Very Long-term Survival Following Resection for Pancreatic Cancer Is Not Explained by Commonly Mutated Genes: Results of Whole-Exome Sequencing Analysis.
Very Long-term Survival Following Resection for Pancreatic Cancer Is Not Explained by Commonly Mutated Genes: Results of Whole-Exome Sequencing Analysis.
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DOI：
10.1158/1078-0432.ccr-14-2600
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发表时间：
2015-04-15
期刊：
影响因子：
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通讯作者：
Wood LD
中科院分区：
文献类型：
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作者：
Dal Molin M;Zhang M;de Wilde RF;Ottenhof NA;Rezaee N;Wolfgang CL;Blackford A;Vogelstein B;Kinzler KW;Papadopoulos N;Hruban RH;Maitra A;Wood LD
胰腺导管腺癌（PDAC）手术切除后的中位生存期目前<20个月。然而，生存期≥10年的患者只有一小部分，定义为极长期生存者（VLTS）。本研究的目的是确定切除的PDAC中的特定遗传改变是否决定了非常长期的生存。我们对来自存活≥10年的患者的8个PDAC的外显子组进行了测序。基于外显子组分析的结果，在来自VLTS的一系列27个另外的PDAC中进行所选基因的靶向测序。在35例VLTS癌症中的33例（94%）中鉴定出KRAS突变，代表了我们队列中最普遍的改变。TP 53、SMAD 4和CDKN 2A突变的发生率分别为69%、26%和17%。RNF 43的突变，以前与导管内乳头状粘液性肿瘤相关，在35例癌症中的4例（11%）中被发现。总之，我们的数据显示，与PDACs的生存率数据相比，VLTS癌的体细胞突变没有差异。VLTS和匹配对照组之间的临床病理特征的比较表明，年龄较小，早期阶段，良好/中度分化，和阴性切除边缘与VLTS。然而，更先进的阶段，穷人级或淋巴结疾病并不妨碍长期生存。我们的研究结果表明，在大多数患者中，常见突变基因的体细胞突变不太可能是手术切除PDAC后长期生存的主要决定因素。
The median survival following surgical resection of pancreatic ductal adenocarcinoma (PDAC) is currently <20 months. However, survival ≥10 years is achieved by a small subset of patients who are defined as very long-term survivors (VLTSs). The goal of this study was to determine whether specific genetic alterations in resected PDACs determined very long-term survival. We sequenced the exomes of 8 PDACs from patients who survived ≥10 years. Based on the results of the exomic analysis, targeted sequencing of selected genes was performed in a series of 27 additional PDACs from VLTSs. KRAS mutations were identified in 33 of 35 (94%) cancers from VLTSs and represented the most prevalent alteration in our cohort. TP53, SMAD4, and CDKN2A mutations occurred in 69%, 26%, and 17%, respectively. Mutations in RNF43, which have been previously associated with intraductal papillary mucinous neoplasms, were identified in 4 of the 35 cancers (11%). Taken together, our data show no difference in somatic mutations in carcinomas from VLTSs compared to available data from PDACs unselected for survival. Comparison of clinico-pathological features between VLTSs and a matching control group demonstrated that younger age, earlier stage, well/moderate grade of differentiation, and negative resection margins were associated with VLTS. However, more advanced stage, poor grade or nodal disease did not preclude long-term survival. Our results suggest that in most patients somatic mutations in commonly mutated genes are unlikely to be the primary determinant of very long-term survival following surgical resection of PDAC.