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A child with neuroblastoma and metachronous anaplastic sarcoma of the kidney: Underlying DICER1 syndrome?

To the Editor: Approximately 10% of pediatric cancer patients harbor a germline variant in cancer predisposition genes.1,2 DICER1 syndrome (OMIM #601200), caused by pathogenic germline variants in DICER1, predisposes individuals to the development of various benign and malignant tumors.3-6 A recently described phenotype is anaplastic sarcoma of the kidney (ASK).7-12 For other conditions, for example neuroblastoma, the association with DICER1 syndrome appears to be uncertain. We present the case of a child who manifested with a neuroblastoma and 6 years later developed an ASK. Given the development of two tumors at a young age, an underlying cancer predisposition syndromewas suspected.We thoughtDICER1syndromemight bepresent because of the ASK. However, given the genetic results, the possibility that the ASK arose as a consequence of the neuroblastoma treatment was considered. A 7-year-old boy with no family history of DICER1-associated phenotypes in 23 known relatives presented with abdominal distension, severe pain, and poor oral intake. CT scan revealed a right adrenal mass, and elevated urine catecholamine levels were detected. A biopsy revealed a poorly differentiated neuroblastoma positive for chromogranin, CD56, and synaptophysin. Given the age, the unfavorable histology and the presence of tibial and rib metastasis, the neuroblastoma was classified as high risk.13-15 Accordingly, the child received chemotherapy along with surgery, autologous bone marrow transplant, local radiotherapy, and immunotherapy (ANBL0032 protocol). Histopathological review of the resected adrenal mass showed a small round blue cell Schwannian stroma-poor tumor, composed of undifferentiated neuroblasts with few foci of neuropil, <5% of maturing/mature ganglion cells, and low mitotic karyorrhectic index (Figure S1). Immunohistochemistry for PHOX2B confirmed the diagnosis of neuroblastoma (Figure S1). Five years after treatment completion, he presented with fever and abdominal pain, and a cystic solid right renal mass was found. Workup for neuroblastoma recurrence was negative and nephrectomy was performed. The tumor was confined to the kidney, and lymph nodes were negative. It was largely composed of small and spindle undifferentiatedmesenchymal cells, with rare areas of anaplasia and extensive chondroid differentiation (Figure S1). The diagnosis of ASK was made. The patient is currently healthy. The study was approved by theMcGill Faculty of Medicine Institutional Review Board (A08-M61-09B) and informed consent was obtained. Germline and tumor DNA was subjected to genetic screening. No pathogenic germline variant, complete exon deletion or gain inDICER1 was detected in the proband’s germline DNA. Only oneDICER1 coding variant (c.4891T>G; p.S1631A) was detected in heterozygosity in the child, hismother, and hismaternal half-brother. Classification using the American College of Medical Genetics guidelines16 deemed the variant to be likely benign (Figure S2).Moreover, subsequent cDNAstudies (see below) supported this classification of the variant and made it an unlikely candidate to cause DICER1 syndrome. In addition, 52 pediatric cancer predisposing genes (including DICER1 and familial neuroblastoma genes ALK and PHOX2B) were screened using an Invitae tumor panel and no pathogenic alterations were detected. DICER1 screening performed in tumorDNA revealed oneRNase IIIb hotspot mutation (c.5439G>T; p.E1813D) and loss-of-heterozygosity (LOH) in the ASK (Figure 1A); whereas in the neuroblastoma, no pathogenic DICER1 mutation was found. cDNA sequencing confirmed that only one allele was expressed in ASK, carrying c.4891G and c.5439T. As both neuroblastomas and sarcomas are characterized by the presence of chromosomal alterations, genome-wide copy number and LOHprofiles were analyzed using anOncoScan assay. The neuroblastoma showed high-level amplification in 2p24 containing theMYCN gene, loss in 1p36, and gain in 17q, typical aberrations found in highrisk neuroblastomas (Figure 1B, Table S1). No imbalances or copyneutral changes were observed for the region containing DICER1. For the ASK, several deletions were observed, including loss in 17p11-13 containing the TP53 gene and loss in 14q21-32 encompassing DICER1 (Figure 1C, Table S2). We have here described the case of a child who developed two different tumors, both of which have been associated with inherited susceptibility but here none was found. The analysis of tumor DNA revealed twoDICER1 alterations inASK. These somatic results are concordant with previous studies, as most ASKs reported harbor DICER1 mutations,7-11 and stress that the identification of an ASK should raise suspicion of DICER1 mutations even in the absence of DICER1 syndrome. Regarding neuroblastoma, the link with DICER1 is not clear. Although various somatic and germline alterations have been proven to play a role in its pathogenesis17,18; only two patients with DICER1 syndrome have been previously described to develop neuroblastomas and in both cases, the tumor lacked somatic RNase IIIb mutations.19,20 These observations, coupled with genetic analyses of large series