Fanconi Anemia/Brca Pathway and Head and Neck Squamous Cell Carcinomas

DNA repair defect is one of the hallmarks of tumorigenesis, and is intimately linked to various human cancers, both inherited and sporadic (1). The two best examples are perhaps the DNA mismatch repair pathway in colorectal cancer, and the Fanconi Anemia/Brca (Fanc/Brca) pathway in head and neck squamous cell carcinomas (HNSCCs) (1). In this book chapter, I will review the updated knowledge of Fanc/Brca pathway in human cancers particularly in HNSCCs. Fanconi anemia is a rare autosomal recessive or X-linked chromosomal instability disorder, with incidence of 1 to 5 cases per millions. The affected children have multiple congenital defects, and typically develop bone marrow failure during the first decade of life. They are at the risk for developing hematological cancers with the acute myelogenous leukemia (AML) the most frequent (2). Recently studies also showed a predisposition of Fanconi anemia patients to multiple solid tumors (3, 4), particularly to HNSCCs (5). Other tumors include gynecologic SCCs, and tumors of esophagus, liver, and skin (3, 4). Since Fanconi anemia is characterized by spontaneous chromosome breakage and cellular hypersensitivity to DNA cross-linking agents, such as mitomycin C, or diepoxybutane (DEB), the DEBinduced chromosome-breakage assay is widely used as a diagnostic test for Fanconi anemia patients, and the complementation test is used to define the Fanconi anemia subtypes. Androgens, hematopoietic growth factors, or stem-cell transplantation is currently used for treating bone marrow failure in Fanconi anemia patients(2). The Fanconi anemia pathway is complex and interacts with other DNA repair pathways (6, 7). The pathway itself is regulated by so far thirteen Fanconi anemia proteins (FANCA, B, C, D1, D2, E, F, G, I, J, L, M and N). Among those proteins, eight are assembled in a nuclear ubiquitin E3 ligase complex (FANCA/B/C/E/F/G/L/M), known as the Fanconi anemia core complex, which mono-ubiquitinates FANCD2 and FANCI. The mono-ubiquitinated FANCD2/FANCI complex is targeted to chromatin, where it interacts, either directly or indirectly, with additional downstream Fanconi anemia proteins (FANCD1, FANCN, and FANCJ) (6, 7). The first evidence of the convergence of Fanconi anemia pathway with