Cross-cancer profiling of molecular alterations within the human autophagy interaction network.
Cross-cancer profiling of molecular alterations within the human autophagy interaction network.
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DOI：
10.1080/15548627.2015.1067362
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发表时间：
2015
期刊：
影响因子：
13.3
通讯作者：
Gorski SM
中科院分区：
文献类型：
--
作者：
Lebovitz CB;Robertson AG;Goya R;Jones SJ;Morin RD;Marra MA;Gorski SM
自噬的异常激活或破坏在各种癌症的临床前模型中促进肿瘤发生，但自噬途径是否是人类癌症患者样本中复发性分子改变的靶点尚不清楚。为了解决这个悬而未决的问题，我们调查了211个人类自噬相关基因的DNA序列和RNA表达水平的肿瘤相关改变，并使用来自癌症基因组图谱联盟的序列数据研究了它们与多种癌症类型患者生存结局的相关性。我们发现3个（RB 1CC 1/FIP 200，ULK 4，WDR 45/WIPI 4）和一个（ATG 7）核心自噬基因分别在子宫内膜癌和肾透明细胞癌的体细胞突变中处于阳性选择之下，而29个自噬调节因子和通路相互作用因子，包括先前鉴定的KEAP 1，NFE 2L 2和MTOR，在检查的11种癌症类型中的6种中发生了显著突变。基因表达分析显示，GABARAPL 1和MAP 1 LC 3C/LC 3C转录在乳腺癌和非小细胞肺癌中的丰度低于匹配的正常组织对照; ATG 4D转录在肺鳞状细胞癌中增加，ATG 16 L2转录在肾癌中也是如此。肿瘤中自噬相关mRNA水平的无监督聚类对9种癌症类型中的3种（急性髓性白血病，透明细胞肾癌和头颈癌）的患者总生存期进行了分层。这些分析提供了人类肿瘤中反复改变的自噬相关基因的第一个综合资源，并突出了自噬干扰可能与患者总体生存相关的癌症类型和亚型。
Aberrant activation or disruption of autophagy promotes tumorigenesis in various preclinical models of cancer, but whether the autophagy pathway is a target for recurrent molecular alteration in human cancer patient samples is unknown. To address this outstanding question, we surveyed 211 human autophagy-associated genes for tumor-related alterations to DNA sequence and RNA expression levels and examined their association with patient survival outcomes in multiple cancer types with sequence data from The Cancer Genome Atlas consortium. We found 3 (RB1CC1/FIP200, ULK4, WDR45/WIPI4) and one (ATG7) core autophagy genes to be under positive selection for somatic mutations in endometrial carcinoma and clear cell renal carcinoma, respectively, while 29 autophagy regulators and pathway interactors, including previously identified KEAP1, NFE2L2, and MTOR, were significantly mutated in 6 of the 11 cancer types examined. Gene expression analyses revealed that GABARAPL1 and MAP1LC3C/LC3C transcripts were less abundant in breast cancer and non-small cell lung cancers than in matched normal tissue controls; ATG4D transcripts were increased in lung squamous cell carcinoma, as were ATG16L2 transcripts in kidney cancer. Unsupervised clustering of autophagy-associated mRNA levels in tumors stratified patient overall survival in 3 of 9 cancer types (acute myeloid leukemia, clear cell renal carcinoma, and head and neck cancer). These analyses provide the first comprehensive resource of recurrently altered autophagy-associated genes in human tumors, and highlight cancer types and subtypes where perturbed autophagy may be relevant to patient overall survival.