DICER-Dx: The First Liquid Biopsy for Early Detection and Monitoring of DICER1 Syndrome Pediatric Cancers

PROJECT SUMMARY/ABSTRACTPleuropulmonary blastoma (PPB) is the most common lung cancer of childhood, and the most common manifestation of DICER1 syndrome; a genetic predisposition to early-onset embryonal tumors of multiple organ sites. The syndrome is defined by germline mutations in the DICER1 gene (OMIM #606241). In addition to PPB, the spectrum of syndromic neoplasias includes ovarian Sertoli-Leydig cell tumor, cystic nephroma and renal sarcoma or Wilms tumor, embryonal rhabdomyosarcoma, nodular hyperplasia and carcinoma of the thyroid gland, nasal chondromesenchymal hamartoma, pituitary blastoma and pineoblastoma. PPB diagnosed in its earliest, cystic stage, called Type I, is treated by surgical resection with or without adjuvant chemotherapy. There is no reliable way to distinguish patients who will recur without adjuvant therapy from those who would not. More advanced PPB (Type II or Type III) is treated by surgery plus a standard multidrug chemotherapy regime. Tumor resistance to standard chemotherapy indicates more intense treatments, but currently, response to therapy can be assessed only by imaging studies, which have limited sensitivity. Lack of an effective test for residual disease or therapy resistance is a major barrier to improving the survivals of children with PPB and results in unnecessary treatment-related morbidities.Genetic pathogenesis in DICER1 syndrome is unique and offers a solution to the detection problems that hinder clinical management. From tumor sequencing studies, we know that virtually all DICER1 syndrome cancers carry a second, somatically acquired DICER1 mutation. These are invariably missense mutations, restricted to just five codons of the gene; the DICER1 hotspot mutations. The hotspot mutations are promising as potential biomarkers because they are so unambiguously associated with DICER1 syndrome cancers.ResourcePath, LLC is developing DICER-Dx, the first biomarker assay for DICER1 syndrome cancers. DICER-Dx is a panel of droplet digital PCR (ddPCR) assays for ultra-sensitive detection of DICER1 hotspot mutations in circulating tumor DNA (ctDNA). It has the potential to transform standards of care for children with DICER1 syndrome cancers by: 1) Clarifying the differential diagnosis of Type I PPB vs. benign lung cysts; 2) Guiding treatment decisions for children with PPB or other DICER1 syndrome tumors, e.g., by detecting occult residual disease after surgical removal of Type I PPB; 3) Monitoring tumor response to standard chemotherapy for Type II/III PPB so that timely changes in treatment can be made if needed, and; 4) Enabling early detection of any disease recurrence after treatment is completed. DICER1-Dx testing for ctDNA will become an essential component of treatment and biology studies conducted by the International PPB Registry. DICER-Dx assays will also become an indispensable tool to assess the efficacy of new therapeutics for DICER1 syndrome cancers in preclinical research and clinical trials.Project Narrative Pleuropulmonary blastoma (PPB) is the most common lung cancer of childhood. Only half of children with advanced PPB survive. The inability to detect minimal residual disease and evaluate resistance to standard therapy in real-time are major barriers to improving survival. ResourcePath is developing an ultrasensitive blood biomarker test that will address these problems in a manner that is safer, more effective and less costly than CT scans.