Yan Weixin, Zhang Aiguo, Powell Michael J
Robotics Research Institute, School of Mechanical Engineering, Shanghai Jiao Tong University, Shanghai, 200240, P.R. China.
DiaCarta Inc., 2600 Hilltop Drive, Richmond, CA, 94806, USA.
Chin J Cancer. 2016 Jul 21;35(1):68. doi: 10.1186/s40880-016-0131-1.
Gastrointestinal stromal tumors (GISTs) have been recognized as a biologically distinctive type of tumor, different from smooth muscle and neural tumors of the gastrointestinal tract. The identification of genetic aberrations in proto-oncogenes that drive the growth of GISTs is critical for improving the efficacy of cancer therapy by matching targeted drugs to specific mutations. Research into the oncogenic mechanisms of GISTs has found that these tumors frequently contain activating gene mutations in either platelet-derived growth factor receptor A (PDGFRA) or a receptor tyrosine protein associated with a mast cell growth factor receptor encoded by the KIT gene. Mutant cancer subpopulations have the potential to disrupt durable patient responses to molecularly targeted therapy for GISTs, yet the prevalence and size of subpopulations remain largely unexplored. Detection of the cancer subpopulations that harbor low-frequency mutant alleles of target proto-oncogenes through the use of molecular genetic methods, such as polymerase chain reaction (PCR) target amplification technology, is hampered by the high abundance of wild-type alleles, which limit the sensitivity of detection of these minor mutant alleles. This is especially true in the case of mutant tumor DNA derived "driver" and "drug-resistant" alleles that are present in the circulating cell-free tumor DNA (cfDNA) in the peripheral blood circulation of GIST patients. So-called "liquid biopsy" allows for the dynamic monitoring of the patients' tumor status during treatment using minimally invasive sampling. New methodologies, such as a technology that employs a xenonucleic acid (XNA) clamping probe to block the PCR amplification of wild-type templates, have allowed improved molecular detection of these low-frequency alleles both in tissue biopsy samples and in cfDNA. These new methodologies could be widely applied for minimally invasive molecular testing in the therapeutic management of GISTs.
胃肠道间质瘤（GISTs）已被公认为一种生物学特性独特的肿瘤类型，不同于胃肠道的平滑肌肿瘤和神经肿瘤。识别驱动GISTs生长的原癌基因中的遗传畸变，对于通过将靶向药物与特定突变相匹配来提高癌症治疗效果至关重要。对GISTs致癌机制的研究发现，这些肿瘤通常在血小板衍生生长因子受体A（PDGFRA）或由KIT基因编码的与肥大细胞生长因子受体相关的受体酪氨酸蛋白中含有激活基因突变。突变的癌症亚群有可能破坏患者对GISTs分子靶向治疗的持久反应，但亚群的患病率和大小在很大程度上仍未得到充分探索。通过使用分子遗传学方法，如聚合酶链反应（PCR）靶向扩增技术，检测携带靶原癌基因低频突变等位基因的癌症亚群，受到野生型等位基因高丰度的阻碍，这限制了对这些微小突变等位基因的检测灵敏度。在GIST患者外周血循环中循环游离肿瘤DNA（cfDNA）中存在的突变肿瘤DNA衍生的“驱动”和“耐药”等位基因的情况下尤其如此。所谓的“液体活检”允许使用微创采样在治疗期间动态监测患者的肿瘤状态。新的方法，如一种采用异源核酸（XNA）钳夹探针来阻断野生型模板PCR扩增的技术，已能够在组织活检样本和cfDNA中改进对这些低频等位基因的分子检测。这些新方法可广泛应用于GISTs治疗管理中的微创分子检测。
