文献综述 Open Access
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
世界华人消化杂志. 2017-08-08; 25(22): 2045-2050
在线出版日期: 2017-08-08. doi: 10.11569/wcjd.v25.i22.2045
KRAS/BRAF基因与结肠癌糖代谢研究现状
刘亮, 黄劲柏, 邱大胜
刘亮, 长江大学第一临床医学院 长江大学附属第一医院 湖北省荆州市 434000
黄劲柏, 荆州市第一人民医院放射科 湖北省荆州市 434000
邱大胜, 湖北省肿瘤医院PET/CT中心 湖北省武汉市 430079
刘亮, 住院医师, 主要从事分子影像学方面的研究.
作者贡献分布: 刘亮负责综述; 黄劲柏与邱大胜负责审校.
通讯作者: 邱大胜, 主任医师, 430079, 湖北省武汉市洪山区卓刀泉南路116号, 湖北省肿瘤医院PET/CT中心. hbpetct@163.com
收稿日期: 2017-03-31
修回日期: 2017-06-19
接受日期: 2017-06-27
在线出版日期: 2017-08-08

正电子发射断层成像术(positron emission tomography, PET)/计算机断层扫描(computed tomography, CT)显像可用于结肠癌的诊断、监测疗效和预后评估. 18F标记葡萄糖(2-fluorine-18-fluoro-2-deeoxy-D-glucose, 18F-FDG)是PET/CT常用显像剂, 可以反映结肠癌活体组织葡萄糖代谢. KRAS/BRAF基因检测常用于结肠癌靶向治疗方案的选择及评估其治疗效果. 文献报道18F-FDG-PET/CT显像可预测结肠癌KRAS/BRAF基因状态, 能以无创的方式预测结肠癌抗表皮生长因子受体靶向治疗效果. 目前国内有关KRAS/BRAF基因与结肠癌糖代谢的研究相对较少, 本文结合近期的相关文献进行概述.

关键词: 结肠癌; KRAS/BRAF基因; 正电子发射断层扫描; 葡萄糖转运体-1

核心提要:KRAS/BRAF基因检测对结肠癌的治疗及判断预后具有重要意义, 肿瘤细胞微环境(低糖或低氧)与KRAS/BRAF突变以及FDG摄取存在明显相关性, 18F-FDG-PET/CT显像作为一种无创的检查手段, 对预测结直肠癌KRAS/BRAF基因状态具有重要意义, 从而为临床提供重要参考.
引文著录: 刘亮, 黄劲柏, 邱大胜. KRAS/BRAF基因与结肠癌糖代谢研究现状. 世界华人消化杂志 2017; 25(22): 2045-2050
Association between KRAS/BRAF gene and glucose metabolism in colon cancer
Liang Liu, Jin-Bai Huang, Da-Sheng Qiu
Liang Liu, First Clinical Medical College of Yangtze University; the First Affiliated Hospital of Yangtze University, Jingzhou 434000, Hubei Province, China
Jin-Bai Huang, Department of Radiology, the First People's Hospital of Jingzhou City, Jingzhou 434000, Hubei Province, China
Da-Sheng Qiu, PET/CT Center of Hubei Cancer Hospital, Wuhan 430079, Hubei Province, China
Correspondence to: Da-Sheng Qiu, Chief Physician, PET/CT Center of Hubei Cancer Hospital, 116 Zhuodaoquan South Road, Hongshan District, Wuhan 430079, Hubei Province, China. hbpetct@163.com
Received: March 31, 2017
Revised: June 19, 2017
Accepted: June 27, 2017
Published online: August 8, 2017

Positron emission tomography (PET)/computed tomography (CT), a diagnostic tool to evaluate glucose metabolic activity by measuring accumulation of FDG (18F-fluorodeoxy glucose, an analogue of glucose), can be used for detecting tumors, monitoring treatment response and predicting patients' prognosis in colon cancer. KRAS/BRAF gene test has been used to determine the choice of target therapy for colon cancer and to predict its prognosis. It has been reported that FDG-PET/CT has a potential in predicting mutational status and therefore may play an important role in determining therapeutic strategies by non-invasively predicting treatment response to anti-epidermal growth factor receptor (EGFR) therapy. However, it is inconclusive whether KRAS/BRAF gene mutation correlates with glucose metabolism detected by PET/CT in colon cancer. In this review, we summarize the current findings discussing the underlying mechanisms between glucose metabolism and KRAS/BRAF gene mutation in colon cancer.

