High Burden of Non-Clonal Chromosome Aberrations Before Onset of Detectable Neoplasia in Fanconi Anemia Bone Marrow

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Fanconi anemia (FA) is an inherited bone marrow failure syndrome characterized by chromosome instability and predisposition to develop myelodysplastic neoplasm (MDS) and acute myeloid leukemia (AML). Clonal chromosome aberrations (CCA) in chro-mosomes 1, 3, and 7 frequently appear in the bone marrow (BM) of patients with FA and associate to MDS/AML progression. Given the underlying DNA repair defect that characterizes FA, non-clonal chromosomal abnormalities (NCCA) are expected to be common events in the FA BM, however little is known about its presence and significance. Here, we transversally examined the BM karyotypes of 43 non-transplanted patients with FA, 41 with non-clinically detectable hematologic neoplasia and two with diagnosed MDS. We searched for the presence of NCCAs, complex karyotypes (CKs) and CCA, and their association with the natural history of the disease, including age, degree of BM failure, and neoplastic transformation. NCCAs were observed in the metaphase spreads of 41/43 FA patients; CKs were observed in 25/43 patients, whereas CCAs were found in 15/43 patients, CCA involving chromosomes 1, 3 and/or 7 in four patients, and other autosomes in the remaining 11 patients. Overall, we observed a baseline large karyotypic heterogeneity in the BM of FA patients, demonstrated by the ubiquitous presence of NCCA; such karyotypic heterogeneity preceding the eventual emergence of CKs and selection of cells carrying fitness-improving CCAs. Finally, CCAs involving chromosomes 1, 3 and 7, well-known drivers of hematological malignancy in FA, become established. Overall, we observed that the frequency of NCCA and CCA increased with age, even though a significant correlation was not found. Preleukemic BM of patients with FA displays a baseline large karyotypic heterogeneity, evidenced by the ubiquitous presence of NCCA; such karyotypic heterogeneity preceding the eventual emergence of CKs and selection of cells carrying fitness-improving CCAs. Finally, CCAs involving chromosomes 1, 3 and 7, well-known drivers of hematological malignancy in FA, become established. These observations fit the model of evolution towards cancer that comprises a first phase of macroevolution represented by NCCA and karyotypic heterogeneity, followed by the establishment of clones with CCA, leading to microevolution and cancer.

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