Dana-Farber Cancer Institute, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA.
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA; New York Genome Center, New York, NY, USA; Tri-institutional Ph.D. Program in Computational Biology and Medicine, New York, NY, USA; Caryl and Israel Englander Institute for Precision Medicine and Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
Cell Rep. 2021 Feb 2;34(5):108707. doi: 10.1016/j.celrep.2021.108707.
RTK/RAS/RAF pathway alterations (RPAs) are a hallmark of lung adenocarcinoma (LUAD). In this study, we use whole-genome sequencing (WGS) of 85 cases found to be RPA(-) by previous studies from The Cancer Genome Atlas (TCGA) to characterize the minority of LUADs lacking apparent alterations in this pathway. We show that WGS analysis uncovers RPA(+) in 28 (33%) of the 85 samples. Among the remaining 57 cases, we observe focal deletions targeting the promoter or transcription start site of STK11 (n = 7) or KEAP1 (n = 3), and promoter mutations associated with the increased expression of ILF2 (n = 6). We also identify complex structural variations associated with high-level copy number amplifications. Moreover, an enrichment of focal deletions is found in TP53 mutant cases. Our results indicate that RPA(-) cases demonstrate tumor suppressor deletions and genome instability, but lack unique or recurrent genetic lesions compensating for the lack of RPAs. Larger WGS studies of RPA(-) cases are required to understand this important LUAD subset.
RTK/RAS/RAF 通路改变（RPAs）是肺腺癌（LUAD）的标志。在这项研究中，我们使用全基因组测序（WGS）对先前来自癌症基因组图谱（TCGA）的 85 例 RPA（-）的研究进行分析，以描绘该通路中明显缺乏改变的 LUAD 的少数情况。我们发现，WGS 分析揭示了 85 个样本中的 28 个（33%）为 RPA（+）。在其余的 57 个病例中，我们观察到靶向 STK11（n=7）或 KEAP1（n=3）启动子或转录起始位点的局灶性缺失，以及与 ILF2 表达增加相关的启动子突变（n=6）。我们还发现了与高水平拷贝数扩增相关的复杂结构变异。此外，在 TP53 突变病例中发现了局灶性缺失的富集。我们的结果表明，RPA（-）病例表现出肿瘤抑制基因缺失和基因组不稳定性，但缺乏补偿 RPAs 缺乏的独特或反复发生的遗传病变。需要对 RPA（-）病例进行更大规模的 WGS 研究，以了解这一重要的 LUAD 亚组。
