Nault JC, Mallet M, Pilati C, et al.: High frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions. Nat Commun 4: 2218, 2013. [PUBMED Abstract]



The genomic landscape of osteosarcoma is distinctive from that of other childhood cancers. It is characterized by an exceptionally high number of structural variants with relatively small numbers of single nucleotide variants compared with many adult cancers.[1,2]
Key observations regarding the genomic landscape of osteosarcoma are summarized below:
  • The number of structural variants observed for osteosarcoma is very high, at more than 200 structural variants per genome;[1,2] thus, osteosarcoma has the most chaotic genome among childhood cancers. The Circos plots shown in Figure 6 illustrate the exceptionally high numbers of intra- and inter-chromosomal translocations that typify osteosarcoma genomes.
    ENLARGEDiagrams of osteosarcoma cases from the NCI TARGET project.
    Figure 6. Circos plots of osteosarcoma cases from the National Cancer Institute's Therapeutically Applicable Research to Generate Effective Treatments (TARGET) project. The red lines in the interior circle connect chromosome regions involved in either intra- or inter-chromosomal translocations. Osteosarcoma is distinctive from other childhood cancers because it has a large number of intra- and inter-chromosomal translocations. Credit: National Cancer Institute.
  • The number of mutations per osteosarcoma genome that affect protein sequence (approximately 25 per genome) is higher than that of some other childhood cancers (e.g., Ewing sarcoma and rhabdoid tumors) but is far below that for adult cancers such as melanoma and non-small cell lung cancer.[1,2]
  • Genomic alterations in TP53 are present in most osteosarcoma cases, with a distinctive form of TP53 inactivation occurring by structural variations in the first intron of TP53 that lead to disruption of the TP53 gene.[1] Other mechanisms of TP53 inactivation are also observed, including missense and nonsense mutations and deletions of the TP53 gene.[1,2] The combination of these various mechanisms for loss of TP53 function leads to biallelic inactivation in most cases of osteosarcoma.
  • MDM2 amplification is observed in a minority of osteosarcoma cases (approximately 5%) and provides another mechanism for loss of TP53 function.[1,2]
  • RB1 is commonly inactivated in osteosarcoma, sometimes by mutation but more commonly by deletion.[1,2]
  • Other genes with recurrent alterations in osteosarcoma include ATRX and DLG2.[1] Additionally, pathway analysis showed that the PI3K/mammalian target of rapamycin (mTOR) pathway was altered by mutation/loss/amplification in approximately one-fourth of patients, with PTEN mutation/loss being the most common alteration.[2]
  • The range of mutations reported for osteosarcoma tumors at diagnosis do not provide obvious therapeutic targets, as they primarily reflect loss of tumor suppressor genes (e.g., TP53RB1PTEN) rather than activation of targetable oncogenes.
Several germline mutations are associated with susceptibility to osteosarcoma; Table 5 summarizes the syndromes and associated genes for these conditions.
Mutations in TP53 are the most common germline alterations associated with osteosarcoma. Mutations in this gene are found in approximately 70% of patients with Li-Fraumeni syndrome (LFS), which is associated with increased risk of osteosarcoma, breast cancer, various brain cancers, soft tissue sarcomas, and other cancers. While rhabdomyosarcoma is the most common sarcoma arising in patients aged 5 years and younger with TP53-associated LFS, osteosarcoma is the most common sarcoma in children and adolescents aged 6 to 19 years.[3] One study observed a high frequency of young osteosarcoma cases (age <30 years) carrying a known LFS-associated or likely LFS-associated TP53 mutation (3.8%) or rare exonic TP53 variant (5.7%), with an overall TP53 mutation frequency of 9.5%.[4] Another study observed germline TP53 mutations in 7 of 59 osteosarcoma cases (12%) subjected to whole-exome sequencing.[2] Other groups have reported lower rates (3%–7%) of TP53 germline mutations in patients with osteosarcoma.[5,6]
Table 5. Genetic Diseases That Predispose to Osteosarcomaa
AML = acute myeloid leukemia; IL-1 = interleukin-1; MDS = myelodysplastic syndrome; RANKL = receptor activator of nuclear factor kappa beta ligand; TNF = tumor necrosis factor.
