Mutually exclusive mutations in NOTCH1 and PIK3CA associated with clinical prognosis and chemotherapy responses of esophageal squamous cell carcinoma in China.
Mutually exclusive mutations in NOTCH1 and PIK3CA associated with clinical prognosis and chemotherapy responses of esophageal squamous cell carcinoma in China.
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NOTCH1和PIK3CA的互斥突变与中国食管鳞癌临床预后和化疗反应的关系
DOI：
10.18632/oncotarget.6120
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发表时间：
2016-01-19
期刊：
影响因子：
--
通讯作者：
Cui Y
中科院分区：
文献类型：
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作者：
Song B;Cui H;Li Y;Cheng C;Yang B;Wang F;Kong P;Li H;Zhang L;Jia Z;Bi Y;Wang J;Zhou Y;Liu J;Wang J;Zhao Z;Zhang Y;Hu X;Shi R;Yang J;Liu H;Yan T;Li Y;Xu E;Qian Y;Xi Y;Guo S;Chen Y;Wang J;Li G;Liang J;Jia J;Chen X;Guo J;Wang T;Zhang Y;Li Q;Wang C;Cheng X;Zhan Q;Cui Y
与临床特征相关的复发性遗传异常可用于确定患者的预后，选择治疗方法和预测对治疗的反应。食管鳞状细胞癌（ESCC）包含临床意义不明的基因组改变。我们的目的是确定在ESCC中经常检测到的互斥突变，并表征其与临床变量的相关性。我们分析了来自中国太行山地区的104个ESCC的下一代测序数据;选择了96对用于基于深度靶捕获的验证和临床和病理数据分析。我们使用Szczurek提出的模型来识别排他性突变，并将这些突变与病理学结果相关联。采用单因素和多因素分析及考克斯比例风险模型分析突变与总生存率和化疗反应的关系。研究结果在太行山89例食管鳞癌患者的样本分析中得到了验证。我们确定了ESCC样本中NOTCH 1和PIK 3CA突变之间的统计学显著互斥性。NOTCH 1基因突变与高分化、早期恶性肿瘤和区域淋巴结转移较少相关。尽管如此，NOTCH 1突变患者的生存时间比没有NOTCH 1突变的患者短，并且对化疗没有反应。相比之下，PIK 3CA突变的患者对化疗的反应更好，生存时间比没有PIK 3CA突变的患者更长。在中国患者的ESCC遗传分析中，我们发现了NOTCH 1和PIK 3CA的互斥突变。这些发现可能增加我们对ESCC发展的理解，并可作为预后因素。
Recurrent genetic abnormalities that correlate with clinical features could be used to determine patients' prognosis, select treatments and predict responses to therapy. Esophageal squamous cell carcinoma (ESCC) contains genomic alterations of undefined clinical significance. We aimed to identify mutually exclusive mutations that are frequently detected in ESCCs and characterized their associations with clinical variables. We analyzed next-generation-sequencing data from 104 ESCCs from Taihang Mountain region of China; 96 pairs were selected for deep target-capture-based validation and analysis of clinical and pathology data. We used model proposed by Szczurek to identify exclusive mutations and to associate these with pathology findings. Univariate and multivariate analyses with Cox proportional hazards model were used to examine the association between mutations and overall survival and response to chemotherapy. Findings were validated in an analysis of samples from 89 patients with ESCC from Taihang Mountain. We identified statistically significant mutual exclusivity between mutations in NOTCH1 and PIK3CA in ESCC samples. Mutations in NOTCH1 were associated with well-differentiated, early-stage malignancy and less metastasis to regional lymph nodes. Nonetheless, patients with NOTCH1 mutations had shorter survival times than patients without NOTCH1 mutations, and failed to respond to chemotherapy. In contrast, patients with mutations in PIK3CA had better responses to chemotherapy and longer survival times than patients without PIK3CA mutations. In a genetic analysis of ESCCs from patients in China, we identified mutually exclusive mutations in NOTCH1 and PIK3CA. These findings might increase our understanding of ESCC development and be used as prognostic factors.