Image: A ribbon model of an X-ray diffraction based 3D structure of FANCM- FAAP24 complex, as shown in ID# 4BXO of the Protein Database (PDB) (Photo courtesy of Coulthard R et al, 2013, PDB).
The syndrome was found and characterized by studying patients with biallelic mutations (mutations in both inherited gene copies) in the FANCM gene. These mutations predisposed the body to development of tumors and to hypersensitivity to and rejection of chemotherapy treatments. Contrary to what has been thought, the study suggests that mutations in the FANCM gene does not cause Fanconi anemia, a rare disease that affects ~ 1 of every 100,000 children.
A research team led by Jordi Surrallés, professor at Autonomous University of Barcelona (UAB; Barcelona, Spain) and Genetics Unit director at Hospital de la Santa Creu i Sant Pau, identified this genetic syndrome in which patients are predisposed to early formations of tumors and to chemotherapy toxicity.
In one of two co-published studies, first-author Massimo Bogliolo, from the Centre for Biomedical Network Research on Rare Diseases (CIBERER) group led by Jordi Surrallés, analyzed biallelic FANCM mutations in 3 individuals. Despite the number of patients being low in these types of studies (dealing with rare diseases), it was observed that the patients did not present any congenital malformations or hematological phenotype that could suggest being affected by the disease Fanconi anaemia, yet they did have an early onset of cancer and toxicity to chemotherapy.
In the second study, researchers from Dr Surrallés' group and the group led by Javier Benítez at the CNIO and CIBERER confirmed that women with biallelic mutations in the FANCM gene did not develop Fanconi anaemia, but did present a higher risk of breast cancer, chemotherapy toxicity, and chromosomal fragility. This study was coordinated by Paolo Peterlongo of the Milan Institute of Molecular Oncology and included the participation of several hospitals and research centers of Italy, Germany, Spain, and Sweden.
Given that in 2005 the biallelic mutation was observed in patients suffering from Fanconi anaemia "it was thought that biallelic mutations in the FANCM gene caused Fanconi anaemia. But we have now demonstrated that it is not so, given that in the two studies there were 8patients with these mutations and none of them had anemia," Dr. Surrallés. The patients however had suffered from cancer at very early ages and presented chemotherapy toxicity. In view of this newfound syndrome, the authors recommend modifying the clinical monitoring of patients with biallelic FANCM mutations and taking precautions when using chemotherapy and radiation therapies.
The researchers also conducted functional genetic complementation tests, an important type of analysis in mass sequencing projects in which there are several mutated genes and it is not clear which are the source of the disease. Patients’ cells showed a clear phenotype of chemical hypersensitivity to DEB (a DNA damaging agent) such the cells did not survive high doses of DEB. In contrast, when a healthy FANCM gene copy was transferred (using lentiviral transductions) into cells from patients, the researchers observed reversal of this phenotype: the cells behaved as if they were healthy, with a response similar to that of a healthy donor. This functional study provided a demonstration that the gene causing the disease is FANCM and that these biallelic FANCM mutations are of a pathogenic nature.
The two studies, by Bogliolo M et al and by Catucci I et al, were co-published August 24, 2017, in the journal Genetics in Medicine.
Autonomous University of Barcelona