aAdapted from Kansara et al.[7]
Bloom syndrome [8]Rare inherited disorder characterized by short stature and sun-sensitive skin changes. Often presents with a long, narrow face, small lower jaw, large nose, and prominent ears.15q26.1BLM (RecQL3)DNA helicase
Diamond-Blackfan anemia [9]Inherited pure red cell aplasia. Patients at risk for MDS and AML. Associated with skeletal abnormalities such as abnormal facial features (flat nasal bridge, widely spaced eyes). Ribosomal proteinsRibosome production [9,10]
Li-Fraumeni syndrome [11]Inherited mutation in TP53 gene. Affected family members at increased risk of bone tumors, breast cancer, leukemia, brain tumors, and sarcomas.17p13.1P53DNA damage response
Paget disease [12]Excessive breakdown of bone with abnormal bone formation and remodeling, resulting in pain from weak, malformed bone.18q21-qa22LOH18CR1IL-1/TNF signaling; RANKL signaling pathway
Retinoblastoma [13]Malignant tumor of the retina. Approximately 66% of patients are diagnosed by age 2 years and 95% of patients by age 3 years. Patients with heritable germ cell mutations at greater risk of subsequent neoplasms.13q14.2RB1Cell-cycle checkpoint
Rothmund-Thomson syndrome (also called poikiloderma congenitale) [14,15]Autosomal recessive condition. Associated with skin findings (atrophy, telangiectasias, pigmentation), sparse hair, cataracts, small stature, and skeletal abnormalities. Increased incidence of osteosarcoma at a younger age.8q24.3RTS (RecQL4)DNA helicase
Werner syndrome [16]Patients often have short stature and in their early twenties, develop signs of aging, including graying of hair and hardening of skin. Other aging problems such as cataracts, skin ulcers, and atherosclerosis develop later.8p12-p11.2WRN (RecQL2)DNA helicase; exonuclease activity
Refer to the following PDQ summaries for more information about these genetic syndromes:
(Refer to the PDQ summary on Osteosarcoma and Malignant Fibrous Histiocytoma Treatment for information about the treatment of osteosarcoma.)

Ewing Sarcoma

The detection of a translocation involving the EWSR1 gene on chromosome 22 band q12 and any one of a number of partner chromosomes is the key feature in the diagnosis of Ewing sarcoma (refer to Table 6).[17] The EWSR1 gene is a member of the TET family [TLS/EWS/TAF15] of RNA-binding proteins.[18] The FLI1 gene is a member of the ETS family of DNA-binding genes. Characteristically, the amino terminus of the EWSR1 gene is juxtaposed with the carboxy terminus of the STS family gene. In most cases (90%), the carboxy terminus is provided by FLI1, a member of the family of transcription factor genes located on chromosome 11 band q24. Other family members that may combine with the EWSR1 gene are ERGETV1ETV4 (also termed E1AF), and FEV.[19] Rarely, TLS, another TET family member, can substitute for EWSR1.[20] Finally, there are a few rare cases in which EWSR1 has translocated with partners that are not members of the ETS family of oncogenes. The significance of these alternate partners is not known.
Besides these consistent aberrations involving the EWSR1 gene at 22q12, additional numerical and structural aberrations have been observed in Ewing sarcoma, including gains of chromosomes 2, 5, 8, 9, 12, and 15; the nonreciprocal translocation t(1;16)(q12;q11.2); and deletions on the short arm of chromosome 6. Trisomy 20 may be associated with a more aggressive subset of Ewing sarcoma.[21]
Three papers have described the genomic landscape of Ewing sarcoma and all show that these tumors have a relatively silent genome, with a paucity of mutations in pathways that might be amenable to treatment with novel targeted therapies.[22-24] These papers also identified mutations in STAG2, a member of the cohesin complex, in about 15% to 20% of the cases, and the presence of these mutations was associated with advanced-stage disease. CDKN2A deletions were noted in 12% to 22% of cases. Finally, TP53 mutations were identified in about 6% to 7% of cases and the coexistence of STAG2 and TP53 mutations is associated with a poor clinical outcome.[22-24]
Figure 7 below from a discovery cohort (n = 99) highlights the frequency of chromosome 8 gain, the co-occurrence of chromosome 1q gain and chromosome 16q loss, the mutual exclusivity of CDKN2A deletion and STAG2 mutation, and the relative paucity of recurrent single nucleotide variants for Ewing sarcoma.[22]
ENLARGEChart showing a comprehensive profile of the genetic abnormalities in Ewing sarcoma and associated clinical information.
