Germline Mutations in FAN1 Cause Hereditary Colorectal Cancer by Impairing DNA Repair
Germline Mutations in FAN1 Cause Hereditary Colorectal Cancer by Impairing DNA Repair
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DOI：
10.1053/j.gastro.2015.05.056
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发表时间：
2015-09-01
期刊：
影响因子：
29.4
通讯作者：
Valle, Laura
中科院分区：
文献类型：
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作者：
Segui, Nuria;Mina, Leonardo B.;Valle, Laura
鉴定与遗传性癌症相关的基因有助于对有癌症家族史的患者进行管理。我们对3名符合阿姆斯特丹遗传性非息肉病性结直肠癌风险标准的结直肠癌患者的DNA进行了外显子组测序。这些个体都有错配修复熟练的肿瘤，并且每个人都携带FANCD2/ fancy相关核酸酶1基因（FAN1）的无义变体，该基因编码一种参与DNA链间交联修复的核酸酶。我们对另外176个有结直肠癌病史的家族的FAN1进行了测序，并对鉴定出的FAN1突变形式进行了体外功能分析。我们在大约3%的符合阿姆斯特丹标准的家庭中检测到FAN1突变，这些家庭患有错配修复熟练的癌症，以前没有相关突变。这些发现将结肠直肠癌易感性与范可尼贫血DNA修复途径联系起来，支持基因组完整性与癌症风险之间的联系。
Identification of genes associated with hereditary cancers facilitates management of patients with family histories of cancer. We performed exome sequencing of DNA from 3 individuals from a family with colorectal cancer who met the Amsterdam criteria for risk of hereditary nonpolyposis colorectal cancer. These individuals had mismatch repair-proficient tumors and each carried nonsense variant in the FANCD2/FANCI-associated nuclease 1 gene (FAN1), which encodes a nuclease involved in DNA inter-strand cross-link repair. We sequenced FAN1 in 176 additional families with histories of colorectal cancer and performed in vitro functional analyses of the mutant forms of FAN1 identified. We detected FAN1 mutations in approximately 3% of families who met the Amsterdam criteria and had mismatch repair-proficient cancers with no previously associated mutations. These findings link colorectal cancer predisposition to the Fanconi anemia DNA repair pathway, supporting the connection between genome integrity and cancer risk.