Studies of inherited cancer syndromes have provided unique opportunities to uncover and explain important cellular pathways with broad relevance to both sporadic cancers and human development. This proposal studies the cancer predisposition syndrome originally described as a familial form of pleuropulmonary blastoma (PPB). PPB is an aggressive lung cancer that affects young children. Children with PPB and/or their family members are at increased risk for a number of conditions, including Wilms tumor, rhabdomyosarcoma, brain tumors, ovarian tumors and nodular hyperplasia of the thyroid gland. In 2009, we mapped a PPB locus and identified germline, loss of function mutations in one copy of DICER1 as a risk for developing PPB. DICER1 encodes a protein that performs the final critical step in maturation of microRNAs (miRNAs). miRNAs are an important form of gene regulation. Sequencing studies have revealed a unique pattern of mutations in both copies of the DICER1 gene in tumors. Generally, one copy of DICER1 has complete loss of function, while the other copy has a mutation that prohibits DICER1 from cleaving an important subclass of miRNAs. Tumors are deficient in miRNAs that serve as the brakes for the genes responsible for rapid growth of the embryo during gestation, so-called oncofetal genes.
In Aim 1 of this proposal we will determine the critical oncogenes needed for PPB cell survival through which we hope to also gain insight into the normal suppression of tumorigenesis during human development.
In Aim 2 we propose to replace deficient miRNAs (let-7 and others) to restore natural regulation of this developmental program and push tumor cells into apoptosis or permanent maturation. Specific sub-aims will be development of the first mouse xenograft models of PPB and ovarian Sertoli-Leydig cell tumors, which will be indispensable for preclinical testing, and application of a novel, third generation technology for therapeutic gene silencing known as U1 Adaptors.
Aim 3 will focus on important, unresolved questions regarding the genetic pathogenesis and risk for malignancy in the two most common conditions in DICER1 syndrome mutation carriers, benign thyroid nodules and lung cysts. Conceptually, PPB represents a naturally-occurring, developmental model of embryonal organ-based neoplasia. We hope that understanding the natural controls on this oncofetal gene program can be leveraged into novel therapeutic approaches for PPB and other childhood neoplasms.

Public Health Relevance

This work uses our understanding of the genetics of this pediatric cancer predisposition syndrome to facilitate early detection and design novel, personalized treatments for pleuropulmonary blastoma and related tumors such as rhabdomyosarcoma, Sertoli-Leydig cell tumors, and Wilms tumor.

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National Cancer Institute (NCI)
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Cancer Genetics Study Section (CG)
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Johnson, Ronald L
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Children's Research Institute
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Schultz, Kris Ann P; Williams, Gretchen M; Kamihara, Junne et al. (2018) DICER1 and Associated Conditions: Identification of At-risk Individuals and Recommended Surveillance Strategies. Clin Cancer Res 24:2251-2261
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