Myelodysplasia and leukemia of Fanconi anemia are associated with a specific pattern of genomic abnormalities that includes cryptic RUNX1/AML1 lesions

Abstract

Fanconi anemia (FA) is a genetic condition associated with bone marrow (BM) failure, myelodysplasia (MDS), and acute myeloid leukemia (AML). We studied 57 FA patients with hypoplastic or aplastic anemia (n ‫؍‬ 20), MDS (n ‫؍‬ 18), AML (n ‫؍‬ 11), or no BM abnormality (n ‫؍‬ 8). BM samples were analyzed by karyotype, high-density DNA arrays with respect to paired fibroblasts, and by selected oncogene sequencing. A specific pattern of chromosomal abnormalities was found in MDS/AML, which included 1q؉ (44.8%), 3q؉ (41.4%), ؊7/7q (17.2%), and 11q؊ (13.8%). Moreover, cryptic RUNX1/AML1 lesions (translocations, deletions, or mutations) were observed for the first time in FA (20.7%). Rare mutations of NRAS, FLT3-ITD, MLL-PTD, ERG amplification, and ZFP36L2-PRDM16 translocation, but no TP53, TET2, CBL, NPM1, and CEBP␣ mutations were found. Frequent homozygosity regions were related not to somatic copy-neutral loss of heterozygosity but to consanguinity, suggesting that homologous recombination is not a common progression mechanism in FA. Importantly, the RUNX1 and other chromosomal/genomic lesions were found at the MDS/AML stages, except for 1q؉, which was found at all stages. These data have implications for staging and therapeutic managing in FA patients, and also to analyze the mechanisms of clonal evolution and oncogenesis in a background of genomic instability and BM failure. (Blood. 2011;117(15):e161-e170)

Detectable clonal mosaicism in blood as a biomarker of cancer risk in Fanconi anemia

“…Given the very low probability for the occurrence of 5 of 51 breakpoints in this genomic region by chance (P 5 7.3 3 10 29 ), the MHC locus seems to be a hotspot for somatic rearrangements in FA. Other recurrent CMEs in FA were gains at 3q (n 5 6) and 1q (n 5 5), with both rearrangements strongly associated with hematologic cancer development and poor prognosis [21][22][23] ( Figure 3B,C). On this direction, we were able to detect CMEs that are typically associated with hematologic malignancy (1q/3q gains and chromosome 7 monosomy) in 10 out of 15 FA patients with both CMEs and hematologic problems (bone marrow failure, hematologic premalignancy or malignancy) ( Table 1).…”

The Fanconi anaemia pathway orchestrates incisions at sites of crosslinked DNA

“…The same pattern of chromosomal alterations, but with increased frequency and complexity, are observed among myelodysplastic FA patients [29]. The genetic alterations in MDS and AML in FA affect many oncogenes, including RUNX1, that have previously been implicated in non-FA MDS/AML [36]. It is therefore likely that the genomic instability in FA drives the cytogenetic alterations leading to both myelodysplasia and AML.…”

From the Molecular Biology to the Gene Therapy of a DNA Repair Syndrome: Fanconi Anemia

“…Myelodisplasia is often presented as a refractory cytopenia with multilineage dysplasia, with or without excess of blasts [49]. Acute myeloid leukemia can be diagnosed primarily or after a MDS phase, with an increasing fraction of blast cells in the BM [50]. The high selective pressure during their teens or early adulthood is probably involved in the development of clonal MDS and AML.…”

“…The high selective pressure during their teens or early adulthood is probably involved in the development of clonal MDS and AML. The most common abnormalities found in FA patients with MDS/AML are gains of chromosome 1q, monosomy 7, gains of 3q (where EVI1 is included) [44,[49][50][51], and abnormalities in RUNX1/AML1 gene at chromosome 21q [50]. Results by Quentin et al also suggest a model of multi-step oncogenesis progression in the BM of FA patients, in which 1q+ (which can be found in the aplastic anemia form of the disease) would possibly constitute the initiating event, while the 3q+, -7/7q and RUNX1 abnormalities would lead to high grade MDS or AML.…”

“…Results by Quentin et al also suggest a model of multi-step oncogenesis progression in the BM of FA patients, in which 1q+ (which can be found in the aplastic anemia form of the disease) would possibly constitute the initiating event, while the 3q+, -7/7q and RUNX1 abnormalities would lead to high grade MDS or AML. In this model 1q+ might clonally rescue the BMF of FA patients, but would not protect against progression towards MDS and leukemia [50]. A remarkable aspect concerning the clinical symptoms of the disease is the observation that some of FA patients can undergo somatic mosaicism by means of a spontaneous reverse mutation or mitotic recombination in one of the FA pathogenic mutations in particular somatic cells [52][53][54].…”