文章：

范可尼贫血症和癌症：一种复杂的关系

Fanconi anaemia and cancer: an intricate relationship

原文发布日期：2018-01-29

DOI: 10.1038/nrc.2017.116

类型: Review Article

开放获取: 否

要点：

1. Fanconi anaemia (FA) is a complex genetic syndrome associated with risk of congenital malformations, bone marrow failure and cancer. Diagnosis of FA is challenging, as the clinical presentation differs between patients and as other genetic syndromes resemble FA, but a correct diagnosis is needed to optimize clinical care.
2. All patients with FA have a high risk of cancer, particularly acute myeloid leukaemia (AML) and squamous cell carcinoma. Close expert surveillance is needed from early childhood to detect malignancies early, should they occur.
3. FA is caused by inherited mutations in any one of at least 21 genes. Genotype–phenotype correlations in FA are beginning to emerge: patients with FA due to biallelic mutations within BRCA1 or BRCA2 have an increased risk of brain tumours in addition to AML.
4. The FA pathway maximizes efficient DNA damage repair through homologous recombination, coordinates DNA replication and fine-tunes mitotic checkpoints to ensure error-free chromosome segregation during cell division. Therefore, FA proteins guard the genome stability throughout the cell cycle.
5. Impaired DNA damage repair, faulty DNA replication and chromosome mis-segregation together cause genomic instability in cells deficient in the FA pathway, which may lead to p53-dependent cell cycle arrest and bone marrow failure, or if cell cycle checkpoints fail, this instability may lead to propagation of mutations and cancer.
6. Acquired mutations in FA genes occur in malignancies in children and adults who do not have FA. As loss of FA pathway activity renders cancer cells sensitive to inhibition of poly(ADP-ribose) polymerase (PARP) and other signalling pathways, knowledge of the FA pathway status in tumours can be utilized for the rational development of personalized precision medicine cancer therapies.

要点翻译：

1. 范可尼贫血（FA）是一种复杂的遗传综合征，与先天性畸形、骨髓衰竭和癌症风险相关。FA的诊断具有挑战性，因为患者的临床表现各异，且其他遗传综合征与FA相似，但正确的诊断对于优化临床护理至关重要。
2. 所有FA患者均具有较高的癌症风险，特别是急性髓系白血病和鳞状细胞癌。从幼儿期开始就需要密切的专家监测，以便在恶性肿瘤发生时及早发现。
3. FA由至少21个基因中任一基因的遗传突变引起。FA的基因型-表型相关性开始显现：由于BRCA1或BRCA2双等位基因突变导致的FA患者，除急性髓系白血病外，脑肿瘤风险也会增加。
4. FA通路通过同源重组最大化DNA损伤修复效率，协调DNA复制并微调有丝分裂检查点，以确保细胞分裂过程中无误差的染色体分离。因此，FA蛋白在整个细胞周期中守护基因组稳定性。
5. DNA损伤修复受损、DNA复制错误和染色体错误分离共同导致FA通路缺陷细胞的基因组不稳定性，这可能引起p53依赖性细胞周期停滞和骨髓衰竭；如果细胞周期检查点失效，这种不稳定性可能导致突变传播和癌症。
6. 在未患FA的儿童和成人恶性肿瘤中，会出现FA基因的获得性突变。由于FA通路活性丧失会使癌细胞对聚（ADP-核糖）聚合酶（PARP）和其他信号通路抑制敏感，了解肿瘤中FA通路状态可用于合理开发个性化精准医学癌症疗法。

英文摘要：

Fanconi anaemia (FA) is a genetic disorder that is characterized by bone marrow failure (BMF), developmental abnormalities and predisposition to cancer. Together with other proteins involved in DNA repair processes and cell division, the FA proteins maintain genome homeostasis, and germline mutation of any one of the genes that encode FA proteins causes FA. Monoallelic inactivation of some FA genes, such as FA complementation group D1 (FANCD1; also known as the breast and ovarian cancer susceptibility gene BRCA2), leads to adult-onset cancer predisposition but does not cause FA, and somatic mutations in FA genes occur in cancers in the general population. Carcinogenesis resulting from a dysregulated FA pathway is multifaceted, as FA proteins monitor multiple complementary genome-surveillance checkpoints throughout interphase, where monoubiquitylation of the FANCD2–FANCI heterodimer by the FA core complex promotes recruitment of DNA repair effectors to chromatin lesions to resolve DNA damage and mitosis. In this Review, we discuss how the FA pathway safeguards genome integrity throughout the cell cycle and show how studies of FA have revealed opportunities to develop rational therapeutics for this genetic disease and for malignancies that acquire somatic mutations within the FA pathway.

摘要翻译： 

范可尼贫血（FA）是一种遗传性疾病，其特征是骨髓衰竭（BMF）、发育异常和易患癌症。FA蛋白与其他参与DNA修复过程和细胞分裂的蛋白共同维持基因组稳态，任何编码FA蛋白的基因发生种系突变都会导致FA。某些FA基因（如FA互补群D1（FANCD1；也称为乳腺癌和卵巢癌易感基因BRCA2））的单等位基因失活会导致成年期癌症易感性，但不会引起FA，而FA基因的体细胞突变则发生在普通人群的癌症中。FA通路失调导致的致癌作用是多方面的，因为FA蛋白在整个间期监控多个互补的基因组监视检查点，其中FA核心复合物对FANCD2-FANCI异二聚体的单泛素化促进DNA修复效应物招募到染色质损伤位点，以解决DNA损伤和有丝分裂问题。在本综述中，我们讨论了FA通路如何在整个细胞周期中保护基因组完整性，并展示了FA研究如何为开发针对这种遗传疾病以及获得FA通路体细胞突变的恶性肿瘤的合理疗法提供机会。

原文链接：

Fanconi anaemia and cancer: an intricate relationship