Fanconi anemia (FA) is a complex genetic disorder characterized by bone marrow failure (BMF), congenital defects, inability to repair DNA interstrand cross-links (ICLs), and cancer predisposition. FA presents two seemingly opposite characteristics: (a) massive cell death of the hematopoietic stem and progenitor cell (HSPC) compartment due to extensive genomic instability, leading to BMF, and (b) uncontrolled cell proliferation leading to FA-associated malignancies. The canonical function of the FA proteins is to collaborate with several other DNA repair proteins to eliminate clastogenic (chromosome-breaking) effects of DNA ICLs. Recent discoveries reveal that the FA pathway functions in a critical tumor-suppressor network to preserve genomic integrity by stabilizing replication forks, mitigating replication stress, and regulating cytokinesis. Homozygous germline mutations (biallelic) in 22 FANC genes cause FA, whereas heterozygous germline mutations in some of the FANC genes (monoallelic), such as BRCA1 and BRCA2, do not cause FA but significantly increase cancer susceptibility sporadically in the general population. In this review, we discuss our current understanding of the functions of the FA pathway in the maintenance of genomic stability, and we present an overview of the prevalence and clinical relevance of somatic mutations in FA genes.

中文翻译：

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癌症中的范可尼贫血途径。

范可尼贫血 (FA) 是一种复杂的遗传性疾病，其特征是骨髓衰竭 (BMF)、先天性缺陷、无法修复 DNA 链间交联 (ICL) 和癌症易感性。FA 呈现出两个看似相反的特征：(a) 由于广泛的基因组不稳定性导致造血干细胞和祖细胞 (HSPC) 区室的大量细胞死亡，导致 BMF，以及 (b) 不受控制的细胞增殖导致 FA 相关的恶性肿瘤。FA 蛋白的典型功能是与其他几种 DNA 修复蛋白协作，以消除 DNA ICL 的染色体断裂（染色体断裂）效应。最近的发现表明，FA 通路在关键的肿瘤抑制网络中发挥作用，通过稳定复制叉、减轻复制压力和调节胞质分裂来保持基因组完整性。22 个 FANC 基因的纯合种系突变（双等位基因）会导致 FA，而某些 FANC 基因（单等位基因）的杂合种系突变（例如 BRCA1 和 BRCA2）不会导致 FA，但会显着增加普通人群中偶发的癌症易感性。在这篇综述中，我们讨论了我们目前对 FA 通路在维持基因组稳定性方面的功能的理解，并概述了 FA 基因中体细胞突变的普遍性和临床相关性。