Background/objectives: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 (CCAs) in chromosomes 1, 3, and 7 frequently appear in the bone marrow (BM) of patients with FA and are associated with MDS/AML progression. Given the underlying DNA repair defect that characterizes FA, non-clonal chromosomal abnormalities (NCCAs) are expected to be common events in the FA BM; in this study, we investigated the presence and significance of NCCA and CCA in the bone marrow (BM) of patients with FA.Methods: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 CCAs as well as their association with the natural history of the disease, including age, degree of BM failure, and neoplastic transformation.Results:NCCAs were observed in the metaphase spreads of 41/43 FA patients; CKs were observed in 25/43 patients; CCAs were found in 15/43 patients; CCAs involving chromosomes 1, 3 and/or 7 were found in four patients; and other autosomes were found 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 precedes 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 NCCAs and CCAs increased with age, even though a significant correlation was not found.Conclusions:These observations fit the model of evolution towards cancer that comprises a first phase of macroevolution represented by NCCAs and karyotypic heterogeneity, followed by the establishment of clones with CCAs, leading to microevolution and cancer. NCCAs are the most frequent chromosomal alterations in the bone marrow of patients with AF and constitute a genome with extensive karyotypic heterogeneity that evolves into clones with more complex genomes and can eventually progress to cancer.
背景/目的：范可尼贫血（FA）是一种遗传性骨髓衰竭综合征，以染色体不稳定和易发展为骨髓增生异常肿瘤（MDS）及急性髓系白血病（AML）为特征。在FA患者的骨髓（BM）中，染色体1、3和7上的克隆性染色体畸变（CCAs）频繁出现，并与MDS/AML进展相关。鉴于FA以DNA修复缺陷为根本特征，非克隆性染色体异常（NCCAs）预计在FA骨髓中较为常见；本研究旨在探讨FA患者骨髓中NCCA和CCA的存在情况及其意义。 方法：本研究横向分析了43例未接受移植的FA患者的骨髓核型，其中41例无临床可检测的血液肿瘤，2例已确诊MDS。我们检测了NCCAs、复杂核型（CKs）和CCAs的存在情况，并分析了它们与疾病自然史（包括年龄、骨髓衰竭程度和肿瘤转化）的关联。 结果：在43例FA患者中，41例的中期分裂相中观察到NCCAs；25例观察到CKs；15例发现CCAs；其中4例患者检测到涉及染色体1、3和/或7的CCAs；其余11例患者发现涉及其他常染色体的CCAs。总体而言，我们观察到FA患者骨髓中存在基线水平的较大核型异质性，这通过NCCA的普遍存在得以证明；这种核型异质性先于CKs的最终出现以及携带适应性改善CCAs的细胞的选择。最终，涉及染色体1、3和7的CCAs（已知在FA中驱动血液恶性肿瘤）得以确立。总体来看，我们观察到NCCAs和CCAs的频率随年龄增长而增加，尽管未发现显著相关性。 结论：这些观察结果符合癌症进化模型，该模型包含以NCCAs和核型异质性为代表的宏观进化第一阶段，随后是携带CCAs的克隆的确立，进而导致微观进化和癌症。NCCAs是AF患者骨髓中最常见的染色体改变，构成了具有广泛核型异质性的基因组，该基因组可进化为具有更复杂基因组的克隆，并最终可能进展为癌症。
肿瘤(癌症)患者之家