Rothmund-Thomson syndrome (RTS) is a rare inherited, chromosomal instability syndrome belonging to the RecQ family of helicase disorders, and is characterized by skin rash, skeletal abnormalities, small stature, juvenile cataracts, and a significant cancer predisposition, particularly for osteosarcoma. The hypothesis of this study is that detailed study of rare cancer predisposition syndromes, such as RTS, will provide significant new insights into the molecular basis of genomic stability and the etiology of both inherited and sporadic cancers. The broad objectives of this project are to understand the molecular, clinical, and cellular features of RTS. The clinical findings will have implications in many areas of pediatrics, including genetics, dermatology, ophthalmology, and oncology. The molecular and cellular findings will contribute to understanding of other related chromosome instability syndromes and may lead to an assay for the diagnosis of RTS. The first specific aim involves comprehensive molecular analysis coupled with detailed clinical description of RTS patients enrolled in an IRB-approved General Clinical Research Center study at Baylor College of Medicine (BCM). Screening for mutations in the RECQL4 gene will be performed by sequencing of genomic DNA and DHPLC screening of cDNA in probands. Genotype/phenotype associations will be generated from clinical and molecular data. The second specific aim will involve investigation of the presently unknown cellular defects in RTS. The response of RTS cells to a variety of agents that cause DNA damage or replication blocks will be analyzed with respect to sensitivity and cell cycle progression. Understanding the basic helicase defect through study of paradigm disorders such as RTS may provide insight into mechanisms of cancer pathogenesis and may have important clinical implications in the management of these patients. This Mentored Clinical Scientist Development Award would serve as a vehicle to allow the candidate to accomplish her immediate training goals in a mentored scientific environment, and to reach the candidate's long-term career goals as a physician-scientist in pediatric oncology. The mentor and the superb facilities and resources at BCM will provide the ideal environment for the candidate during the period covered by the K08 award. This experience will provide the foundation upon which to build the candidate's career as an independent investigator.
