Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
State Key Laboratory of Natural Medicines, Research Center of Biostatistics and Computational Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
Genome Biol. 2021 Jan 4;22(1):7. doi: 10.1186/s13059-020-02230-w.
Crosstalk between genetic, epigenetic, and immune alterations in upper tract urothelial carcinomas and their role in shaping muscle invasiveness and patient outcome are poorly understood.
We perform an integrative genome- and methylome-wide profiling of diverse non-muscle-invasive and muscle-invasive upper tract urothelial carcinomas. In addition to mutations of FGFR3 and KDM6A, we identify ZFP36L1 as a novel, significantly mutated tumor suppressor gene. Overall, mutations of ZFP36 family genes (ZFP36, ZFP36L1, and ZFP36L2) are identified in 26.7% of cases, which display a high mutational load. Unsupervised DNA methylation subtype classification identifies two epi-clusters associated with distinct muscle-invasive status and patient outcome, namely, EpiC-low and EpiC-high. While the former is hypomethylated, immune-depleted, and enriched for FGFR3-mutated, the latter is hypermethylated, immune-infiltrated, and tightly associated with somatic mutations of SWI/SNF genes.
Our study delineates for the first time the key role for convergence between genetic and epigenetic alterations in shaping clinicopathological and immune upper tract urothelial carcinoma features.
上尿路尿路上皮癌中遗传、表观遗传和免疫改变之间的串扰及其在塑造肌肉侵袭性和患者预后中的作用尚不清楚。
我们对不同的非肌肉浸润性和肌肉浸润性上尿路尿路上皮癌进行了全基因组和全甲基化谱分析。除了 FGFR3 和 KDM6A 的突变外，我们还鉴定出 ZFP36L1 是一种新的、显著突变的肿瘤抑制基因。总体而言，ZFP36 家族基因（ZFP36、ZFP36L1 和 ZFP36L2）的突变在 26.7%的病例中被发现，具有很高的突变负荷。无监督的 DNA 甲基化亚型分类确定了两个与不同肌肉侵袭状态和患者预后相关的 epi 簇，即 EpiC-low 和 EpiC-high。前者呈低甲基化、免疫耗竭状态，并且富含 FGFR3 突变，后者呈高甲基化、免疫浸润状态，与 SWI/SNF 基因的体细胞突变密切相关。
我们的研究首次描绘了遗传和表观遗传改变之间的趋同在塑造上尿路尿路上皮癌临床病理和免疫特征中的关键作用。
