Abstract 2021: Wilms tumor and pure erythroid leukemia arising from the same clone in an adolescent
Authors: Villani Anita , Lo Winnie , Li Yisu , Abdelhaleem Mohamed , Shago Mary , Comitani Federico , Thibodeau My Linh , Alexander Sarah , Tabori Uri , Malkin David , Shlien Adam , Brzezinski Jack 
Published: June 2022

Wilms tumor and pure erythroid leukemia (PEL) are distinct malignancies arising from different tissues. Here we describe a case of an adolescent with a constitutional pathogenic BRCA2 variant who was diagnosed with a Wilms tumor and developed PEL while undergoing treatment. We provide evidence that both malignancies are distinct and arose from the same clone. A 16-year-old boy presented with a diffusely anaplastic Wilms tumor metastatic to liver. He was treated with radical nephrectomy, partial hepatectomy, radiation, and multiagent chemotherapy. Six months into treatment he developed new lung and liver lesions along with cytopenias. A bone marrow aspirate confirmed a diagnosis of PEL. His disease progressed after one cycle of myeloid leukemia-directed chemotherapy and he died of disease shortly after. Samples from his initial renal tumor, blood at Wilms tumor diagnosis, and diagnostic bone marrow for PEL were characterized by whole genome sequencing and RNA sequencing. Two sequence variants were shared in both tumors but were not found in the constitutional tissue (blood at first presentation): a promoter variant in TERT (c.-124C&gt;T) and a missense variant in PDE4DIP (p.Gln1045His). Although neither variant has been reported in Wilms tumor or PEL, the TERT variant has been well described in other tumor types and is associated with decreased survival in some carcinomas. Both tumors also had pathogenic TP53 variants albeit a different one in each tumor (p.Arg175His in the Wilms tumor, p.Asp228* in PEL). Loss of heterozygosity at TP53 was present in both malignancies via copy number loss of 17p with a shared breakpoint. Furthermore, while both malignancies had complex and distinct karyotypes, 7p loss and 22q loss with identical breakpoints were present in both. None of these variants or copy number variants were present in constitutional tissue. RNA sequencing data confirmed the histologic finding that these were distinct malignancies as the expression patterns for each malignancy were consistent with previously published expression data for Wilms tumors and myeloid leukemias respectively. Although the patient had a constitutional pathogenic BRCA2 variant, loss of heterozygosity at that locus was not found in either tumor. Chromosome fragility testing for Fanconi anemia was uninterpretable due to the concomitant use of chemotherapeutic agents at the time of testing, however the patient had no phenotypic features to support this diagnosis. In this case there are multiple lines of evidence suggesting that a Wilms tumor and PEL arose from the same clone including shared TERT variants and copy number variant breakpoints. Kidney and hematopoietic tissue both arise from the embryonic mesoderm suggesting that the earliest alterations occurred in this tissue. The contribution of each shared pathogenic variant (TERT, BRCA2, 17p loss) to tumorigenesis and the role of chemotherapy in PEL development are still under investigation.

Citation Format: Anita Villani, Winnie Lo, Yisu Li, Mohamed Abdelhaleem, Mary Shago, Federico Comitani, My Linh Thibodeau, Sarah Alexander, Uri Tabori, David Malkin, Adam Shlien, Jack Brzezinski. Wilms tumor and pure erythroid leukemia arising from the same clone in an adolescent [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2021.