Research Article: Chromosomal Aberrations Associated with Clonal Evolution and Leukemic Transformation in Fanconi Anemia: Clinical and Biological Implications

Date Published: May 23, 2012

Publisher: Hindawi Publishing Corporation

Author(s): Stefan Meyer, Heidemarie Neitzel, Holger Tönnies.


Fanconi anaemia (FA) is an inherited disease with congenital and developmental abnormalities, bone marrow failure, and extreme risk of leukemic transformation. Bone marrow surveillance is an important part of the clinical management of FA and often reveals cytogenetic aberrations. Here, we review bone marrow findings in FA and discuss the clinical and biological implications of chromosomal aberrations associated with leukemic transformation.

Partial Text

Fanconi anemia (FA) is an inherited disease with bone marrow failure, variable congenital and developmental abnormalities, and extreme cancer predisposition. The most common malignancies in FA are myeloid leukemia and squamous cell carcinoma. On a cellular level, FA is characterized by chromosomal instability and cross-linker sensitivity, which is the diagnostic hallmark of FA. For diagnostic testing, this is determined by demonstration of hypersensitivity to mitomycin C (MMC) or diepoxybutane (DEB) of patient derived peripheral blood cells or fibroblasts [1–3]. FA cells also display hypersensitivity to proapoptotic stimuli of certain cytokines, such as TNF-α and IFN-γ, which has been implicated in haematological manifestations of FA [4–6]. Cell cycle analysis of FA cells shows a characteristic arrest in the G2 phase, which is exacerbated by exposure to MMC [7–9]. This clinical and cellular phenotype results from a defect in a DNA damage response (DDR) pathway (FA/BRCA pathway), in which FA and associated proteins interact. So far, 15 FA genes (FANCA, FANCB, FANCC, FANCD1/BRCA2, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ, FANCL, FANCM, FANCN/PALPB2, FANCO/RAD51C, and FANCP/SLX4) have been identified that can be mutated in FA [2, 10–12], of which FANCA, FANCG, and FANCC are the most commonly mutated genes in studied FA populations [2]. Importantly, the discovery that mutations in BRCA2 causes FA in the subgroup FA-D1, which comprises less than 5% of all FA patients, linked the FA DNA damage response pathway to hereditary breast and ovarian cancer (HBOC) [13, 14]. Hematopoiesis in the bone marrow (BM) is the most commonly affected organ system in FA, and most FA patients will develop clinically relevant hematological complications in their first or second decades of life [15]. BM complications of FA can manifest with hypoplasia, often initially being limited to thrombocytopenia in peripheral blood counts, or general aplasia. When the diagnosis of FA is made, which might happen with considerable delay, bone marrow appearances can already be more advanced and consistent with myelodysplasia. In FA, this often presents as refractory cytopenia with multilineage dysplasia, with or without excess of blasts on morphologic evaluation. Common morphologic abnormalities on bone marrow examination include irregular nuclear contours, budding nuclei, and karyorrhexis [16]. In some patients, the diagnosis of FA is only made on presentation with overt myeloid leukemia. How common undiagnosed FA presents with AML is not known, but FA should be considered especially in young patients with AML, even in the absence of sometimes only subtle congenital malformations such as short stature and microcephaly, in particular when excess toxicity or prolonged aplasia after chemotherapy of extreme toxicity is encountered [17–19]. Less than ten cases of lymphoblastic leukemias have been reported in FA, which have been mostly of T-lineage, and appear to be limited to patients with mutations in FANCD1/BRCA2 and FANCD2 [19–21].




Leave a Reply

Your email address will not be published.