Tumor heterogeneity is a recurrent concept as well as a frequent keyword in modern oncology. However, it has long been known that solid tumors originating from the same organ often show morphologic variability [1]. For certain tumors, the histologic phenotype and the degree of differentiation have prognostic significance, although they are usually of limited value in deciding the best therapeutic intervention, which is mainly based on the clinical stage. However, certain aspects of molecular heterogeneity are certainly of greater significance from a therapeutic point of view. For example, the estrogen receptor detection in breast cancer led to the selection of cases benefiting from antiestrogen treatments [2]. Identification of specific molecular alterations in tumors has resulted in targeted therapeutic approaches based on small organic compounds and/or monoclonal antibodies. For instance, in breast cancer expressing HER2, trastuzumab, an antibody targeting this membrane receptor, and lapatinib, an HER2 tyrosine kinase inhibitor, have given clear benefit particularly in combination with chemotherapy [3]. In colorectal cancer, examination of molecular alterations indicated that activating mutations in KRAS, which is downstream from EGFR in the RAS-MEK-ERK signaling pathway, conferred resistance to anti-EGFR antibodies cetuximab or panitumumab [4]. Another example concerns the BRAF inhibitors, vemurafenib and dabrafenib, both approved for melanoma bearing BRAF aberrations, but have proved effective also against BRAF-mutated tumors of different histologic types [5]. A major advance in the definition of tumor heterogeneity has come with high-throughput genomic technologies that identify the whole profile of chromosomal and point mutations of neoplasms. Analysis of the simultaneous presence of different aberrations means one can investigate the state of activation of entire pathways rather than just single proteins. Assessment of the whole profile of gene expression, epigenetic alterations and different regulatory elements, such as microRNAs and long ncRNAs, will probably soon enter clinical practice, together with proteomic and metabolomic measurements [6]. The challenge will be how to integrate all these data for a fuller characterization of cancers.

中文翻译：

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不仅肿瘤，而且治疗异质性。

肿瘤异质性是一个经常出现的概念，也是现代肿瘤学中的常见关键词。然而，早就知道起源于同一器官的实体瘤通常表现出形态变异性[1]。对于某些肿瘤，组织学表型和分化程度具有预后意义，尽管在决定最佳治疗干预措施（通常主要基于临床阶段）方面通常价值有限。但是，从治疗的角度来看，分子异质性的某些方面无疑具有更大的意义。例如，乳腺癌中雌激素受体的检测导致选择受益于抗雌激素治疗的病例[2]。肿瘤中特定分子改变的鉴定已导致基于小的有机化合物和/或单克隆抗体的靶向治疗方法。例如，在表达HER2的乳腺癌中，曲妥珠单抗（一种靶向该膜受体的抗体）和拉帕替尼（一种HER2酪氨酸激酶抑制剂）已获得明显的获益，特别是与化学疗法联用[3]。在大肠癌中，分子改变的检查表明激活突变在KRAS位于RAS-MEK-ERK信号通路中EGFR的下游，赋予了对抗EGFR抗体西妥昔单抗或帕尼单抗的抗性[4]。另一个例子涉及BRAF抑制剂vemurafenib和dabrafenib，它们均被批准用于携带BRAF畸变的黑色素瘤，但也被证明对BRAF有效组织学类型不同的突变肿瘤[5]。高通量基因组技术在肿瘤异质性定义方面取得了重大进展，该技术可以鉴定染色体的整体概况和肿瘤的点突变。对不同像差同时存在的分析意味着人们可以研究整个途径而不是单个蛋白质的激活状态。评估基因表达，表观遗传学改变和不同调控元件（如microRNA和长ncRNA）的整体情况，以及蛋白质组学和代谢组学测量，可能很快就会进入临床实践[6]。挑战将是如何整合所有这些数据以更全面地表征癌症。