Figure 7. A comprehensive profile of the genetic abnormalities in Ewing sarcoma and associated clinical information. Key clinical characteristics are indicated, including primary site, type of tissue, and metastatic status at diagnosis, follow-up, and last news. Below is the consistency of detection of gene fusions by RT-PCR and whole-genome sequencing (WGS). The numbers of structural variants (SV) and single-nucleotide variants (SNV) as well as indels are reported in grayscale. The presence of the main copy-number changes, chr 1q gain, chr 16 loss, chr 8 gain, chr 12 gain, and interstitial CDKN2A deletion is indicated. Listed last are the most significant mutations and their types. For gene mutations, “others” refers to: duplication of exon 22 leading to frameshift (STAG2), deletion of exon 2 to 11 (BCOR), and deletion of exons 1 to 6 (ZMYM3). Reprinted from Cancer Discovery, Copyright 2014, 4 (11), 1342–53, Tirode F, Surdez D, Ma X, et al., Genomic Landscape of Ewing Sarcoma Defines an Aggressive Subtype with Co-Association of STAG2 and TP53 mutations, with permission from AACR.
Ewing sarcoma translocations can all be found with standard cytogenetic analysis. A more rapid analysis looking for a break apart of the EWS gene is now frequently done to confirm the diagnosis of Ewing sarcoma molecularly.[25] This test result must be considered with caution, however. Ewing sarcomas that utilize the TLS translocations will have negative tests because the EWSR1 gene is not translocated in those cases. In addition, other small round tumors also contain translocations of different ETS family members with EWSR1, such as desmoplastic small round cell tumor, clear cell sarcoma, extraskeletal myxoid chondrosarcoma, and myxoid liposarcoma, all of which may be positive with a EWS fluorescence in situ hybridization (FISH) break-apart probe. A detailed analysis of 85 patients with small round blue cell tumors that were negative for EWSR1 rearrangement by FISH with an EWSR1 break-apart probe identified eight patients with FUS rearrangements.[26] Four patients who had EWSR1-ERG fusions were not detected by FISH with an EWSR1 break-apart probe. The authors do not recommend relying solely on EWSR1 break-apart probes for analyzing small round blue cell tumors with strong immunohistochemical positivity for CD99.
Undifferentiated small blue round cell sarcomas with the EWSR1-NFATc2 fusion have been studied with DNA methylation profiling; this revealed a homogeneous methylation cluster for these sarcomas with EWSR1-NFATc2 fusions, which clearly segregated them from the more common form of Ewing sarcoma with EWS-ETS translocations.[27]
Small round blue cell tumors of bone and soft tissue that are histologically similar to Ewing sarcoma but do not have rearrangements of the EWSR1 gene have been analyzed and translocations have been identified. These include BCOR-CCNB3CIC-DUX4, and CIC-FOX4.[28-31] The molecular profile of these tumors is different from the profile of EWS-FLI1 translocated Ewing sarcoma, and limited evidence suggests that they have a different clinical behavior. In almost all cases, the patients were treated with therapy designed for Ewing sarcoma on the basis of the histologic and immunohistologic similarity to Ewing sarcoma (refer to the Undifferentiated Round Cell Sarcomas With BCOR-CCNB3 Rearrangements and Undifferentiated Round Cell Sarcomas With CIC-DUX4 Rearrangements sections of this summary for more information). There are too few cases associated with each translocation to determine whether the prognosis for these small round blue cell tumors is distinct from the prognosis of Ewing sarcoma of similar stage and site.[28-31]
Some undifferentiated round cell sarcomas are characterized by paracentric inversion of chromosome X and a BCOR-CCNB3 rearrangement; alternative BCOR partners, including MAML3 and ZC3H7B, have also been reported.[32] Despite clinical pathologic similarities to Ewing sarcoma, these tumors are biologically different by expression profiling and single-nucleotide polymorphism array analysis. (Refer to the Undifferentiated Round Cell Sarcomas With BCOR-CCNB3 Rearrangements section of this summary for more information about the treatment of this disease.)
