Association of Alterations in Main Driver Genes With Outcomes of Patients With Resected Pancreatic Ductal Adenocarcinoma.
Association of Alterations in Main Driver Genes With Outcomes of Patients With Resected Pancreatic Ductal Adenocarcinoma.
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DOI：
10.1001/jamaoncol.2017.3420
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发表时间：
2018-03-08
期刊：
影响因子：
28.4
通讯作者：
Wolpin BM
中科院分区：
文献类型：
--
作者：
Qian ZR;Rubinson DA;Nowak JA;Morales-Oyarvide V;Dunne RF;Kozak MM;Welch MW;Brais LK;Da Silva A;Li T;Li W;Masuda A;Yang J;Shi Y;Gu M;Masugi Y;Bui J;Zellers CL;Yuan C;Babic A;Khalaf N;Aguirre A;Ng K;Miksad RA;Bullock AJ;Chang DT;Tseng JF;Clancy TE;Linehan DC;Findeis-Hosey JJ;Doyle LA;Thorner AR;Ducar M;Wollison B;Laing A;Hahn WC;Meyerson M;Fuchs CS;Ogino S;Hornick JL;Hezel AF;Koong AC;Wolpin BM
虽然胰腺腺癌切除术患者的疾病复发风险很高，但很少有标志物可用于告知患者的预后。评估胰腺腺癌的四个主要驱动基因的改变和癌症切除后的患者预后。我们通过免疫组织化学和下一代测序分析了来自356名切除胰腺腺癌患者的福尔马林固定石蜡包埋肿瘤的KRAS、CDKN2A、SMAD4和TP53的蛋白表达和DNA改变，这些患者在美国三个中心进行了评估。使用Cox比例风险回归评估驱动基因改变与无病生存期（DFS）和总生存期（OS）的关系，评估风险比（HR）和95%置信区间（CI），并调整年龄、性别、肿瘤特征、机构和围手术期治疗。KRAS突变型肿瘤患者的DFS和OS较KRAS野生型肿瘤患者差，中位OS分别为20.3个月和38.6个月，5年OS分别为13.0%和30.2%。KRAS g12d突变肿瘤患者的预后特别差，其中位OS为15.3个月。肿瘤缺乏CDKN2A表达的患者与肿瘤保留CDKN2A的患者相比，DFS和OS更差，中位OS分别为19.7个月和24.6个月，5年OS为11.9%和19.5%。SMAD4状态与DFS或OS无关，而TP53状态仅与DFS相关（P=0.04）。驱动基因改变较多的患者DFS和OS较差。与0 ~ 2个基因改变的患者相比，4个基因改变的患者的DFS HR为1.79 (1.24 ~ 2.59，P<0.01)， OS为1.38 （0.98 ~ 1.94，P=0.06）。0-2基因改变患者的5年总生存率为18.4%，3基因改变患者为14.1%，4基因改变患者为8.2%。四种驱动基因的改变与作为疾病复发第一部位的局部复发无显著相关。患者预后与胰腺腺癌切除术后四个主要驱动基因的改变有关。
Although patients with resected pancreatic adenocarcinoma are at high risk for disease recurrence, few markers are available to inform patient outcomes. To evaluate alterations of the four main driver genes for pancreatic adenocarcinoma and patient outcomes after cancer resection. We analyzed protein expression and DNA alterations for KRAS, CDKN2A, SMAD4, and TP53 by immunohistochemistry and next-generation sequencing in formalin-fixed, paraffin-embedded tumors from 356 patients with resected pancreatic adenocarcinoma evaluated at three U.S. centers. Associations of driver gene alterations with disease-free survival (DFS) and overall survival (OS) were evaluated using Cox proportional hazards regression with estimation of hazard ratios (HR) and 95% confidence intervals (CI) and adjustment for age, sex, tumor characteristics, institution, and peri-operative treatment. DFS and OS among patients with resected pancreatic adenocarcinoma Patients with KRAS mutant tumors had worse DFS and OS compared to patients with KRAS wild-type tumors, with median OS of 20.3 versus 38.6 months and 5-year OS of 13.0% versus 30.2%, respectively. Particularly poor outcomes were identified in patients with KRAS G12D-mutant tumors, who had median OS of 15.3 months. Patients whose tumors lacked CDKN2A expression had worse DFS and OS compared to patients whose tumors retained CDKN2A, with median OS of 19.7 versus 24.6 months and 5-year OS of 11.9% versus 19.5%, respectively. SMAD4 status was not associated with DFS or OS, while TP53 status was associated only with DFS (P=0.04). Patients had worse DFS and OS with greater number of altered driver genes. Compared to patients with 0-2 altered genes, those with 4 altered genes had HR for DFS of 1.79 (1.24-2.59; P<0.01) and OS of 1.38 (0.98-1.94; P=0.06). Five-year OS was 18.4% for patients with 0-2 gene alterations, 14.1% for 3 alterations and 8.2% for 4 alterations. Alterations in the four driver genes were not significantly associated with local recurrence as the first site of disease recurrence. Patient outcomes are associated with alterations of the four main driver genes in resected pancreatic adenocarcinoma.
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影响因子：
9
作者：
Winter JM;Tang LH;Klimstra DS;Liu W;Linkov I;Brennan MF;DʼAngelica MI;DeMatteo RP;Fong Y;Jarnagin WR;Oʼreilly EM;Allen PJ
通讯作者：
Allen PJ
影响因子：
64.8
作者：
Bailey, Peter;Chang, David K.;Grimmond, Sean M.
通讯作者：
Grimmond, Sean M.
影响因子：
9
作者：
Gerdes, B;Ramaswamy, A;Bartsch, DK
通讯作者：
Bartsch, DK
影响因子：
45.3
作者：
Iacobuzio-Donahue, Christine A.;Fu, Baojin;Laheru, Daniel
通讯作者：
Laheru, Daniel
影响因子：
254.7
作者：
Siegel, Rebecca L.;Miller, Kimberly D.;Jemal, Ahmedin
通讯作者：
Jemal, Ahmedin