Abstract A01: Novel childhood genitourinary manifestations of <i>DICER1</i> syndrome
Authors: Maria V. Apellaniz-Ruiz, Catherine Goudie, Noelle Cullinan, Elvis T. Valera, Krisztina Z. Hanley, Luiz G. Tone, Paula Marrano, Ronald Grant, W. Glenn McCluggage, Gordan M. Vujanic, Paul S. Thorner, William D. Foulkes
Journal: Cancer Research (2020)

Abstract Pathogenic germline variants in DICER1, a gene encoding an RNase key in microRNA-mediated silencing, cause DICER1 syndrome. This genetic disorder predisposes to the development of a wide array of mainly childhood-onset conditions including genitourinary tumors such as cystic nephroma (CN), anaplastic sarcoma of the kidney, Wilms’ tumor (WT), Sertoli-Leydig cell tumor (SLCT), and cervical embryonal rhabdomyosarcoma (ERMS). As the spectrum of clinical manifestations is not yet fully defined, we sought to explore the involvement of DICER1 mutations in pediatric genitourinary lesions not previously well studied. A series of 31 formalin-fixed, paraffin-embedded tumor samples including 15 paratesticular ERMS (ptERMS), one unclassifiable ovarian sex cord-stromal tumor, one fallopian tube ERMS (ftERMS), six cystic partially differentiated nephroblastomas (CPDN), two cystic WT, two CN, and four rare renal lesions were collected. Median age at diagnosis was 4 years. Tumor DNA was screened for DICER1 variants using Sanger sequencing or a Fluidigm array. Sanger sequencing on tumor DNA was used to validate the variants, and on normal DNA, to determine the germline status. Seven samples harbored biallelic DICER1 mutations and in 6/7 cases, the loss-of-function variant was confirmed to be of germline origin. The paratesticular tumors were initially diagnosed as ERMS, but pathology review reclassified one as an ectomesenchymoma and another as an undifferentiated low-grade myxoid sarcoma. No DICER1 mutation was identified in any of the ptERMS, but the myxoid sarcoma had DICER1 mutations. Interestingly, the patient with the paratesticular myxoid sarcoma also developed a CN. We identified DICER1 mutations in a tumor originally classified as an ovarian WT. Subsequent pathologic evaluation of the lesion led to its reclassification as a retiform SLCT with rhabdomyosarcomatous elements. A typical hotspot and a potential splicing mutation were detected in the ftERMS. Also, two atypical cystic kidney lesions harbored DICER1 mutations: one composed of blastema-type cells expressing nuclear WT1 diagnosed as a CPDN and another unusual multicystic renal lesion considered to be a CN that had moved into a proliferative phase but lacked blastema and anaplastic foci. The patient with the latter renal lesion had previously developed a unilateral CN with a distinct hotspot mutation. As expected, the two classical CN had DICER1 mutations. Based on these results, patients diagnosed with rare genitourinary tumors (except for ptERMS), may have DICER1 syndrome, especially if these individuals have a personal or family history of DICER1-associated lesions. In these cases, surveillance for DICER1-related conditions is advised given that the risk of tumor development is highest in early childhood. In summary, specialist pathology review and DICER1 testing in this setting will lead to improved diagnosis with potential implications for clinical care. Citation Format: Maria V. Apellaniz-Ruiz, Catherine Goudie, Noelle Cullinan, Elvis T. Valera, Krisztina Z. Hanley, Luiz G. Tone, Paula Marrano, Ronald Grant, W. Glenn McCluggage, Gordan M. Vujanic, Paul S. Thorner, William D. Foulkes. Novel childhood genitourinary manifestations of DICER1 syndrome [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A01.