Key Words: Colon cancer; KRAS/BRAF gene; PET/CT; GLUT-1
0 引言

结肠癌是我国消化系统常见的恶性肿瘤之一, 发病率年均上升3%-4%. 目前, 我国结直肠癌发病率虽然低于欧美发达国家, 但我国结直肠癌发病和死亡例数均居第1位, 分别占世界发病和死亡总例数的18.6%和20.1%[1]. 结肠癌发病与基因突变关系密切, 研究[2,3]表明左半结肠癌与抑癌基因(例如APC、P53)的失活和KRAS基因突变等相关, 而右半结肠癌与癌基因激活、BRAF基因突变、CpG岛甲基化表型等相关. KRAS/BRAF基因检测对结肠癌靶向治疗及判断预后具有重要意义, 18F标记葡萄糖(2-fluorine-18-fluoro-2-deeoxy-D-glucose, 18F-FDG)-正电子发射断层成像术(positron emission tomography, PET)/计算机断层扫描(computed tomography, CT)作为一种无创的检查方式, 能准确的反映活体结肠癌组织葡萄糖代谢, 对结肠癌的诊断、分期、判断预后和评估疗效有其不可替代的优势, 本文就KRAS/BRAF突变与结肠癌糖代谢相关性的研究近况作简要概述.

1 KRAS/BRAF基因

RAS基因是由Robert Weinberg从人类膀胱肿瘤中分离的首个癌基因, 活化的Ras导致丝裂酶原活化蛋白激酶(mitogen-actived protein kinase, MAPK)通路的活化, 进而调控细胞的生长与分化, 目前RAS-RAF-MAPK通路了解的最为清楚[4]. RAS基因包括HRAS、KRAS、NRAS, 其中KRAS突变与人类表皮生长因子受体(epidermal growth factor receptor, EGFR)级联反应相关, 并且与结肠癌(colorectal cancer, CRC)和非小细胞肺癌的发生发展有关[5-7]. CRC的KRAS突变多位于第12、13位, 以腺癌和黏液腺癌多见[8,9]. RAF是RAS的下游基因, RAF激活对多种肿瘤的发生、发展产生重要影响, 如结直肠癌、胰腺癌、乳头状甲状腺癌、卵巢癌、肺癌[10-14]. RAF家族包括丝氨酸/苏氨酸激酶(ARAF、BRAF及CRAF), RAF突变以BRAF常见, BRAF突变常见于V600E位点[15,16]. KRAS/BRAF突变导致RAS-RAF-MAPK通路传导异常, 引起细胞过度增殖和分化而诱发肿瘤, 并对肿瘤的增殖、侵袭和转移发挥重要作用. 因此KRAS/BRAF突变会影响CRC的靶向治疗效果[17-19].

2 KRAS/BRAF基因检测与CRC的靶向治疗

结肠癌的治疗以手术为主、放化疗为辅, 而抗EGFR靶向治疗是目前的研究热点. 研究[20]表明, 西妥昔单抗可尝试作为一线药辅助治疗CRC, 并可增加KRAS基因野生型CRC的化疗效果, 然而对于KRAS突变型CRC, 目前还没有疗效较好的靶向药物[21], 2016版美国国立综合癌症网络指南推荐对于初始可切除RAS野生型转移性结直肠癌(metastatic colorectal cancer, mCRC)术前使用新辅助化疗. 文献[22]报道BRAF基因的突变率为23%, 与KRAS基因突变相比, BRAF基因突变常见于尚未发生远处转移的结肠癌, 以Ⅱ、Ⅲ期CRC患者多见, BRAF突变型CRC的恶性程度高、淋巴结转移率和局部晚期发生率高[23]. PETACC-3研究检测了1404例Ⅱ、Ⅲ期结肠癌患者的KRAS/BRAF突变结果显示, KRAS/BRAF突变型患者的总生存率比野生型患者差. 故KRAS/BRAF基因检测对于评估抗EGFR抗体生物靶向治疗的选择及其远期疗效评估具有指导意义[24-27], 然而KRAS/BRAF基因检测除了与KRAS/BRAF突变的异质性[28,29]相关外, 还与受检标本密切相关, 而用于KRAS/BRAF基因检测的标本源于活检或手术, 且转移性CRC的检测样本不容易获取. 此外组织切片的目标DNA含量较低对KRAS/BRAF基因检测结果亦有重要影响. 因此, 能有效反映CRC活体组织KRAS/BRAF基因状态的无创检查对CRC靶向治疗具有重要价值, 研究[30,31]表明结肠癌18F-FDG的摄取及KRAS/BRAF的状态明显相关, 这表明KRAS/BRAF突变与结肠癌糖代谢密切相关.

