Germline mutations in oncogene-induced senescence pathways are associated with multiple sessile serrated adenomas.
Germline mutations in oncogene-induced senescence pathways are associated with multiple sessile serrated adenomas.
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DOI：
10.1053/j.gastro.2013.10.045
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发表时间：
2014-02
期刊：
影响因子：
29.4
通讯作者：
Chung DC
中科院分区：
文献类型：
--
作者：
Gala MK;Mizukami Y;Le LP;Moriichi K;Austin T;Yamamoto M;Lauwers GY;Bardeesy N;Chung DC
关于导致无柄锯齿状腺瘤(SSA)发生的遗传因素，我们知之甚少。SSA在发育早期的BRAF或KRAS中包含体细胞突变。然而，来自人类和小鼠模型的证据表明，这些突变会导致癌基因诱导的肠道隐窝细胞衰老(OIS)。进展为锯齿状肿瘤需要细胞通过肿瘤抑制通路的失活来逃避OIS。我们调查了患有多个SSA的个体是否在调节OIS-p16-Rb和ATM-ATR DNA损伤反应通路的基因中携带胚系功能丧失突变(无义和剪接点)。通过对文献的生物信息学分析，我们确定了一组在p16-Rb和ATM-ATR DNA损伤反应通路的主要节点上发挥功能的基因。我们对20名有多个SSA的无关个体进行了全外显子组测序；大多数人都有锯齿状息肉病的特征。我们将序列与4300个种族匹配的个体的序列进行了比较(对照)。我们还使用了一种综合基因组学方法来识别与衰老机制有关的其他基因。我们在5/20名患有多发性SSA的个体中发现了调节衰老的基因突变(ATM、PIF1、TELO2、XAF1和RBL1)(优势比[OR]=3.0；95%可信区间[CI]，0.9-8.9；P=0.04)。在2例个体中，我们发现RNF43基因无义突变，提示其与多发性锯齿状息肉有关(OR=460；95%CI，23.1~16384；P=6.8×10−5)。在对暴露在紫外线下的胰管细胞进行的击倒实验中，RNF43似乎起到了ATM-ATR DNA损伤反应的调节作用。我们将调节衰老途径的基因中的种系功能丧失变异与多个SSA的发生联系起来。我们确定RNF43是DNA损伤反应的调节因子，并与该基因的无意义变异相关，具有发生SSA的高风险。
Little is known about the genetic factors that contribute to development of sessile serrated adenomas (SSAs). SSAs contain somatic mutations in BRAF or KRAS early in development. However, evidence from humans and mouse models indicates that these mutations result in oncogene-induced senescence (OIS) of intestinal crypt cells. Progression to serrated neoplasia requires cells to escape OIS, via inactivation of tumor suppressor pathways. We investigated whether individuals with multiple SSAs carry germline loss-of-function mutations (nonsense and splice-site) in genes that regulate OIS – the p16–Rb and ATM–ATR DNA damage response pathways. Through bioinformatic analysis of the literature, we identified a set of genes that function at main nodes of the p16–Rb and ATM–ATR DNA damage response pathways. We performed whole-exome sequencing of 20 unrelated individuals with multiple SSAs; most had features of serrated polyposis. We compared sequences with those from 4300 individuals, matched for ethnicity (controls). We also used an integrative genomics approach to identify additional genes involved in senescence mechanisms. We identified mutations in genes that regulate senescence (ATM, PIF1, TELO2, XAF1, and RBL1) in 5/20 individuals with multiple SSAs (odds ratio [OR]=3.0; 95% confidence interval [CI], 0.9–8.9; P=.04). In 2 individuals, we found nonsense mutations in RNF43, indicating that it is also associated with multiple serrated polyps (OR=460; 95% CI, 23.1– 16384; P=6.8×10−5). In knockdown experiments with pancreatic duct cells exposed to ultraviolet light, RNF43 appeared to function as a regulator of ATM–ATR DNA damage response. We associated germline loss-of-function variants in genes that regulate senescence pathways with the development of multiple SSAs. We identified RNF43 as a regulator of the DNA damage response, and associated nonsense variants in this gene with high risk of developing SSAs.
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影响因子：
64.8
作者：
Bartkova, Jirina;Rezaei, Nousin;Gorgoulis, Vassilis G.
通讯作者：
Gorgoulis, Vassilis G.
DOI：
10.1186/bcr2919
发表时间：
2011-07-25
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Goldgar DE;Healey S;Dowty JG;Da Silva L;Chen X;Spurdle AB;Terry MB;Daly MJ;Buys SM;Southey MC;Andrulis I;John EM;BCFR;kConFab;Khanna KK;Hopper JL;Oefner PJ;Lakhani S;Chenevix-Trench G
通讯作者：
Chenevix-Trench G
影响因子：
64.8
作者：
Hao, Huai-Xiang;Xie, Yang;Cong, Feng
通讯作者：
Cong, Feng
影响因子：
5.7
作者：
Huang, Jia;Yao, Wei-yan;Yuan, Yao-zong
通讯作者：
Yuan, Yao-zong
影响因子：
29.4
作者：
Chow, Elizabeth;Lipton, Lara;Macrae, Finlay
通讯作者：
Macrae, Finlay