IntroductionFanconi anemia (FA) is an autosomal recessive disorder characterized by a progressive bone marrow failure, developmental defects, and cancer. Individuals with FA have a 500-to 1000-fold increased risk of developing myeloid leukemia and a range of solid tumors that preferentially affect the head and neck, skin, and gastrointestinal and genitourinary systems. [1][2][3][4] Recent studies have identified the existence of 7 FA gene products (denoted FANCA-FANCG) that appear to function, at least in part, in a complex of signaling proteins that modulate genomic stability (for a review, see Joenje and Patel 5 ). In addition, one gene product (FANCC) appears to have a role in modulating apoptosis in addition to its role in the FANCA-FANCG complex. [6][7][8] The ways the different FA proteins interact with each other and with other biochemical pathways to maintain genomic stability and prevent tumor formation is an area of active investigation.Although the mechanisms underlying tumor formation in patients with FA are incompletely understood, epidemiologic and experimental observations raise a number of possibilities. First, the development of malignant cells from primary cells frequently requires alterations in apoptosis or cell cycle control. Because myeloid malignancies predominantly occur in the context of progressive apoptotic depletion of hematopoietic progenitors in patients with FA 9 and in Fancc Ϫ/Ϫ mice, 10 it has been hypothesized that leukemogenesis results from an accumulation of mutations that precipitates the emergence of apoptotic-resistant precursors. Second, p53 is a pivotal sensor of genotoxic and nongenotoxic stress and activates signaling pathways that result in cell cycle arrest or apoptosis. The apoptosis in FANCC-deficient lymphoblasts has previously been shown to be due to activation of protein kinase R (PKR). 11 Because p53 is a downstream effector of PKR, 12-14 inactivation or polymorphisms of p53 or proteins in the p53 pathway may be an important target for cellular transformation in FA-associated myeloid malignancies. Third, patients with FA are predisposed to solid tumors, including epithelial and squamous cell carcinomas, which have a high rate of p53 alteration in sporadic malignancies. 15,16 The risk of these solid tumors in patients with FA goes up markedly after 20 years of age and increases to a cumulative risk of 90% by 40 years of age. 2 Finally, recent studies have positioned the FA proteins in a biochemical pathway that includes BRCA1 and BRCA2. 17,18 In fact, truncating, hypomorphic mutations of BRCA2 were observed in the FA-D1 complementation group. 18 Further, studies using Brca1 and Brca2 conditional knockout mice support a role for p53 in tumor progression. [19][20][21] Although epidemiologic and biochemical data suggest a role for p53 in mediating apoptosis and cancer in FA, a previous study found that a dominant-negative p53 did not affect apoptosis in FANCC-deficient, immortalized lymphoblasts exposed to genotoxic stress. 22 However, the use of immortalized cell ...
