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Abstract：
Two independent exome sequencing initiatives aimed to identify new genes involved in the predisposition to nonpolyposis colorectal cancer led to the identification of heterozygous loss-of-function variants in NPAT, a gene that encodes a cyclin E/CDK2 effector required for S phase entry and a coactivator of histone transcription, in two families with multiple members affected with colorectal cancer. Enrichment of loss-of-function and predicted deleterious NPAT variants was identified in familial/early-onset colorectal cancer patients compared to non-cancer gnomAD individuals, further supporting the association with the disease. Previous studies in Drosophila models showed that NPAT abrogation results in chromosomal instability, increase of double strand breaks, and induction of tumour formation. In line with these results, colorectal cancers with NPAT somatic variants and no DNA repair defects have significantly higher aneuploidy levels than NPAT-wildtype colorectal cancers. In conclusion, our findings suggest that constitutional inactivating NPAT variants predispose to mismatch repair-proficient nonpolyposis colorectal cancer.
摘要：
两个独立的外显子组测序计划旨在鉴定与非息肉病性结直肠癌易感性有关的新基因，从而鉴定了NPAT中的杂合功能丧失变体，编码S期进入所需的细胞周期蛋白E/CDK2效应子和组蛋白转录共激活因子的基因，在两个有多个成员患有结直肠癌的家庭中。与非癌症gnomAD个体相比，家族性/早发性结直肠癌患者中发现了功能丧失和预测的有害NPAT变体的富集。进一步支持与疾病的联系。先前在果蝇模型中的研究表明，NPAT废除导致染色体不稳定，双链断裂的增加，和诱导肿瘤形成。根据这些结果,与NPAT野生型结直肠癌相比,具有NPAT体细胞变异且无DNA修复缺陷的结直肠癌具有显著更高的非整倍体水平。总之,我们的研究结果表明,体质失活NPAT变异体易导致错配修复有效的非息肉病性结直肠癌.
