Pleuropulmonary blastoma (PPB) is the most common lung cancer of childhood, and usually the earliest indication 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. Early detection is imperative for survival in children with PPB. When discovered in its earliest, cystic stage, called Type I PPB, 91% of children diagnosed and treated for Type I PPB survive. The outcomes for children with cystic and solid (Type II) and purely solid (Type III) PPB are significantly worse despite surgery and intensive multidrug chemotherapy. About half of children with Type III PPB survive long-term. There are no effective treatments for refractory or recurrent disease. Late diagnosis and the resistance to therapy are the two major barriers to improving survivals of children with PPB. Genetic pathogenesis in DICER1 syndrome is unique, and it suggests a solution to the detection problems that hinder clinical management. From sequencing studies in over 200 cases of PPB and other DICER1 syndrome cancers, we know that virtually all carry a second DICER1 mutation, acquired somatically during early development. We propose to develop DICER-Dx, a panel of droplet digital PCR (ddPCR) assays for the detection and quantification of DICER1 hotspot mutations, which are specifically, and invariably, associated with DICER1 syndrome cancers. DICER-Dx will be the first non- invasive biomarker assay for DICER1 syndrome cancers. It has the potential to transform standards of care for PPB and DICER1 syndrome by: 1) Improving the specificity and sensitivity of surveillance for tumor emergence in children at risk, while reducing or eliminating the need for CT scans and the attendant risks from radiation exposure and sedation; 2) Clarifying the differential diagnosis of Type I PPB vs. benign lung cysts discovered in imaging studies; 3) Guiding treatment decisions for children with PPB or other DICER1 syndrome tumors, e.g., whether or not adjuvant chemotherapy is needed after surgical removal of Type I PPB; 4) Monitoring for recurrence following chemotherapy; and 5) Evaluating tumor response to therapy. DICER-Dx may be useful not only in monitoring response to therapy in children with tumors, but also in preclinical mouse models. DICER1-Dx sample collection and testing will be an essential component of treatment and biology studies for the International PPB Registry.
An estimated 1 in 3000 individuals carry germline mutations in DICER1 which is associated with predisposition to a group of childhood cancers. In this Phase I SBIR, ResourcePath plans to develop a diagnostic blood test that can detect the earliest development of cancer or recurrence in children with cancers associated with DICER1 mutations. Detecting tumors earlier when they are most responsive to therapy will improve survival for pleuropulmonary blastoma and related tumors such as rhabdomyosarcoma, Sertoli-Leydig cell tumors, and Wilms tumor.
