INCREASED CANCER RISK IN FANCONI ANEMIA: A GENETIC PERSPECTIVE

This review aims to analyze the genetic mechanisms underlying the increased risk of development of various cancers in patients with Fanconi Anemia. We will address recent discoveries and advancements, including the identification of specific mutations and their implications on prognosis, treatment outcomes and disease prevention. We conducted a literature review by analyzing articles published between 2017 and 2023, sourced from MedLine via PubMed. The following MeSH-compliant keywords were used for this search: “Fanconi Anemia”, “Neoplasm,” and “Genetics”. Fanconi Anemia (FA) is a rare human genetic disorder characterized by chromosomal instability, which leads to a high cancer predisposition. The disease is caused predominantly by autosomal recessive inheritance of germline mutations in key genes acting on DNA damage response. Mutations in 22 genes have been associated with its development, with biallelic pathogenic variants in FANCA representing the most common cause of FA. These genes constitute what is known as the Fanconi Anemia DNA repair pathway. This pathway is activated as a result of DNA replication or DNA damage, especially when triggered by DNA crosslinking agents, which are found in pesticides, tobacco smoke and other carcinogenic substances. The FA pathway then coordinates the removal of interstrand cross-links (ICLs). However, in FA patients, this pathway is flawed, leading ICLs to build up in DNA, hindering its ability to be replicated, transcribed and repaired. This causes significant genomic instability. As a result, in rapidly replicating cells, such as hematopoietic stem cells in the bone marrow, FA patients face bone marrow failure and various cancers at an astonishingly high incidence. For instance, acute myeloid leukemia (AML) occurs at an incidence 700-fold higher in FA patients in comparison to the general population. Currently, Hematopoietic Stem Cell Transplantation (HSCT) is the only curative treatment for hematopoietic disease in FA patients. However, HSCT increases the risk of solid tumor development, as its conditioning regimen can crosslink DNA. Recently, genotype-phenotype correlations in FA are beginning to emerge, and assessments including clinical characteristics, chromosomal breakage studies and molecular testing are shaping our understanding of FA's prognosis, treatment and further complications prevention. Fanconi anemia is a DNA damage syndrome caused by pathogenic variants in key components of the Fanconi DNA repai