This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ABSTRACT Certain genetic syndromes are known to predispose affected patients to cancer more than the general population. Rothmund-Thomson syndrome (RTS) is one of these cancer syndromes and specifically predisposes patients to developing osteosarcoma (OS), a primary bone tumor that occurs in children and adolescents. Mutations in a gene called RECQL4 accounts for two-thirds of cases of RTS;however, for the other one-third of patients, the gene defect has not yet been discovered. We are interested in studying patients with RTS and related syndromes, as well as patients with atypical forms of OS, in order to understand the molecular mechanisms underlying OS predisposition and pathogenesis. This study would allow the collection of samples and medical information from patients with RTS and related disorders and their family members, as well as from patients with atypical osteosarcoma that may have a genetic basis, so that molecular and genetic studies can be conducted to better understand the primary syndrome (RTS), the predisposition toward cancer development, as well as the molecular pathogenesis of OS. I. HYPOTHESIS Studying rare cancer predisposition syndromes (RTS) both at the clinical and molecular level will provide insight into the pathogenesis of cancer (OS) in the general population. II.
SPECIFIC AIMS Specific Aim 1: Collect and analyze clinical samples from patients affected by RTS and related syndromes and atypical forms of OS as well as their family members. Samples would include blood, tissues (normal and tumor) and body fluids which would be made available to investigators for the purpose of conducting research that will help to define and characterize the underlying genetic defects which cause these inherited disorders and their propensity toward cancer.
Specific Aim 2 : Collect and analyze medical records from patients affected by RTS and related syndromes and atypical forms of OS as well as their family members. Clinical information will allow genotype-phenotype analyses in combination with molecular studies. III. BACKGROUND AND SIGNIFICANCE RTS is a genetic disorder that belongs to a class of familial cancer predisposition syndromes including ataxia-telangiectasia, Fanconi anemia, xeroderma pigmentosum, dyskeratosis congenita, Bloom syndrome, and Werner syndrome. Patients with these disorders all have known genetic defects that place them at an increased risk for certain types of cancers. RTS patients are particularly prone to developing OS, a primary malignant bone tumor. They may also have other clinical features such as poikiloderma, small stature, skeletal defects, sparse or absent scalp hair, eyebrows or lashes, juvenile cataracts, gastrointestinal disturbances, and dental abnormalities. The molecular basis of RTS is known for a subset (approximately 2/3rds) of patients and involves mutation of the RECQL4 gene. The molecular basis for the other 1/3 of patients is not currently known, but likely involves mutation of another gene or genes (genetic heterogeneity). The function of the RECQL4 protein is not fully understood, but it is believed to play a role in DNA replication and in the maintenance of genomic stability. Among RTS patients, those who carry truncating mutations in the RECQL4 gene are at significantly higher risk of developing OS and of having bone defects compared to RTS patients without RECQL4 mutations. Thus the RECQL4 gene pathway is felt to play a role in the pathogenesis of OS and skeletal development. Several other genes, including p53 and RB, are thought to play central roles in the pathogenesis of sporadic OS, and constitutional mutations of these genes are responsible for Li-Fraumeni Syndrome and hereditary retinoblastoma, respectively. Both of these syndromes are also associated with an increased risk for OS, but neither carries a higher or more specific risk for OS than RTS. Recently two other syndromes, RAPADILINO syndrome and Baller-Gerold syndrome (BGS), have also been found to be caused in some cases by mutations in RECQL4;however, the risk for OS in these syndromes has not yet been defined. For RTS as well as the other familial cancer predisposition syndromes, there is a continued need to collect and generate primary data both at the clinical and molecular levels in order to understand the underlying molecular defects and the clinical consequences particularly in relation to cancer. Because these are rare disorders worldwide, accumulating data on affected patients and their relatives in order to study their genetic material becomes a difficult task. The purpose of this study is the collection and analysis of clinical data and biologic specimens from patients affected by RTS and related disorders or unusual forms of OS, as well as their family members. One of the major long-term goals of this project is to further understanding of the biology of OS through the study of patients with RTS or other RECQL4 disorders. Previously patients with RTS were enrolled in a broader study entitled The Molecular Basis of Familial Cancer Predisposition Syndromes (H-7207). Because over the past several years we have been able to better define RTS both clinically and molecularly, and because we continue to receive RTS correspondence from around the world, this current protocol is designed to study and answer questions specifically about RTS patients and conditions that result in inherited predisposition to cancer, specifically OS.

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