Recent insights into the molecular basis of Fanconi anemia: genes, modifiers, and drivers

Abstract

Fanconi anemia (FA), the most common form of inherited bone marrow failure, predisposes to leukemia and solid tumors. FA is caused by the genetic disruption of a cellular pathway that repairs DNA interstrand crosslinks. The impaired function of this pathway, and the genetic instability that results, is considered the main pathogenic mechanism behind this disease. The identification of breast cancer susceptibility genes (for example, BRCA1/FANCS and BRCA2/FANCD1) as being major players in the FA pathway has led to a surge in molecular studies, resulting in the concept of the FA-BRCA pathway. In this review, we discuss recent advances in the molecular pathogenesis of FA from three viewpoints: i) new FA genes, ii) modifier pathways that influence the cellular and clinical phenotypes of FA and iii) non-canonical functions of FA genes that may drive disease progression independently of deficient DNA repair. Potential therapeutic approaches for FA that are relevant to each will also be proposed.

The identification of pathogenic variants in BRCA1/2 negative, high risk, hereditary breast and/or ovarian cancer patients: High frequency of FANCM pathogenic variants

“…FA is a hereditary recessive bone marrow failure and cancer predisposition syndrome. To date, 21 genes have been associated with FA; all of them encode proteins involved in DNA interstrand crosslink repair . One of the FA‐genes, FANCM , has recently been excluded as a gene predisposing for FA but has been suggested as a predisposition gene for hereditary breast cancer .…”

“…To date, 21 genes have been associated with FA; all of them encode proteins involved in DNA interstrand crosslink repair. [43][44][45] One of the FA-genes, FANCM, has recently been excluded as a gene predisposing for FA but has been suggested as a predisposition gene for hereditary breast cancer. 21,22,33,45 FANCM is one of the eight FA-genes that form the FA core complex, responsible for monoubiquitination of FANCI/D2, which is a crucial step for its recruitment to the site of DNA damage.…”

Fanconi anemia in twins with neutropenia: A case report

“…As a hereditary disease, at least 16 genes including Fanconi Anemia Complementation Group (FANC)A, FANCC, FANCG, FANCD1 and FANCD2 have been identified to cause FA. Among these, mutations in the FANCD1 and FANCD2 genes are the causative factor in 5% of all cases of this disease (6)(7)(8)(9)(10)(11)(12). The present case report describes a pair of twins whom suffered recurrent upper respiratory tract infections for >2 years prior to the study.…”

RecQ and Fe–S helicases have unique roles in DNA metabolism dictated by their unwinding directionality, substrate specificity, and protein interactions

“…FANCJ (also designated BRIP1 or BACH1 ) encodes an Fe–S DNA helicase and is one of over 20 genes in which mutations are responsible for Fanconi Anemia (FA) [55], characterized by progressive bone marrow failure (BMF) [56], cancer, and congenital abnormalities [57]. Recent evidence suggests that FA phenotypes are due to an inability to repair cellular DNA damage induced by endogenous formaldehydes, leading to failure of the hematopoietic stem cell compartment [58].…”