3 结肠癌PET/CT显像与KRAS/BRAF突变

PET/CT显像作为一种无创的检查手段, 能更好从形态学和功能学为疾病诊断提供重要信息, 已被广泛用于肿瘤的诊断、监测、分期、再分期以及疗效评估[32,33]. 正电子核素18F-FDG是PET/CT显像常用的显像剂, 能准确地从分子水平上反映CRC葡萄糖代谢. 文献[34]报道18F-FDG-PET/CT显像对CRC转移灶的术前评估和术后随访具有重要价值, 可以减少无意义的开腹手术, 有助于发现隐匿的转移灶并制定相应手术范围, 为根治性切除提供依据. 18F-FDG-PET/CT显像常用的观察指标是最大标准化摄取值(maximum standard uptake value, SUVmax), SUVmax的高低主要与细胞膜表面的葡萄糖转运体(glucose transporter, GLUT)数量及己糖激酶有关. 肿瘤细胞增殖迅速, 通过加强糖酵解来增加能量供给, 即沃伯格效应(Warburg effect)[35]. 肿瘤细胞GLUT-1的过度表达可以促进葡萄糖的吸收, 为沃伯格效应提供了大量能量底物. GLUT-1最早从人红细胞膜中提取的葡萄糖转运蛋白, 是葡萄糖转运蛋白的亚型之一, 其广泛分布于所有组织的细胞膜, 是转运葡萄糖的主要载体. 研究[36-39]表明GLUT-1在多种肿瘤过度表达, 如结直肠癌、肝癌、胰腺癌、食管癌、肺癌、乳腺癌、卵巢癌、肾癌等. GLUT-1表达受抑制时, 通过介导EGFR、MAPK信号途径导致细胞分化减少、葡萄糖摄取减低、细胞运动和侵袭减弱[40]. 当EGFR的配体受抑制时, GLUT-1的表达及葡萄糖摄取均降低[41]. 研究[42]表明缺氧、KRAS突变与GLUT-1表达存在协同交互作用: 结肠癌细胞系在缺氧状态下, KRAS突变通过PI3K信号路径使缺氧耐受因子-1α的表达增加. 缺氧同样会导致KRAS突变增加, 这表明缺氧与KRAS突变可能存在反馈机制[43]. 此外, 缺氧通过介导缺氧耐受因子-1α增加GLUT-1表达[44], 亦有研究[45,46]表明KRAS突变型CRC细胞在含氧量正常的情况下通过GLUT-1表达上调来增加18F-FDG的摄取. 研究[30]表明GLUT-1的表达与18F-FDG的摄取及KRAS/BRAF的状态明显相关而与己糖激酶Ⅱ无明显相关. 此外, 有学者通过对结直肠癌细胞系进行体外研究[47]表明肿瘤细胞的低糖环境促使KRAS、BRAF突变进而促进GLUT-1表达及葡萄糖摄取, 结肠癌细胞18F-FDG-PET/CT显像检出癌前病变进展的时间与KRAS或BRAF突变的时间一致, 这表明结肠癌细胞葡萄糖摄取与KRAS或BRAF突变存在相关性. 曾有学者对50例行PET/CT检查的CRC患者进行回顾性分析[30], 他们发现与KRAS/BRAF野生型相比, KRAS/BRAF突变型患者原发灶SUVmax更高, 当以13或14作为SUVmax的临界值时, 18F-FDG-PET/CT显像预测结直肠癌KRAS/BRAF突变的准确率可达75%. Lee等[48]研究表明SUVmax及SUVpeak可以预测KRAS突变及淋巴结转移, 但受到炎症的影响. 研究[31]表明SUVmax及TW40%(40% threshold level for maximal uptake of tumor width)可以预测KRAS突变, SUVmax预测结肠癌突变较准确而TW40%预测直肠癌突变较准确. Cho等[49]研究表明较高的FDG指数(SUVmax、总病灶糖酵解)可以预测KRAS突变状态. Kawada等[50]研究表明转移性结直肠癌FDG摄取与KRAS突变状态有关, 18F-FDG-PET/CT显像有助于预测转移性结直肠癌KRAS突变状态并对其治疗决策产生影响. 亦有文献[51]报道18F-FDG-PET/CT显像可以反映结直肠癌及非小细胞肺癌KRAS突变状态. 综上, KRAS/BRAF突变可通过GLUT-1影响活体结肠癌组织SUVmax, 18F-FDG-PET/CT有可能成为反映活体组织结肠癌突变状态有效的无创检查方式, 从而为结肠癌的治疗和预后提供重要参考.

