Clinical significance of the genetic landscape of pancreatic cancer and implications for identification of potential long-term survivors.
Clinical significance of the genetic landscape of pancreatic cancer and implications for identification of potential long-term survivors.
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DOI：
10.1158/1078-0432.ccr-12-1215
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发表时间：
2012-11-15
期刊：
影响因子：
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通讯作者：
Iacobuzio-Donahue CA
中科院分区：
文献类型：
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作者：
Yachida S;White CM;Naito Y;Zhong Y;Brosnan JA;Macgregor-Das AM;Morgan RA;Saunders T;Laheru DA;Herman JM;Hruban RH;Klein AP;Jones S;Velculescu V;Wolfgang CL;Iacobuzio-Donahue CA
KRAS、CDKN 2A、TP 53和SMAD 4的遗传改变是胰腺癌中最常见的事件。我们确定了这四种改变在同一种癌中共存的程度，以及它们对患者预后的影响。对接受尸检的胰腺癌患者进行了研究（n=79）。评估匹配的原发和转移组织中KRAS、CDKN 2A和TP 53的基因内突变，并对CDKN 2A、TP 53和SMAD 4蛋白产物进行免疫标记。每种癌中改变的驱动基因的数量与临床病理特征相关。Kaplan-Meier估计用于确定中位无病生存期和总生存期，考克斯比例风险模型用于比较风险因素。癌症中基因改变的驱动基因的数量是可变的，只有29名患者（37%）在所有四个基因分析中都有改变。改变的驱动基因的数量与无病生存期（p=0.008）、总生存期（p=0.041）和尸检时的转移负荷（p=0.002）显著相关。在多变量分析中，胰腺癌中驱动基因改变的数量与总生存率独立相关（p=0.046）。仅具有1至2个驱动基因改变的癌症富集于具有最长生存期的那些患者（中值23个月，范围1-53）。确定胰腺癌中四个主要驱动基因的状态，特别是它们在个体患者癌症中共存的程度，提供了关于疾病进展和生存的独特信息，其独立于临床分期和治疗状态。
Genetic alterations of KRAS, CDKN2A, TP53 and SMAD4 are the most frequent events in pancreatic cancer. We determined the extent to which these four alterations are coexistent in the same carcinoma, and their impact on patient outcome. Pancreatic cancer patients who underwent an autopsy were studied (n=79). Matched primary and metastasis tissues were evaluated for intragenic mutations in KRAS, CDKN2A and TP53 and immunolabeled for CDKN2A, TP53 and SMAD4 protein products. The number of altered driver genes in each carcinoma was correlated to clinicopathologic features. Kaplan-Meier estimates were used to determine median disease free and overall survival, and a Cox proportional hazards model used to compare risk factors. The number of genetically altered driver genes in a carcinoma was variable, with only 29 patients (37%) having an alteration in all four genes analyzed. The number of altered driver genes was significantly correlated with disease free survival (p=0.008), overall survival (p=0.041) and metastatic burden at autopsy (p=0.002). On multivariate analysis, the number of driver gene alterations in a pancreatic carcinoma remained independently associated with overall survival (p=0.046). Carcinomas with only one to two driver alterations were enriched for those patients with the longest survival (median 23 months, range 1–53). Determinations of the status of the four major driver genes in pancreatic cancer, and specifically the extent to which they are coexistent in an individual patients cancer, provides distinct information regarding disease progression and survival that is independent of clinical stage and treatment status.