Mutational Spectrum of Fanconi Anemia Associated Myeloid Neoplasms

Abstract

Individuals with Fanconi anemia (FA) have a high risk of developing myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), yet the secondary somatic mutations lending to these malignancies remain to be further elucidated. We employed a next-generation sequencing myeloid neoplasia gene panel to determine the mutational spectrum of FA-related MDS/AML. Ten of 16 patients showed missense, nonsense, insertion or duplication mutations in 13 genes. In contrast to findings in MDS in the general population, mutations in genes involved in RNA splicing were rarely affected. Mutations in and genes of the RAS pathway appeared more instrumental in the pathogenesis of FA myeloid malignancies. mutations were associated with more advanced disease. Interestingly, one patient with refractory anemia with ring sideroblasts harbored the p.K700E mutation highlighting the mutation's causative role in MDS with ring sideroblasts even in the context of FA. On the whole, our findings implicate a different genetic architecture of FA MDS/AML from adult sporadic MDS. Notably, the genetic events resemble those described in pediatric MDS.

Application of the Moran Model in Estimating Selection Coefficient of Mutated CSF3R Clones in the Evolution of Severe Congenital Neutropenia to Myeloid Neoplasia

“…On the other hand, TP53 mutations in Shwachman-Diamond are controversial in that the mutations do not augur for transformation (Xia et al, 2018 ). Furthermore, the prevalence of mutations in TP53 and in other genes such RUNX1 in Fanconi anemia or dyskeratosis congenita appears to be much less than that of CSF3R in SCN (Chao et al, 2017 ; Lane, 2017 ; Kirschner et al, 2018 ). Despite this, modified Moran model might be applicable to other bone marrow failure syndromes that are associated with leukemia transformation.…”

Next‐generation sequencing in hypoplastic bone marrow failure: What difference does it make?

“…WES and targeted NGS studies 41,46,47 have identified disease‐causing mutations in FANC genes in patients, clinically diagnosed with FA. Other studies 43,48,49 have uncovered FA‐associated mutations in patients with MDS/AML, demonstrating that FA may present as a myeloid malignancy in adulthood, rather than as a paediatric disorder. Allogeneic HSCT is the main therapeutic modality of choice in patients with FA, 50 although androgen therapy has shown improvement of bone marrow failure in a significant proportion of patients 51 .…”

“…Allogeneic HSCT is the main therapeutic modality of choice in patients with FA, 50 although androgen therapy has shown improvement of bone marrow failure in a significant proportion of patients 51 . Identification of FA‐associated mutations through NGS may have important diagnostic and therapeutic implications, as patients with FA exhibit an increased vulnerability to chemotherapy due to chromosomal instability 49 . A suspected diagnosis of FA is usually supported by a chromosomal breakage analysis 50 …”

Causes and Consequences of Chromosomal Instability in Fanconi Anemia. Alterations at the Cellular and Organism Level

“…Cytogenetic and next generation sequencing analysis of MDS and AML bone marrow samples from patients with FA have identified gross chromosomal abnormalities. The most frequent findings include partial duplication of chromosome 1q (1q+, 44.8%), partial duplication of chromosome 3q+ (41.3%), duplications in 21q+ (20.7%), monosomy of chromosome 7 or deletion of chromosome 7q-(17.2%), and 11q+ (13.8%); whereas mutations are more commonly in the genes RUNX1 and RAS [90,91].…”

“…Although some of the chromosome abnormalities mentioned above are shared between patients with FA and MDS/AML from the general population, mutations in MDS/AML oncogenes and tumor-suppressor genes classically found in MDS/AML samples are rarely found in FA. On the other hand, chromosomal lesions that seem to be specific to FA include 1q+ and 3q+; of note 1q+ has been observed in the BM of patients with FA in all MDS/AML stages and even in normocellular bone marrow or hypoplastic bone marrow without signs of transformation, suggesting that 1q+ clones might confer a survival advantage to the HSPCs from FA patients without being a part of the malignant transformation process [90,91].…”