Clinical Characterization of Myeloid Neoplasms Patients with Fanconi Anemia Gene Mutations
Authors: Zhang Yuhui , Teng Guangshuai , Duan Yifan , Du Chenxiao , Wang Yan , Zhang Huiqin , Hu Xin , Zhao Yunhan , Zhou Yuan , Yuan Weiping , Bai Jie 
Published: December 2024

Background
Fanconi anemia (FA) is a rare autosomal recessive cancer-prone inherited bone marrow failure syndrome, due to mutations in 16 FA genes, including BRCA2, BRIP1, and PALB2, and their protein products comprise a DNA repair pathway (Brosh RM Jr et al. Ageing Res Rev. 2017). The major complications of FA are aplastic anemia, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and specific solid tumors. Myeloid neoplasms (MN) include AML, MDS, myeloproliferative neoplasms (MPN), or MDS/MPN. (Nie D et al. Leukemia. 2017; Samuel Quentin et al. Blood 2011). The recent inclusion of the “Myeloid Neoplasms with Germline Predisposition” category in the revised 5th Edition of the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues further emphasizes the increased recognition and importance of germline evaluation in patients with myeloid neoplasms (Khoury J.D.et al. Leukemia. 2022). The Fanconi anemia gene has been shown to have a certain mutation rate in myeloid neoplasms, while the roles of the Fanconi anemia genes in myeloid neoplasm development are still unclear.
Methods
To analyze the mutation frequency, function and mechanism of Fanconi anemia gene mutation in hematological malignancies. In this study, 850 patients with hematological malignancies who underwent whole exon sequencing were retrospectively analyzed to determine the proportion of MN in patients with Fanconi anemia gene mutations. The clinical characteristics, prognosis and survival of MN patients with Fanconi anemia gene mutations were also evaluated. In addition, MPN patients were divided into two groups according to the presence or absence of Fanconi anemia gene mutations. The clinical features, laboratory features, cytogenetics, disease progression and survival of the two groups were examined. P&lt;0.05 was considered statistically significant.
Results
A total of 850 patients with hematological malignancies were analyzed. The results showed that of these patients, a total of 98 had Fanconi related gene mutations, of which SLX4 was the most common (20.4%), followed by FANCD2 (13.3%) and BRAC2 (10.2%). Exhaustion bone marrow diseases is the disease with highest percentage of FA gene mutations (41.8%), followed by MPN (30.5%), AML (3.1%), MDS (7.1%), MDS/MPN (6.1%).
The most frequently mutated gene in MPN patients was BRAC2 (28.6%, 12/42), FANCD2 (16.7%, 7/42), SLX4 (11.9%, 5/42). Since MPN patients have the second highest proportion of genes mutations involved with FA disease type, we further analyzed the clinical features, according to age, sex, matching without Fanconi anemia related genes MPN patients with their clinical features, laboratory parameters and survival data in MPN patients with Fanconi anemia related genes. The results showed that MPN patients with Fanconi anemia-related genes were younger (53 years vs 60 years), more likely to have chromosomal abnormalities (44.4% vs 23.5%), and had worse overall survival (P&lt;0.05).
Further analysis of clinical characteristics and survival analysis of MPN patients with different Fanconi anemia gene mutations showed that 58.3% of the 12 BRAC2 MPN patients were younger than 60 years old, and 57.1% of the 7 FANCD2 MPN patients had thrombosis.
Conclusion
Genetic susceptibility genes include mutations in genes related to Fanconi anemia, and their mutation rates are high in myeloid neoplasms, especially in myeloproliferative neoplasms. By comparing the clinical characteristics and prognosis of MPN patients with or without Fanconi anemia mutation. We found that Fanconi anemia gene mutation is correlated with the prognosis of MPN. Additional attention should be paid to MPN patients with FA related gene mutations, and the mutation consequence should be pursued if possible in future studies.