文章：

结直肠癌的共识分子亚型和精准医学的发展

Consensus molecular subtypes and the evolution of precision medicine in colorectal cancer

原文发布日期：2017-01-04

DOI: 10.1038/nrc.2016.126

类型: Review Article

开放获取: 否

要点：

1. Molecular alterations fostering the progression of colorectal cancers are acquired early in the carcinogenesis process, and there is inter-connectivity among genomic drivers (gene mutations and chromosomal instability), transcriptomic subtypes (microsatellite instability immune, canonical, metabolic or mesenchymal) and immune signatures (highly immunogenic, poorly immunogenic or inflamed and immune tolerant).
2. Primary and metastatic samples display major similarities at the genomic level: novel gene alterations are usually related to chemotherapy or targeted therapy pressure. More studies on inter-metastatic spatial heterogeneity, molecular shifts at the transcriptomic level and changes in microenvironment markers are needed.
3. Until recently, the evolution of biomarkers for targeted therapies in colorectal cancer has been restrictive, with the identification of multiple negative predictive factors determining the response to epidermal growth factor receptor (EGFR) monoclonal antibodies. At progression to these agents, there is convergent reactivation of MAPK pathway
4. Emerging positive predictive markers for targeted therapies include infrequent genomic events, such as BRAF^V600E mutations, ERBB2 amplifications, anaplastic lymphoma kinase (ALK) and neurotrophic receptor tyrosine kinase (NTRK) fusions and alterations in upstream nodes of the WNT pathway, such as ring finger protein 43 (RNF43), zinc and ring finger 3 (ZNRF3) and R-spondin (RSPO) genes. For immune checkpoint inhibitors, promising biomarkers include microsatellite instability and DNA polymerase-ε (POLE) mutations
5. Biomarker–drug co-development has evolved to accommodate a 'multi-molecular, multi-drug' perspective of precision medicine. Novel contexts of vulnerability are likely to be identified, leading to drug-repurposing strategies and combination therapies to halt tumour evolution and tackle minimal residual disease.

要点翻译：

1. 结直肠癌进展相关的分子改变在癌变过程早期即已获得，且基因组驱动因素（基因突变和染色体不稳定性）、转录组亚型（微卫星不稳定免疫型、经典型、代谢型或间充质型）与免疫特征（高免疫原性、低免疫原性/炎症型及免疫耐受型）之间存在相互关联。
2. 原发灶与转移灶样本在基因组层面呈现高度相似性：新出现的基因改变通常与化疗或靶向治疗压力相关。目前亟需加强对转移灶间空间异质性、转录组层面分子动态及微环境标志物变化的研究。
3. 长期以来，结直肠癌靶向治疗生物标志物的演进始终受限，多种阴性预测因子决定了表皮生长因子受体（EGFR）单克隆抗体疗效。在使用这些药物治疗进展时，会出现MAPK通路的汇聚性再激活。
4. 新兴的靶向治疗阳性预测标志物包括罕见基因组事件，如BRAFV600E突变、ERBB2扩增、ALK与NTRK基因融合，以及WNT通路上游节点改变（如RNF43、ZNRF3和RSPO基因）。对于免疫检查点抑制剂，具有潜力的生物标志物包括微卫星不稳定性和DNA聚合酶ε（POLE）突变。
5. 生物标志物-药物协同开发已逐步转向适应精准医学的"多分子-多药物"视角。未来很可能识别出新的肿瘤脆弱性背景，从而推动药物重定位策略与联合疗法开发，以阻断肿瘤演进并清除微小残留病灶。

英文摘要：

Critical driver genomic events in colorectal cancer have been shown to affect the response to targeted agents that were initially developed under the 'one gene, one drug' paradigm of precision medicine. Our current knowledge of the complexity of the cancer genome, clonal evolution patterns under treatment pressure and pharmacodynamic effects of target inhibition support the transition from a one gene, one drug approach to a 'multi-gene, multi-drug' model when making therapeutic decisions. Better characterization of the transcriptomic subtypes of colorectal cancer, encompassing tumour, stromal and immune components, has revealed convergent pathway dependencies that mandate a 'multi-molecular' perspective for the development of therapies to treat this disease.

摘要翻译： 

结直肠癌中的关键驱动基因组事件已被证实会影响靶向药物的反应，而这些药物最初是在“一个基因，一种药物”的精准医学范式下开发的。目前我们对癌症基因组复杂性、治疗压力下克隆演化模式以及靶点抑制的药效学效应的认识，支持在治疗决策时从“一个基因，一种药物”的方法转向“多基因，多药物”模型。对结直肠癌转录组亚型（包括肿瘤、基质和免疫成分）的更精细刻画，揭示了趋同的通路依赖性，这要求在开发治疗该疾病的疗法时采取“多分子”视角。

原文链接：

Consensus molecular subtypes and the evolution of precision medicine in colorectal cancer