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The Defects in the Fanconi Anemia Pathway in Head and Neck Squamous Cell Carcinoma

by O'Leary, Erin Maureen

Abstract (Summary)
Background: The genetic mechanisms that lead to head and neck squamous cell carcinoma (HNSCC) are incompletely understood. Cancer predisposition is associated with chromosome instability and hypersensitivity to DNA damaging agents. Fanconi anemia patients are extremely sensitive to crosslinking agents and are at increased risk of developing several cancers including leukemias, gynecological, and head and neck cancers. The Fanconi Anemia proteins (FANCs) are involved in pathways necessary for crosslink damage recognition and repair. Eight FANC proteins (A/B/C/F/G/I/J/L) assemble into a nuclear complex and two other proteins, FANCD1/BRCA2 and FANCD2 act downstream of the core complex. This FA protein complex is required for the monoubiquitination of the FANCD2 protein in response to DNA damage. By testing head and neck tumors for FANC characteristics, such as hypersensitivity to DNA crosslinking agents, increased chromosome breakage FANCD2 protein ubiquitination, formation of radial figures and genomic instability, we can determine whether this specific DNA damage repair pathway is intact in the tumors. Methods: Head and neck tumor cell lines were treated with the clastogenic crosslinking agent, diepoxybutane (DEB), and double-strand breaks and chromosomal aberrations were quantified. FANCA and FANCD2 cell lines were analyzed as positive controls and normal peripheral blood lymphocytes were used as negative controls. iv Findings: HNSCC cell lines treated with DEB have an increased number of DEB-induced double-strand breaks compared to normal lymphocytes, as evidenced by increased chromosomal breaks and tri- and quadriradials, suggesting defects in the DNA damage response. Interpretation: Patients who are hypersensitive to DNA damage are at increased risk of developing several types of cancer at an early age. Likewise, we predicted and showed that head and neck tumors have defects in the FANC pathway. This might suggest that the genes in the pathway either had germline or acquired alterations (mutations or regulatory defects), which could be tested by comparing normal cells from these patients to the tumor cells. Identifying and examining the mechanisms by which DNA damage occurs and is repaired can lead to a better understanding of genetic predisposition to cancer and to advances in early detection and treatment, therefore reducing morbidity and mortality. v
Bibliographical Information:

Advisor:Susanne Gollin; Laura Niedernhofer; Joel Weissfeld

School:University of Pittsburgh

School Location:USA - Pennsylvania

Source Type:Master's Thesis

Keywords:genetic counseling

ISBN:

Date of Publication:07/05/2005

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