Genetic Alterations in Esophageal Tissues From Squamous Dysplasia to Carcinoma
Genetic Alterations in Esophageal Tissues From Squamous Dysplasia to Carcinoma
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食管组织从鳞状不典型增生到癌的基因改变
DOI：
10.1053/j.gastro.2017.03.033
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发表时间：
2017-07-01
期刊：
影响因子：
29.4
通讯作者：
Su, Min
中科院分区：
文献类型：
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作者：
Liu, Xi;Zhang, Min;Su, Min
背景与目的：食管鳞状细胞癌（ESCC）是最常见的食管癌亚型。在ESCC的发展过程中，发生在食管细胞的遗传变化知之甚少。我们对来自同一患者的食管非肿瘤、上皮内瘤变（IEN）和ESCC组织进行了下一代序列分析，以追踪肿瘤发展过程中的遗传变化。方法：我们对2012年至2015年在中国汕头大学医学院接受切除的70例ESCC患者的227份食管组织样本进行了全基因组、全外显子组或靶向序列分析（没有患者接受化疗或放疗）；我们同时分析了正常组织、单纯增生组织、发育不良组织（IEN）和ESCC组织。我们还从中国潮汕地区（ESCC的高风险地区）（ESCC的高风险地区）获得了1191例非肿瘤食管活检标本，并进行了免疫组织化学和组织学分析以检测炎症。结果：IEN和ESCC组织有相似的突变和拷贝数改变，频率相似；这些突变不同于单纯增生组织中检测到的突变。IEN组织具有与载脂蛋白B信使RNA编辑酶相关的突变，催化多肽样介导的突变（DNA损伤突变特征）。遗传分析表明，大多数escc是由早期的IEN克隆形成的。主干突变（在配对的IEN和ESCC组织中有10%的突变共享）位于调节DNA修复和细胞凋亡、增殖和粘附的基因中。TP53和CDKN2A的突变以及11q（包含CCND1）、3q（包含SOX2）、2q（包含NFE2L2）和9p（包含CDKN2A）的拷贝数改变被认为是主干变异；这些是在配对的IEN和ESCC样本克隆中检测到的高频显性突变。高危人群（潮汕地区）食道活检标本中，68.9%存在慢性炎症；炎症水平与非典型细胞结构和DNA损伤标志物相关。结论：我们分析了来自70例患者的非肿瘤、IEN和ESCC样本的突变和基因拷贝数变化。IEN和escc都有相似的突变和基因组不稳定性标记，包括载脂蛋白B信使RNA编辑酶、催化多肽样。在癌前病变中观察到的基因组变化可能用于识别ESCC风险患者。
BACKGROUND & AIMS: Esophageal squamous cell carcinoma (ESCC) is the most common subtype of esophageal cancer. Little is known about the genetic changes that occur in esophageal cells during the development of ESCC. We performed next-generation sequence analyses of esophageal nontumor, intra-epithelial neoplasia (IEN), and ESCC tissues from the same patients to track genetic changes during tumor development. METHODS: We performed whole-genome, whole-exome, or targeted sequence analyses of 227 esophageal tissue samples from 70 patients with ESCC undergoing resection at Shantou University Medical College in China from 2012 through 2015 (no patients had received chemotherapy or radiation therapy); we analyzed normal tissues, tissues with simple hyperplasia, dysplastic tissues (IEN), and ESCC tissues collected from different regions of the esophagus at the same time. We also obtained 1191 nontumor esophageal biopsy specimens from the Chaoshan region (a high-risk region for ESCC) of China (a high-risk region for ESCC) and performed immunohistochemical and histologic analyses to detect inflammation. RESULTS: IEN and ESCC tissues had similar mutations and copy number alterations, at similar frequencies; these differed from mutations detected in tissues with simple hyperplasia. IEN tissues had mutations associated with apolipoprotein B messenger RNA editing enzyme, catalytic polypeptide-like-mediated mutagenesis (a DNA damage mutational signature). Genetic analyses indicated that most ESCCs were formed from early stage IEN clones. Trunk mutations (mutations shared by > 10% of paired IEN and ESCC tissues) were in genes that regulate DNA repair and cell apoptosis, proliferation and adhesion. Mutations in TP53 and CDKN2A and copy number alterations in 11q (contains CCND1), 3q (contains SOX2), 2q (contains NFE2L2), and 9p (contains CDKN2A) were considered to be trunk variants; these were dominant mutations detected at high frequencies in clones of paired IEN and ESCC samples. In the esophageal biopsy samples from high-risk individuals (residing in the Chaoshan region), 68.9% had an evidence of chronic inflammation; the level of inflammation was correlated with atypical cell structures and markers of DNA damage. CONCLUSIONS: We analyzed mutations and gene copy number changes in nontumor, IEN, and ESCC samples, collected from 70 patients. IEN and ESCCs each had similar mutations and markers of genomic instability, including apolipoprotein B messenger RNA editing enzyme, catalytic polypeptide-like. Genomic changes observed in precancerous lesions might be used to identify patients at risk for ESCC.