Mutation at intronic repeats of the ataxia-telangiectasia mutated (ATM) gene and ATM protein loss in primary gastric cancer with microsatellite instability.
Mutation at intronic repeats of the ataxia-telangiectasia mutated (ATM) gene and ATM protein loss in primary gastric cancer with microsatellite instability.
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DOI：
10.1371/journal.pone.0082769
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Kim WH
中科院分区：
文献类型：
--
作者：
Kim HS;Choi SI;Min HL;Kim MA;Kim WH
ataxia -毛细血管扩张突变（ATM）是一种丝氨酸/苏氨酸蛋白激酶，在DNA损伤诱导的信号传导和细胞周期检查点信号的启动中起关键作用，以响应DNA损伤剂如电离辐射。我们之前报道了16%的人胃癌组织中免疫组化（IHC）的ATM蛋白丢失。我们假设由微卫星不稳定性（microsatellite instability， MSI）靶向的ATM基因内含子突变导致了GC亚群中ATM蛋白的丢失。我们研究了GC中ATM基因内含子、ATM IHC和MSI的单核苷酸突变。通过内含子、RT-PCR、直接测序和免疫组化等方法对10株人胃癌细胞株进行了ATM基因突变的研究。对839例患者的GC组织进行MSI和ATM IHC分析。其中604例分析了外显子6、外显子10和外显子20前内含子的ATM突变。2个人GC细胞系（SNU-1和-638）出现ATM内含子突变，RT-PCR和直接测序缺失，IHC显示ATM蛋白丢失。ATM突变频率为12.9% (78/604)，MSI频率为9.2% (81/882)，ATM蛋白丢失频率为15.2%（134/839）。MSI、ATM基因突变和ATM蛋白丢失之间的关联分析显示，ATM基因改变和MSI高度共存。MSI阳性GC中分别有69.3%（52/75）和53.3%（40/75）检测到ATM内含子突变和ATM蛋白丢失。MSI阳性和ATM蛋白丢失分别占68.4%（52/76）和48.7%（37/76）。ATM突变和ATM蛋白丢失具有老年、肿瘤远端、肿瘤大、组织学肠型等特点。我们的研究可能被解释为MSI可能靶向内含子上的ATM基因突变，并导致一组选定的GC中ATM蛋白丢失。
Ataxia-telangiectasia mutated (ATM) is a Ser/Thr protein kinase that plays a critical role in DNA damage-induced signaling and initiation of cell cycle checkpoint signaling in response to DNA-damaging agents such as ionizing radiation. We have previously reported the ATM protein loss by immunohistochemistry (IHC) in 16% of human gastric cancer (GC) tissue. We hypothesized that ATM gene intron mutations targeted by microsatellite instability (MSI) cause ATM protein loss in a subset of GC. We studied mononucleotide mutations at the intron of ATM gene, ATM IHC and MSI in GC. Ten human gastric cancer cell lines were studied for the ATM gene mutation at introns, RT-PCR, direct sequencing, and immunohistochemistry. GC tissues of 839 patients were analyzed for MSI and ATM IHC. Among them, 604 cases were analyzed for the ATM mutations at introns preceding exon 6, exon 10 and exon 20. Two human GC cell lines (SNU-1 and -638) showed ATM intron mutations, deletion in RT-PCR and direct sequencing, and ATM protein loss by IHC. The frequencies of ATM mutation, MSI, and ATM protein loss were 12.9% (78/604), 9.2% (81/882) and 15.2% (134/839), respectively. Analysis of associations among MSI, ATM gene mutation, and ATM protein loss revealed highly co-existing ATM gene alterations and MSI. ATM intron mutation and ATM protein loss were detected in 69.3% (52/75) and 53.3% (40/75) of MSI positive GC. MSI positivity and ATM protein loss were present in 68.4% (52/76) and 48.7% (37/76) of GC with ATM intron mutation. ATM mutation and ATM protein loss had characteristics of old age, distal location of tumor, large tumor size, and histologic intestinal type. Our study might be interpreted as that ATM gene mutation at intron might be targeted by MSI and lead to ATM protein loss in a selected group of GC.
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影响因子：
5
作者：
Kim, Hee Sung;Kim, Min A.;Kim, Woo Ho
通讯作者：
Kim, Woo Ho
影响因子：
9.8
作者：
Stankovic, T;Kidd, AMJ;Taylor, AMR
通讯作者：
Taylor, AMR
DOI：
10.1158/1078-0432.ccr-10-1027
发表时间：
2010-12-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Graeser M;McCarthy A;Lord CJ;Savage K;Hills M;Salter J;Orr N;Parton M;Smith IE;Reis-Filho JS;Dowsett M;Ashworth A;Turner NC
通讯作者：
Turner NC
影响因子：
5.7
作者：
Williamson CT;Muzik H;Turhan AG;Zamò A;O'Connor MJ;Bebb DG;Lees-Miller SP
通讯作者：
Lees-Miller SP
影响因子：
8
作者：
Giannini, G;Rinaldi, C;Gulino, A
通讯作者：
Gulino, A