4 展望

KRAS/BRAF基因检测对结肠癌的治疗及判断预后具有重要意义, 肿瘤细胞微环境(低糖或低氧)与KRAS/BRAF突变以及FDG摄取存在明显相关性, 18F-FDG-PET/CT显像作为一种无创的检查手段, 对预测结直肠癌KRAS/BRAF基因状态具有重要价值. 然而FDG-PET/CT显像预测结直肠癌KRAS/BRAF突变准确性在60%左右, 且与研究对象、实验方法有密切相关, 是否存在其他基因影响RAS-RAF-MAPK通路传导尚未可知, 现有研究对FDG-PET/CT显像预测结直肠癌KRAS/BRAF突变尚有争议, 尚需大样本研究及探索FDG-PET参数来提高FDG-PET/CT显像预测结直肠癌KRAS/BRAF突变的准确性, 从而为CRC的靶向治疗及预后提供重要参考. 在倡导针对肿瘤精准医疗的时代背景下, 探讨结肠癌PET/CT显像SUVmax与KRAS/BRAF突变状态的内在联系对于结肠癌的精准医疗具有重要意义.

评论
背景资料

结肠癌是我国消化系统常见的恶性肿瘤之一, 发病率年均上升3%-4%. 结肠癌发病与基因突变关系密切, KRAS/BRAF基因检测对结肠癌靶向治疗及判断预后具有重要意义, 有文献报道18F-FDG-PET/CT作为一种无创的检查方式, 能预测结肠癌KRAS/BRAF突变状态, 从而为临床提供重要参考.

研发前沿

18F-FDG-PET/CT显像作为一种无创的检查手段, 对预测结直肠癌KRAS/BRAF基因状态具有重要价值. 然而FDG-PET/CT显像预测结直肠癌KRAS/BRAF突变准确性在60%左右, 且与研究对象、实验方法有密切相关, 是否存在其他基因影响RAS-RAF-MAPK通路传导尚未可知, 现有研究对FDG-PET/CT显像预测结直肠癌KRAS/BRAF突变尚有争议, 尚需大样本研究及探索FDG-PET参数来提高FDG-PET/CT显像预测结直肠癌KRAS/BRAF突变的准确性, 从而为结肠癌(colorectal cancer, CRC)的靶向治疗及预后提供重要参考.

相关报道

有学者通过对结直肠癌细胞系进行体外研究表明肿瘤细胞的低糖环境促使KRAS、BRAF突变进而促进葡萄糖转运体-1表达及葡萄糖摄取, 结肠癌细胞18F-FDG-PET/CT显像检出癌前病变进展的时间与KRAS或BRAF突变的时间一致, 这表明结肠癌细胞葡萄糖摄取与KRAS或BRAF突变存在相关性. 曾有学者对50例行PET/CT检查的CRC患者进行回顾性分析, 他们发现与KRAS/BRAF野生型相比, KRAS/BRAF突变型患者原发灶最大标准化摄取值(maximum standard uptake value, SUVmax)更高, 当以13或14作为SUVmax的临界值时, 18F-FDG-PET/CT显像预测结直肠癌KRAS/BRAF突变的准确率可达75%.

创新盘点

本文结合近期文献, 对KRAS/BRAF基因背景、CRC活体组织KRAS/BRAF基因状态的无创检查对CRC靶向治疗必要性以及18F-FDG-PET/CT反映活体组织结肠癌突变状态的机制和有效性进行了分析.

应用要点

KRAS/BRAF基因检测对结肠癌靶向治疗及判断预后具有重要意义, 有文献报道18F-FDG-PET/CT作为一种无创的检查方式, 能预测结肠癌KRAS/BRAF突变状态, 从而为临床提供重要参考.

同行评议者

刘鹏飞, 主任医师, 东南大学医学院附属江阴医院消化内科

同行评价

本文内容较为全面、深入, 立意新颖、语言精练、层次分明、有逻辑性, 对临床工作有很好的指导意义.

手稿来源: 自由投稿

学科分类: 胃肠病学和肝病学

手稿来源地: 湖北省

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