Heterogeneity of KRAS Mutations in Pancreatic Ductal Adenocarcinoma

Heterogeneity of KRAS Mutations in Pancreatic Ductal Adenocarcinoma
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DOI：
10.1097/mpa.0000000000000624
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发表时间：
2016-09-01
期刊：
PANCREAS
影响因子：
2.9
通讯作者：
Baba, Hideo
Baba, Hideo
中科院分区：
医学4区
文献类型：
--
作者：
Hashimoto, Daisuke;Arima, Kota;Baba, Hideo

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目的：激活Kirsten大鼠肉瘤病毒癌基因同源物（KRAS）突变是胰腺癌中观察到的最常见和最频繁的变化。本研究旨在确定切除的胰腺导管腺癌的肿瘤内和转移淋巴结KRAS突变异质性的频率和程度。方法：从肿瘤中心、浸润前沿（n = 97）和淋巴结（n = 11）大体解剖的肿瘤组织进行DNA提取和KRAS密码子12和13的突变分析。在90个（92.8%）肿瘤中心中检测到KRAS密码子12的激活突变。在所有患者中均未检测到KRAS密码子13突变。在比较肿瘤中心和浸润前沿后，仅在4例（4.1%）病例中观察到KRAS的瘤内异质性。额外的侵袭前肿瘤分析揭示了与每个肿瘤中心一致的相同突变状态。原发肿瘤和转移淋巴结之间没有异质性观察。结论：肿瘤内异质性的KRAS突变状态是罕见的胰腺导管腺癌。此外，在本研究中未检测到原发性肿瘤和转移性淋巴结之间的KRAS异质性。这一发现与KRAS的致癌激活是胰腺癌中第一个驱动突变的假设一致。
Objectives: Activating Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are the most common and frequent changes observed in pancreatic cancer. This study aimed to determine the frequency and extent of intratumoral and metastatic lymph node KRAS mutation heterogeneity of resected pancreatic ductal adenocarcinoma.Methods: Tumor tissues macrodissected from tumor centers, invasion fronts (n = 97), and lymph nodes (n = 11) were subjected to DNA extraction and mutation analysis of KRAS codons 12 and 13 by pyrosequencing.Results: Activating mutations in codon 12 of KRAS were detected in 90 (92.8%) tumor centers. No mutations were detected in KRAS codon 13 in any patient. After a comparison of tumor centers and invasion fronts, intratumoral heterogeneity of KRAS was observed only in 4 (4.1%) cases. Additional invasion front tumor analysis revealed the same mutation status consistent with each tumor center. No heterogeneity was observed between primary tumors and metastatic lymph nodes.Conclusions: Intratumoral heterogeneity of the KRAS mutational status is rare in pancreatic ductal adenocarcinoma. In addition, no KRAS heterogeneity between primary tumors and metastatic lymph nodes was detected in this study. This finding is consistent with the hypothesis that oncogenic activation of KRAS is the first driver mutation in pancreatic cancer.