Other undifferentiated round cell sarcomas are characterized by a CIC-DUX4 fusion resulting from a recurrent t(4;19) or t(10;19) and are the most common EWSR1-FUS fusion–negative undifferentiated round cell sarcomas.[33] (Refer to the Undifferentiated Round Cell Sarcomas With CIC-DUX4 Rearrangements section of this summary for more information about the treatment of this disease.)
Genome-wide association studies have identified susceptibility loci for Ewing sarcoma at 1p36.22, 10q21, and 15q15.[34-36] Deep sequencing through the 10q21.3 region identified a polymorphism in the EGR2 gene, which appears to cooperate with and magnify the enhanced activity of the gene product of the EWSR1-FLI1 fusion that is seen in most patients with Ewing sarcoma.[35] The polymorphism associated with the increased risk is found at a much higher frequency in whites than in blacks or Asians, possibly contributing to the epidemiology of the relative infrequency of Ewing sarcoma in the latter populations. Three new susceptibility loci have been identified at 6p25.1, 20p11.22, and 20p11.23.[36]
Table 6. EWS and TLS Fusions and Translocations in Ewing Sarcoma
TET Family PartnerFusion With ETS-like Oncogene PartnerTranslocationComment
aThese partners are not members of the ETS family of oncogenes.
EWSEWSR1-FLI1t(11;22)(q24;q12)Most common; ~85% to 90% of cases
EWSR1-ERGt(21;22)(q22;q12)Second most common; ~10% of cases
TLS (also called FUS)TLS-ERGt(16;21)(p11;q22)Rare
(Refer to the PDQ summary on Ewing Sarcoma Treatment for information about the treatment of Ewing sarcoma.)


The embryonal and alveolar histologies have distinctive molecular characteristics that have been used for diagnostic confirmation, and may be useful for assigning risk group, determining therapy, and monitoring residual disease during treatment.[37-41]
  1. Embryonal histology: Embryonal tumors often show loss of heterozygosity at 11p15 and gains on chromosome 8.[42-44] Embryonal tumors have a higher background mutation rate and a higher single-nucleotide variant rate than do alveolar tumors, and the number of somatic mutations increases with older age at diagnosis.[45,46] Genes with recurring mutations include those in the RAS pathway (e.g., NRASKRASHRAS, and NF1), which together are observed in approximately one-third of cases. Other genes with recurring mutations include FGFR4PIK3CACTNNB1FBXW7, and BCOR, all of which are present in fewer than 10% of cases.[45,46]
    Embryonal histology with anaplasia: Anaplasia has been reported in a minority of children with rhabdomyosarcoma, primarily arising in children with the embryonal subtype who are younger than 10 years.[47,48] Rhabdomyosarcoma with nonalveolar anaplastic morphology may be a presenting feature for children with Li-Fraumeni syndrome and germline TP53 mutations.[49] Among eight consecutively presenting children with rhabdomyosarcoma and TP53 germline mutations, all showed anaplastic morphology. Among an additional seven children with anaplastic rhabdomyosarcoma and unknown TP53 germline mutation status, three of the seven children had functionally relevant TP53 germline mutations. The median age at diagnosis of the 11 children with TP53 germline mutation status was 40 months (range, 19–67 months).
