Postgraduate Medical Institute, Faculty of Health, Social Care and Education, Anglia Ruskin University, Bishops Hall Lane, Chelmsford, Essex CM1 1SQ, United Kingdom.
Methods. 2013 Jan;59(1):116-25. doi: 10.1016/j.ymeth.2012.10.003. Epub 2012 Oct 16.
Colorectal cancer (CRC) develops and progresses through a systematic selection for (epi) genetic alterations that drive the transformation from normal colon epithelium to adenocarcinoma. These changes affect both noncoding RNAs and mRNAs and so define the clinical behaviour of cancer cells within a distinctive host genetic and environmental context. Although earlier diagnosis and more effective treatment modalities have decreased mortality from CRC, prognostic stratification and adjuvant therapy selection after surgery remain dependent on broad descriptive classifications, opportune histological markers of poor prognosis and chemotherapy efficacy data derived from diverse CRC populations. Crucially, there is significant inter- and intra-individual variability in response to, and tolerance of, chemotherapy treatments. These limitations explain the small clinical benefit of new agents studied in contemporary phase III trials. Molecular assays have the potential to address these constraints and there has been intense interest in the identification of clinically relevant molecular biomarkers. These must be easy to obtain and quantify and ideally represent steps in well-understood carcinogenic pathways or host-response mechanisms. Although some biomarkers can provide broad prognostic information based on CRC subtype (e.g. MSI status) or can somewhat predict response to targeted therapies (e.g. KRAS), no RNA-based biomarkers have entered routine clinical practice. This is due, in part, to the genetic heterogeneity of both patients and CRC. In addition, serious underlying issues with regards to study design, poor technical protocols, inadequate quality controls and inappropriate data analysis prevent successful translation of research results. Consequently, the identification of clinically relevant panels of biomarkers will depend not just on further advances in our understanding of CRC biology, but will need to be coupled with appropriate study designs and more suitable, standardised and transparent techniques.
结直肠癌（CRC）的发生和发展是通过系统选择（表观遗传学）遗传改变来驱动正常结肠上皮向腺癌的转化。这些变化既影响非编码 RNA 又影响 mRNA，从而在独特的宿主遗传和环境背景下定义癌细胞的临床行为。尽管早期诊断和更有效的治疗方法降低了结直肠癌的死亡率，但手术后的预后分层和辅助治疗选择仍然依赖于广泛的描述性分类、预后不良的适时组织学标志物和来自不同 CRC 人群的化疗疗效数据。至关重要的是，对化疗治疗的反应和耐受性存在显著的个体间和个体内差异。这些局限性解释了当代 III 期临床试验中研究的新药物的临床获益较小。分子检测有潜力解决这些限制，并且人们对鉴定临床相关的分子生物标志物产生了浓厚的兴趣。这些标志物必须易于获取和定量，并且理想情况下代表在已知的致癌途径或宿主反应机制中的步骤。尽管一些生物标志物可以基于 CRC 亚型（例如，MSI 状态）提供广泛的预后信息，或者可以在一定程度上预测对靶向治疗的反应（例如，KRAS），但没有基于 RNA 的生物标志物已进入常规临床实践。这部分是由于患者和 CRC 的遗传异质性。此外，研究设计、不良技术方案、不充分的质量控制和不适当的数据分析方面存在严重的根本问题，这阻碍了研究结果的成功转化。因此，临床相关的生物标志物组合的鉴定不仅取决于我们对 CRC 生物学的进一步理解，还需要与适当的研究设计以及更合适、标准化和透明的技术相结合。
