RESUMEN
PURPOSE: DICER1 syndrome is a recently described inherited cancer predisposition syndrome caused by pathogenic variants in DICER1. With the recent increase in integrative clinical sequencing for pediatric patients with cancer, our understanding of the DICER1 syndrome continues to evolve, as new and rare pathogenic variants are reported. As the frequency of integrative clinical sequencing increases, discussions regarding challenges encountered in the interpretation of sequencing results are essential to continue to advance the field of cancer predisposition. The purpose of this work was to identify patients with somatic and/or germline DICER1 variants in our patient population and to discuss sequencing interpretation and the clinical recommendations that result from the integrative clinical sequencing results. METHODS: Patients were enrolled in the PEDS-MIONCOSEQ study. This integrative clinical sequencing study includes paired tumor/normal whole-exome sequencing and tumor transcriptome sequencing. Patients identified as having DICER1 variants were included. RESULTS: We report a DICER1 variant of unknown clinical significance in a patient with a highly unusual response to therapy. Two patients had diagnoses clarified once the integrative clinical sequencing revealing a DICER1 variant was available. We also discovered a patient with low-level DICER1 mosaicism and the challenges encountered in the sequencing interpretation for this patient. In addition to the sequencing data and result interpretation, this work also highlights testing and screening recommendations made to patients with DICER1 variants and their families on the basis of these results. CONCLUSION: This work serves to extend the DICER1 phenotype and advance the utility of clinical integrative sequencing in the fields of pediatric oncology and cancer genetic predisposition.
RESUMEN
Severe congenital neutropenia (SCN) is a rare hematologic disorder characterized by defective myelopoiesis and a high incidence of malignant transformation to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). SCN patients who develop MDS/AML have excessive toxicities to traditional chemotherapy, and safer therapies are needed to improve overall survival in this population. In this report, we outline the use of a prospective integrative clinical sequencing trial (PEDS-MIONCOSEQ) in a patient with SCN and AML to help identify oncogenic targets for less toxic agents. Integrative sequencing identified two somatic cis-mutations in the colony stimulating factor 3 receptor (CSF3R) gene, a p.T640N mutation in the transmembrane region and a p.Q768* truncation mutation in the cytoplasmic domain. A somatic mutation p.H105Y, in the runt homology domain (RHD) of runt-related transcription factor 1 (RUNX1), was also identified. In addition, sequencing discovered a unique in-frame EIF4A2-MECOM (MDS1 and ectopic viral integration site 1 complex) chromosomal translocation with high MECOM expression. His mutations in CSF3R served as potential targets for tyrosine kinase inhibition and therefore provided an avenue to avoid more harmful therapy. This study highlights the utility of integrative clinical sequencing in SCN patients who develop leukemia and outlines a strategy on how to approach these patients in a future clinical sequencing trial to improve historically poor outcomes. A thorough review of leukemia in SCN and the role of CSF3R mutations in oncologic therapy are provided to support a new strategy on how to approach MDS/AML in SCN.