  2. Alveolar histology: About 70% to 80% of alveolar tumors are characterized by translocations between the FOXO1 gene on chromosome 13 and either the PAX3 gene on chromosome 2 (t(2;13)(q35;q14)) or the PAX7 gene on chromosome 1 (t(1;13)(p36;q14)).[37,42,50] Other rare fusions include PAX3-NCOA1 and PAX3-INO80D.[45] Translocations involving the PAX3 gene occur in approximately 59% of alveolar rhabdomyosarcoma cases, while the PAX7 gene appears to be involved in about 19% of cases.[37] Patients with solid-variant alveolar histology have a lower incidence of PAX-FOXO1 gene fusions than do patients showing classical alveolar histology.[51] For the diagnosis of alveolar rhabdomyosarcoma, FOXO1 gene rearrangement may be detected with good sensitivity and specificity using either fluorescence in situ hybridization or reverse transcription–polymerase chain reaction.[52]
    The alveolar histology that is associated with the PAX7 gene in patients with or without metastatic disease appears to occur at a younger age and may be associated with longer event-free survival rates than those associated with PAX3 gene rearrangements.[53-58] Patients with alveolar histology and the PAX3 gene are older and have a higher incidence of invasive tumor (T2). Around 22% of cases showing alveolar histology have no detectable PAX gene translocation.[41,51] In addition to FOXO1 rearrangements, alveolar tumors are characterized by a lower mutational burden than are fusion-negative tumors, with fewer genes having recurring mutations.[45,46BCOR and PIK3CA mutations and amplification of MYCNMIR17HG, and CDK4 have also been described.
  3. Spindle cell/sclerosing histology: Spindle cell/sclerosing rhabdomyosarcoma has been proposed as a separate entity in the World Health Organization Classification of Tumors of Soft Tissue and Bone.[59] For congenital/infantile spindle cell rhabdomyosarcoma, a study reported that 10 of 11 patients showed recurrent fusion genes. Most of these patients had truncal primary tumors, and no paratesticular tumors were found. Novel VGLL2 rearrangements were observed in seven patients (63%), including the VGLL2-CITED2 fusion in four patients and the VGLL2-NCOA2 fusion in two patients.[60] Three patients (27%) harbored different NCOA2 gene fusions, including TEAD1-NCOA2 in two patients and SRF-NCOA2 in one patient. All fusion-positive congenital/infantile spindle cell rhabdomyosarcoma patients with available long-term follow-up were alive and well, and no patients developed distant metastases.[60] Further study is needed to better define the prevalence and prognostic significance of these gene rearrangements in young children with spindle cell rhabdomyosarcoma.
    In older children and adults with spindle cell/sclerosing rhabdomyosarcoma, a specific MYOD1 mutation (p.L122R) has been observed in a large proportion of patients.[60-63] Activating PIK3CA mutations are seen in about one-half of the cases, and 60% of these cases have pure sclerosing morphology.[64] The presence of the MYOD1 mutation is associated with an increased risk of local and distant failure.[60-62] In one study that included 15 children with MYOD1-mutant tumors, the most common primary site was the head and neck region.[65] These patients had sclerosing spindle or mixed histology, and 10 of 15 patients died of disease despite aggressive multimodal therapy.
These findings highlight the important differences between embryonal and alveolar tumors. Data demonstrate that PAX-FOX01 fusion–positive alveolar tumors are biologically and clinically different from fusion-negative alveolar tumors and embryonal tumors.[41,66-69] In a study of Intergroup Rhabdomyosarcoma Study Group patients, which captured an entire cohort from a single prospective clinical trial, the outcome for patients with translocation-negative alveolar rhabdomyosarcoma was better than that observed for translocation-positive patients. The outcome was similar to that seen in patients with embryonal rhabdomyosarcoma and demonstrated that fusion status is a critical factor for risk stratification in pediatric rhabdomyosarcoma.
Genome-wide methylation assays can accurately identify PAX3 and PAX7 fusion–positive rhabdomyosarcomas, as well as wild-type and RAS mutant fusion–negative tumors.[70]
(Refer to the PDQ summary on Childhood Rhabdomyosarcoma Treatment for information about the treatment of childhood rhabdomyosarcoma.)
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