HGF/MET pathway aberrations as diagnostic, prognostic, and predictive biomarkers in human cancers

Cancer is a major cause of death worldwide. MET tyrosine kinase receptor [MET, c-MET, hepatocyte growth factor (HGF) receptor] pathway activation is associated with the appearance of several hallmarks of cancer. The HGF/MET pathway has emerged as an important actionable target across many solid tumors; therefore, biomarker discovery becomes essential in order to guide clinical intervention and patient stratification with the aim of moving towards personalized medicine. The focus of this review is on how the aberrant activation of the HGF/MET pathway in tumor tissue or the circulation can provide diagnostic and prognostic biomarkers and predictive biomarkers of drug response. Many meta-analyses have shown that aberrant activation of the MET pathway in tumor tissue, including MET gene overexpression, gene amplification, exon 14 skipping and other activating mutations, is almost invariably associated with shorter survival and poor prognosis. Most meta-analyses have been performed in non-small cell lung cancer (NSCLC), breast, head and neck cancers as well as colorectal, gastric, pancreatic and other gastrointestinal cancers. Furthermore, several studies have shown the predictive value of MET biomarkers in the identification of patients who gain the most benefit from HGF/MET targeted therapies administered as single or combination therapies. The highest predictive values have been observed for response to foretinib and savolitinib in renal cancer, as well as tivantinib in NSCLC and colorectal cancer. However, some studies, especially those based on MET expression, have failed to show much value in these stratifications. This may be rooted in lack of standardization of methodologies, in particular in scoring systems applied in immunohistochemistry determinations or absence of oncogenic addiction of cancer cells to the MET pathway, despite detection of overexpression. Measurements of amplification and mutation aberrations are less likely to suffer from these pitfalls. Increased levels of MET soluble ectodomain (sMET) in circulation have also been associated with poor prognosis; however, the evidence is not as strong as it is with tissue-based biomarkers. As a diagnostic biomarker, sMET has shown its value in distinguishing cancer patients from healthy individuals in prostate and bladder cancers and in melanoma. On the other hand, increased circulating HGF has also been presented as a valuable prognostic and diagnostic biomarker in many cancers; however, there is controversy on the predictive value of HGF as a biomarker. Other biomarkers such as circulating tumor DNA (ctDNA) and tumor HGF levels have also been briefly covered. In conclusion, HGF/MET aberrations can provide valuable diagnostic, prognostic and predictive biomarkers and represent vital assets for personalized cancer therapy.癌症是全球范围内的主要致死病因。MET酪氨酸激酶受体（MET, c-MET, 肝细胞生长因子（hepatocyte growth factor, HGF）受体）通路的异常激活与多种癌症特征的出现密切相关。HGF/MET通路现已成为多种实体瘤的重要可靶向治疗靶点，因此为指导临床干预与患者分层、推进个体化医疗，生物标志物的发掘变得至关重要。本综述的核心在于探讨肿瘤组织或循环系统中HGF/MET通路的异常激活，如何可作为诊断性、预后性以及药物响应预测性生物标志物。多项荟萃分析显示，肿瘤组织中MET通路的异常激活——包括MET基因过表达、基因扩增、14号外显子跳跃突变及其他激活突变——几乎均与更短的生存期与不良预后相关。此类荟萃分析大多针对非小细胞肺癌（non-small cell lung cancer, NSCLC）、乳腺癌、头颈部癌，以及结直肠癌、胃癌、胰腺癌等胃肠道恶性肿瘤开展。此外，多项研究证实了MET生物标志物在筛选可从HGF/MET靶向治疗（单药或联合治疗方案）中获益最大的患者群体时的预测价值。其中，在肾癌中针对福替尼（foretinib）和赛沃替尼（savolitinib）的响应，以及在非小细胞肺癌与结直肠癌中针对替沃扎尼（tivantinib）的响应，均展现出最高的预测价值。不过，部分研究——尤其是基于MET表达水平的研究——并未在患者分层中体现出显著价值，这可能源于检测方法缺乏标准化：特别是免疫组化检测中的评分系统不统一，或是即便检测到MET过表达，肿瘤细胞也未出现对MET通路的癌基因成瘾性。而基因扩增与突变异常的检测则较少受此类局限影响。循环系统中MET可溶性胞外域（soluble ectodomain, sMET）水平升高同样与不良预后相关，但相关证据强度不及组织来源的生物标志物。作为诊断性生物标志物，sMET在前列腺癌、膀胱癌及黑色素瘤中可有效区分癌症患者与健康个体。另一方面，循环HGF水平升高也被证实可作为多种癌症中具有价值的预后与诊断生物标志物，但关于其作为预测性生物标志物的价值仍存在争议。其他生物标志物如循环肿瘤DNA（circulating tumor DNA, ctDNA）与肿瘤组织HGF水平也在本文中被简要提及。总而言之，HGF/MET通路异常可作为极具价值的诊断性、预后性与预测性生物标志物，是个体化癌症治疗的重要辅助工具。