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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA143167-08
Application #
9553495
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Johnson, Ronald L
Project Start
2010-01-01
Project End
2021-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
8
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Children's Research Institute
Department
Type
DUNS #
143983562
City
Washington
State
DC
Country
United States
Zip Code
20010
Huryn, Laryssa A; Turriff, Amy; Harney, Laura A et al. (2018) DICER1 Syndrome: Characterization of the Ocular Phenotype in a Family-Based Cohort Study. Ophthalmology :
Khan, Nicholas E; Ling, Alexander; Raske, Molly E et al. (2018) Structural renal abnormalities in the DICER1 syndrome: a family-based cohort study. Pediatr Nephrol 33:2281-2288
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
Li, Yunjie; Pawel, Bruce R; Hill, Dana A et al. (2017) Pediatric Cystic Nephroma Is Morphologically, Immunohistochemically, and Genetically Distinct From Adult Cystic Nephroma. Am J Surg Pathol 41:472-481
Khan, Nicholas E; Bauer, Andrew J; Schultz, Kris Ann P et al. (2017) Quantification of Thyroid Cancer and Multinodular Goiter Risk in the DICER1 Syndrome: A Family-Based Cohort Study. J Clin Endocrinol Metab 102:1614-1622
Kim, Jung; Field, Amanda; Schultz, Kris Ann P et al. (2017) The prevalence of DICER1 pathogenic variation in population databases. Int J Cancer 141:2030-2036
Schultz, Kris Ann P; Harris, Anne K; Finch, Michael et al. (2017) DICER1-related Sertoli-Leydig cell tumor and gynandroblastoma: Clinical and genetic findings from the International Ovarian and Testicular Stromal Tumor Registry. Gynecol Oncol 147:521-527
Dehner, Louis P; Messinger, Yoav H; Williams, Gretchen M et al. (2017) Type I Pleuropulmonary Blastoma versus Congenital Pulmonary Airway Malformation Type IV. Neonatology 111:76
Stewart, Douglas R; Givens, Shannon S; Harris, Anne K et al. (2016) Comment on: DICER1-Negative Pleuropulmonary Blastoma in a Patient With Selective IgA Deficiency. Pediatr Blood Cancer 63:1869-70
Schultz, Kris Ann P; Harris, Anne K; Schneider, Dominik T et al. (2016) Ovarian Sex Cord-Stromal Tumors. J Oncol Pract 12:940-946

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