Homozygous inactivation of CHEK2 is linked to a familial case of multiple primary lung cancer with accompanying cancers in other organs.
Homozygous inactivation of CHEK2 is linked to a familial case of multiple primary lung cancer with accompanying cancers in other organs.
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CHEK2的纯合灭活与多种原发性肺癌的家族病例有关，与其他器官中的伴随癌症有关。
DOI：
10.1101/mcs.a001032
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发表时间：
2016-11
影响因子：
1.8
通讯作者：
Kato K
中科院分区：
文献类型：
--
作者：
Kukita Y;Okami J;Yoneda-Kato N;Nakamae I;Kawabata T;Higashiyama M;Kato J;Kodama K;Kato K
在临床实践中，有许多癌症患者具有明确的家族史，但患者在已知的家族性癌症综合征基因中缺乏突变。基因组技术的最新进展提高了在这种情况下确定致病基因的可能性。两个兄弟姐妹，一个姐姐和一个弟弟，在60岁时被发现患有多发性原发性肺癌。前者随后患上乳腺癌，并有子宫肌瘤病史。后者最初在59岁时患上前列腺癌，并有结肠癌病史。单核苷酸多态性（SNP）基因分型显示，两名患者的基因组均为纯合子。外显子组测序揭示了在纯合性运行中的五个基因中的非同义突变：CHEK 2，FCGRT，INPP 5J，MYO 18 B和SFI 1。一级蛋白质结构的进化保守性表明CHEK 2突变p.R474C的功能重要性。该突变通过破坏p.R474和p.E394之间的盐桥改变了CHK2的三级结构。在其他突变基因中没有观察到这种结构变化。随后的基于细胞的转染分析显示，CHK2 p.R474C是不稳定的，几乎没有激活。我们的结论是，纯合子CHEK 2变异是在这种情况下，家族性癌症的贡献。尽管CHEK 2在小鼠中的纯合失活导致多个器官中的癌症，但需要额外的人类病例的积累来确定其在人类中的致病作用。
In clinical practice, there are a number of cancer patients with clear family histories, but the patients lack mutations in known familial cancer syndrome genes. Recent advances in genomic technologies have enhanced the possibility of identifying causative genes in such cases. Two siblings, an elder sister and a younger brother, were found to have multiple primary lung cancers at the age of 60. The former subsequently developed breast cancer and had a history of uterine myoma. The latter had initially developed prostate cancer at the age of 59 and had a history of colon cancer. Single-nucleotide polymorphism (SNP) genotyping revealed that ∼10% of the genomes were homozygous in both patients. Exome sequencing revealed nonsynonymous mutations in five genes in the runs of homozygosity: CHEK2, FCGRT, INPP5J, MYO18B, and SFI1. Evolutionary conservation of primary protein structures suggested the functional importance of the CHEK2 mutation, p.R474C. This mutation altered the tertiary structure of CHK2 by disrupting the salt bridge between p.R474 and p.E394. No such structural changes were observed with the other mutated genes. Subsequent cell-based transfection analysis revealed that CHK2 p.R474C was unstable and scarcely activated. We concluded that the homozygous CHEK2 variant was contributory in this case of familial cancer. Although homozygous inactivation of CHEK2 in mice led to cancers in multiple organs, accumulation of additional human cases is needed to establish its pathogenic role in humans.
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