文章：

非小细胞肺癌生物学和治疗中的共发生基因组改变

Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy

原文发布日期：2019-08-12

DOI: 10.1038/s41568-019-0179-8

类型: Review Article

开放获取: 否

英文摘要：

The impressive clinical activity of small-molecule receptor tyrosine kinase inhibitors for oncogene-addicted subgroups of non-small-cell lung cancer (for example, those driven by activating mutations in the gene encoding epidermal growth factor receptor (EGFR) or rearrangements in the genes encoding the receptor tyrosine kinases anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 (ROS1) and rearranged during transfection (RET)) has established an oncogene-centric molecular classification paradigm in this disease. However, recent studies have revealed considerable phenotypic diversity downstream of tumour-initiating oncogenes. Co-occurring genomic alterations, particularly in tumour suppressor genes such as TP53 and LKB1 (also known as STK11), have emerged as core determinants of the molecular and clinical heterogeneity of oncogene-driven lung cancer subgroups through their effects on both tumour cell-intrinsic and non-cell-autonomous cancer hallmarks. In this Review, we discuss the impact of co-mutations on the pathogenesis, biology, microenvironmental interactions and therapeutic vulnerabilities of non-small-cell lung cancer and assess the challenges and opportunities that co-mutations present for personalized anticancer therapy, as well as the expanding field of precision immunotherapy.

摘要翻译： 

小分子受体酪氨酸激酶抑制剂在非小细胞肺癌致癌基因成瘾亚组（例如由表皮生长因子受体编码基因激活突变或间变性淋巴瘤激酶、ROS原癌基因1及转染期间重排基因编码的受体酪氨酸激酶重排驱动的亚组）中展现的显著临床活性，确立了该疾病以致癌基因为核心的分子分类范式。然而，近期研究揭示了肿瘤起始致癌基因下游存在显著的表型多样性。共存的基因组改变——尤其是TP53和LKB1等肿瘤抑制基因的变异——通过影响肿瘤细胞内在和非细胞自主的癌症特征，已成为致癌基因驱动肺癌亚组分子和临床异质性的核心决定因素。本综述将探讨共突变对非小细胞肺癌发病机制、生物学特性、微环境相互作用及治疗脆弱性的影响，评估共突变为个体化抗癌治疗带来的挑战与机遇，并探讨精准免疫治疗这一不断拓展的领域。

原文链接：

Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy