State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200240, China.
Department of Thoracic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
Nat Commun. 2017 Oct 10;8(1):823. doi: 10.1038/s41467-017-00963-0.
Recent genomic analyses have revealed substantial tumor heterogeneity across various cancers. However, it remains unclear whether and how genomic heterogeneity is constrained during tumor evolution. Here, we sequence a unique cohort of multiple synchronous lung cancers (MSLCs) to determine the relative diversity and uniformity of genetic drivers upon identical germline and environmental background. We find that each multicentric primary tumor harbors distinct oncogenic alterations, including novel mutations that are experimentally demonstrated to be functional and therapeutically targetable. However, functional studies show a strikingly constrained tumorigenic pathway underlying heterogeneous genetic variants. These results suggest that although the mutation-specific routes that cells take during oncogenesis are stochastic, genetic trajectories may be constrained by selection for functional convergence on key signaling pathways. Our findings highlight the robust evolutionary pressures that simultaneously shape the expansion and constraint of genomic diversity, a principle that holds important implications for understanding tumor evolution and optimizing therapeutic strategies.Across cancer types tumor heterogeneity has been observed, but how this relates to tumor evolution is unclear. Here, the authors sequence multiple synchronous lung cancers, highlighting the evolutionary pressures that simultaneously shape the expansion and constraint of genomic heterogeneity.
近年来的基因组分析揭示了各种癌症中存在大量的肿瘤异质性。然而，目前尚不清楚基因组异质性是否以及如何在肿瘤进化过程中受到限制。在这里，我们对一组独特的多个同步肺癌（MSLC）进行了测序，以确定在相同的种系和环境背景下遗传驱动因素的相对多样性和均匀性。我们发现，每个多中心原发性肿瘤都携带有不同的致癌改变，包括实验证明具有功能和治疗靶向性的新突变。然而，功能研究表明，在异质遗传变异的背后存在着明显受限的肿瘤发生途径。这些结果表明，尽管细胞在致癌过程中所采取的突变特异性途径是随机的，但遗传轨迹可能受到选择的限制，以在关键信号通路中实现功能收敛。我们的研究结果强调了强大的进化压力，这些压力同时塑造了基因组多样性的扩展和限制，这一原则对于理解肿瘤进化和优化治疗策略具有重要意义。在癌症类型中观察到肿瘤异质性，但它与肿瘤进化的关系尚不清楚。在这里，作者对多个同步肺癌进行了测序，强调了同时塑造基因组异质性扩展和限制的进化压力。
