Cancer in Fanconi Anemia and Fanconi Anemia Genes in Cancer

Abstract

At the cellular level, defects in Fanconi anemia (FA) genes manifest themselves as hypersensitivity to DNA damaging agents which can be assessed by increased chromosome breakage and cell cycle changes. As long-term manifestations of cellular genetic instability, FA patients are at high risk for the development of a rather narrow spectrum of malignancies. Neoplasia occurs at a much younger age than in non-FA patients, and chiefly includes acute myeloid leukemia (AML) and squamous cell carcinomas (SCC). Given the role of FA genes in the maintenance of genetic stability, one would expect that FA genes are frequently altered in various kinds of tumors arising in non-FA patients. Much to our surprise and with the possible exception of pancreatic carcinoma, there appears to be no convincing evidence for a frequent association between either germline or somatic alterations in FA genes and malignancies arising in non-FA patients. Another notable exception is the FANCF gene which features prominently among the many genes that are silenced in cancer via promoter CpG island hypermethylation. However, the map location of FANCF adjacent to the 11p hotspot region of hypermethylation raises concerns about a strictly causal relationship between FANCF inactivation and tumorigenesis. Altogether, the available evidence suggests that tumor cells just like normal cells benefit from intact FA genes, possibly by keeping their replication machinery intact and by optimizing their defense against the adverse effects of reactive oxygen species.