Fanconi anemia pathway defects in inherited and sporadic cancers

Fanconi anemia (FA) is a recessive chromosomal instability syndrome. It is a hereditary disorder with defects in DNA repair characterized by progressive bone marrow failure, variable congenital malformations and predisposition to develop hematological or solid tumors. Bi-allelic gene mutations in FA cause not only the FA phenotype but also genome instability and additional mutations in their somatic cells resulting in a high predisposition to many different types of cancers. Mono-allelic mutation in FA genes increases the susceptibility to several types of cancers in a sporadic manner in non-FA patients. The strong link between cancer from bi-allelic and mono-allelic FA gene mutations has been well established. Studies have demonstrated a link between FA and cancer due to gene defects which cause the disruption of the FA pathways in a proportion of familial and sporadic cancers. The convincing evidence is that one of the FA genes, FANCD1 is identical to the well-known breast cancer susceptibility gene, BRCA2. Another three FA genes were found to be associated with genes mutated from breast cancer and other types of cancers such as prostate cancer as well. Studies on FA's biological function in genome instability maintenance, DNA damage/repair and its complex regulation pathways have become the main focus within the genetic cancer research field because of many unique features of FA. The lessons learnt from FA studies provided invaluable information towards the understanding of cancer pathogenesis to be translated into targeting cancer therapies. Studies also demonstrated that FA is a paradigm of cancer-prone inherited monogenic disease, offering insights into the pathogenesis of many types of human diseases, particularly in bone marrow failure, cancer and aging. In this review, brief FA clinical characteristics, identification of FA genes and their protein pathways, the pathogenic linking between cancers from bi-allelic and mono-allelic mutated FA genes will be discussed.