Biallelic truncating &ITFANCM&IT mutations cause early-onset cancer but not Fanconi anemia
Biallelic truncating &ITFANCM&IT mutations cause early-onset cancer but not Fanconi anemia
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DOI：
10.1038/gim.2017.124
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发表时间：
2018-04-01
影响因子：
8.8
通讯作者：
Surralles, Jordi
中科院分区：
文献类型：
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作者：
Bogliolo, Massimo;Bluteau, Dominique;Surralles, Jordi
目的：Fanconi anemia (FA)/ BRCA DNA修复通路相关基因突变可引起家族性乳腺癌和Fanconi anemia （FA）等癌症易感性疾病。2005年报道了一例双等位基因FANCM突变的FA患者，但同时发生的FANCA致病性突变排除了FANCM作为FA基因的分配。在这里，我们报告了三个双等位基因FANCM截断突变的个体，他们发展为早发性癌症和化疗毒性，但没有表现出先天性畸形或任何提示FA的血液学表型。&对位;&对位;方法：测定原代成纤维细胞的染色体断裂、链间交联敏感性和FANCD2单泛素化。突变分析通过Sanger测序完成。通过慢病毒介导的野生型FANCM互补DNA转导，对患者来源的细胞进行遗传互补，然后进行功能研究。&对位;&对位;结果：患者来源的细胞表现出染色体脆性，对链间交联过敏，FANCD2单泛素化受损。我们在FANCM中发现了两个纯合突变（c.2586_2589del4; p.Lys863Ilefs*12和c.1506_1507insTA; p.Ile503*）是细胞表型的原因。患者来源的细胞在基因上与野生型FANCM互补DNA表达互补。&对位;&对位;结论：FANCM的功能缺失突变引起的癌症易感综合征在临床上不同于真正的FA。由于预期的急性毒性，这些患者应小心化疗和放疗。
Purpose: Mutations in genes involved in Fanconi anemia (FA)/ BRCA DNA repair pathway cause cancer susceptibility diseases including familial breast cancer and Fanconi anemia (FA). A single FA patient with biallelic FANCM mutations was reported in 2005 but concurrent FANCA pathogenic mutations precluded assignment of FANCM as an FA gene. Here we report three individuals with biallelic FANCM truncating mutations who developed early-onset cancer and toxicity to chemotherapy but did not present congenital malformations or any hematological phenotype suggestive of FA.& para;& para;Methods: Chromosomal breakages, interstrand crosslink sensitivity, and FANCD2 monoubiquitination were assessed in primary fibroblasts. Mutation analysis was achieved through Sanger sequencing. Genetic complementation of patient-derived cells was performed by lentiviral mediated transduction of wild-type FANCM complementary DNA followed by functional studies.& para;& para;Results: Patient-derived cells exhibited chromosomal fragility, hypersensitivity to interstrand crosslinks, and impaired FANCD2 monoubiquitination. We identified two homozygous mutations (c.2586_2589del4; p.Lys863Ilefs*12 and c.1506_1507insTA; p.Ile503*) in FANCM as the cause of the cellular phenotype. Patient-derived cells were genetically complemented upon wild-type FANCM complementary DNA expression. & para;& para;Conclusion: Loss-of-function mutations in FANCM cause a cancer predisposition syndrome clinically distinct from bona fide FA. Care should be taken with chemotherapy and radiation treatments in these patients due to expected acute toxicity.