使用靶向深度测序检测评估KRAS、CDKN2A、TP53和SMAD4基因突变数量作为胰腺癌预后生物标志物的效用
Utility of Assessing the Number of Mutated KRAS, CDKN2A, TP53, and SMAD4 Genes Using a Targeted Deep Sequencing Assay as a Prognostic Biomarker for Pancreatic Cancer.
作者信息
Hayashi Hideyuki, Kohno Takashi, Ueno Hideki, Hiraoka Nobuyoshi, Kondo Shunsuke, Saito Motonobu, Shimada Yoko, Ichikawa Hitoshi, Kato Mamoru, Shibata Tatsuhiro, Morizane Chigusa, Sakamoto Yasunari, Shimada Kazuaki, Komatsu Yoshito, Sakamoto Naoya, Okusaka Takuji
机构信息
From the *Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo; †Division of Genome Biology, National Cancer Center Research Institute, Tokyo; ‡Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo; §Department of Cancer Chemotherapy, Hokkaido University Hospital Cancer Center, Sapporo; ∥Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo; Divisions of ¶Genetics and #Cancer Genomics, National Cancer Center Research Institute, Tokyo; and **Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, Tokyo, Japan.
出版信息
Pancreas. 2017 Mar;46(3):335-340. doi: 10.1097/MPA.0000000000000760.
OBJECTIVES
KRAS, CDKN2A, TP53, and SMAD4 have been recognized as major driver genes in pancreatic carcinogenesis. We examined somatic mutations in 50 cancer-related genes, including the four above-mentioned driver genes, to identify genomic biomarkers for predicting the outcome of patients with pancreatic cancer.
METHODS
Genomic DNA was extracted from fresh-frozen specimens obtained from 100 patients with pancreatic cancer who had undergone a pancreatectomy with curative intent. The mutation profile was obtained using a single targeted deep sequencing assay performed with a next-generation sequencer, and the associations with clinicopathological factors were analyzed.
RESULTS
Mutations in the KRAS, CDKN2A, TP53, and SMAD4 genes were detected in 96% (96/100), 42% (42/100), 13% (13/100), and 7% (7/100) of all patients, respectively. Among the 71 patients who underwent a radical operation followed by adjuvant chemotherapy, patients with fewer mutations among the four driver genes tended to have a better outcome. A multivariate analysis using the Cox proportional hazard model showed that the presence of 0 to 2 mutated driver genes was an independent predictor of a better overall survival (hazard ratio for death, 0.20; P = 0.0040).
CONCLUSIONS
The number of mutated driver genes assessed using a targeted deep sequencing assay was a promising prognostic biomarker for pancreatic cancer.
目的
KRAS、CDKN2A、TP53和SMAD4已被确认为胰腺癌发生过程中的主要驱动基因。我们检测了50个癌症相关基因中的体细胞突变，包括上述4个驱动基因，以确定预测胰腺癌患者预后的基因组生物标志物。
方法
从100例接受了根治性胰腺切除术的胰腺癌患者的新鲜冷冻标本中提取基因组DNA。使用下一代测序仪进行的单靶向深度测序分析获得突变谱，并分析其与临床病理因素的相关性。
结果
在所有患者中，KRAS、CDKN2A、TP53和SMAD4基因的突变检出率分别为96%（96/100）、42%（42/100）、13%（13/100）和7%（7/100）。在71例接受根治性手术并辅助化疗的患者中，4个驱动基因中突变较少的患者往往预后较好。使用Cox比例风险模型进行的多变量分析显示，存在0至2个突变驱动基因是总体生存率较好的独立预测因素（死亡风险比，0.20；P = 0.0040）。
结论
使用靶向深度测序分析评估的驱动基因突变数量是一种很有前景的胰腺癌预后生物标志物。
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