Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
ReviewThe Fanconi anemia pathway: Repairing the link between DNA damage and squamous cell carcinoma
Section snippets
Fanconi anemia pathway mutations play key role in the development of cancer
FA is a rare, autosomal recessive, and X-linked in the case of FANCB, syndrome characterized by congenital defects, bone marrow failure (BMF), and increased susceptibility to cancers. These are predominantly acute myeloid leukemia (AML) and head and neck squamous cell carcinoma (HNSCC) [1], [2], [3], [4]. Disease incidence is rare, estimated at 1 in 200,000 live births, with a carrier frequency of 1 in 181 [5], [6]. A diagnosis of FA is devastating with a median life expectancy of a little over
The FA pathway: multi-protein interactions coordinate DNA repair
Fifteen complementation groups and the corresponding FA genes have now been identified [14], [22], [23], [24], [26], [27], [33], [50], [51], [52], [53], [54], [55], [56], [57], [58], [59], [60], [61], [62], [63]. Their protein products function as either signal transducers and/or DNA processing factors within the larger FA-BRCA DNA damage response network as described below. Our published studies have demonstrated that multiple FA and associated genes are transcriptionally limiting and
Clonal evolution plays a key role in progression to leukemia in the FA population
A majority of FA patients invariably experience progressive bone marrow failure (BMF), and oftentimes leukemia [5], [41], [98], [99], [100]. Marrow dysfunction occurs at approximately 7–8 years old, is associated with stem cell loss in the hematopoietic compartment, and is responsible for the majority of FA childhood mortality (for a review see [101]). The risk of BMF in FA is 90 percent by 50 years of age, although the mechanism for stem cell loss is not fully understood [3]. Rapid
Mutations in the FA pathway lead to increased risk of squamous cell carcinoma
Results from the International FA Registry (IFAR) have revealed that FA patients are highly susceptible to non-hematologic neoplasms [3], [98]. Squamous cell carcinomas (SCCs) of the anogenital region and head and neck, the latter with an up to 1400 fold risk over that of the normal population, are the most commonly diagnosed solid tumors in these patients. A recent report on cancer incidence in the German FA Registry also described an extreme risk of head and neck, vulvar, and esophageal SCC
Oncogenicity: a selection driven or active process in the FA population?
The onset of cancers, such as leukemia and squamous cell carcinoma (SCC), takes place at an unusually early age in persons with FA when compared to control populations. The observed accelerated transformation of FA hematopoietic cells to leukemia, and that of keratinocytes to SCC, may occur through similar or distinct molecular mechanisms. Recent unpublished data generated in our lab indicate that at the level of gene regulation, several pathways specific to epithelial (rather than
Disease biomarker discovery for FA-associated HNSCC
Individuals with sporadic HNSCC frequently present at advanced disease stages, which is a direct result of inferior diagnostic approaches, and necessitates aggressive chemo- and/or radiation therapy [177]. The downside of this scenario in FA patients diagnosed with HNSCC is that these therapeutic methods typically lead to extreme toxicity and sometimes death [128], [131], [132]. To add to the complexity of the situation, in over 20% of FA patients diagnosed with a solid tumor, a diagnosis of FA
Conflict of interest statement
The authors declare that there are no conflicts of interest
Acknowledgements
Research on Fanconi anemia in the Wells laboratory was supported by a Public Health Service Grant CA102357, and by a grant from the Fanconi Anemia Research Fund. We thank Elizabeth Hoskins and Drs. Paul Andreassen, Kasiani Myers, Timothy Chlon and Lisa Privette Vinnedge for critical comments on this report.
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