Cai Hongchen, Chew Su Kit, Li Chuan, Tsai Min K, Andrejka Laura, Murray Christopher W, Hughes Nicholas W, Shuldiner Emily G, Ashkin Emily L, Tang Rui, Hung King L, Chen Leo C, Lee Shi Ya C, Yousefi Maryam, Lin Wen-Yang, Kunder Christian A, Cong Le, McFarland Christopher D, Petrov Dmitri A, Swanton Charles, Winslow Monte M
Department of Genetics, Stanford University School of Medicine, Stanford, California.
Cancer Evolution and Genome Instability Laboratory, University College London Cancer Institute, London, United Kingdom.
Cancer Discov. 2021 Jul;11(7):1754-1773. doi: 10.1158/2159-8290.CD-20-1325. Epub 2021 Feb 19.
Cancer genotyping has identified a large number of putative tumor suppressor genes. Carcinogenesis is a multistep process, but the importance and specific roles of many of these genes during tumor initiation, growth, and progression remain unknown. Here we use a multiplexed mouse model of oncogenic KRAS-driven lung cancer to quantify the impact of 48 known and putative tumor suppressor genes on diverse aspects of carcinogenesis at an unprecedented scale and resolution. We uncover many previously understudied functional tumor suppressors that constrain cancer . Inactivation of some genes substantially increased growth, whereas the inactivation of others increases tumor initiation and/or the emergence of exceptionally large tumors. These functional analyses revealed an unexpectedly complex landscape of tumor suppression that has implications for understanding cancer evolution, interpreting clinical cancer genome sequencing data, and directing approaches to limit tumor initiation and progression. SIGNIFICANCE: Our high-throughput and high-resolution analysis of tumor suppression uncovered novel genetic determinants of oncogenic KRAS-driven lung cancer initiation, overall growth, and exceptional growth. This taxonomy is consistent with changing constraints during the life history of cancer and highlights the value of quantitative genetic analyses in autochthonous cancer models..
癌症基因分型已鉴定出大量假定的肿瘤抑制基因。肿瘤发生是一个多步骤过程，但这些基因中的许多在肿瘤起始、生长和进展过程中的重要性及具体作用仍不清楚。在此，我们使用一种由致癌性KRAS驱动的肺癌多重小鼠模型，以前所未有的规模和分辨率量化48个已知和假定的肿瘤抑制基因对肿瘤发生各个方面的影响。我们发现了许多以前研究较少的抑制癌症的功能性肿瘤抑制因子。一些基因的失活显著增加了肿瘤生长，而其他基因的失活则增加了肿瘤起始和/或出现特别大的肿瘤。这些功能分析揭示了一个出乎意料的复杂肿瘤抑制格局，这对于理解癌症演变、解释临床癌症基因组测序数据以及指导限制肿瘤起始和进展的方法具有重要意义。意义：我们对肿瘤抑制的高通量和高分辨率分析揭示了致癌性KRAS驱动的肺癌起始、总体生长和异常生长的新遗传决定因素。这种分类与癌症生命史中不断变化的限制因素一致，并突出了在原位癌症模型中进行定量遗传分析的价值。
