Background

Upper urinary tract urothelial cancer (UTUC) may have unique etiologic and genomic factors compared to bladder cancer.

Objective

To characterize the genomic landscape of UTUC and provide insights into its biology using comprehensive integrated genomic analyses.

Design, setting, and participants

We collected 31 untreated snap-frozen UTUC samples from two institutions and carried out whole-exome sequencing (WES) of DNA, RNA sequencing (RNAseq), and protein analysis.

Outcome measurements and statistical analysis

Adjusting for batch effects, consensus mutation calls from independent pipelines identified DNA mutations, gene expression clusters using unsupervised consensus hierarchical clustering (UCHC), and protein expression levels that were correlated with relevant clinical variables, The Cancer Genome Atlas, and other published data.

Results and limitations

WES identified mutations in FGFR3 (74.1%; 92% low-grade, 60% high-grade), KMT2D (44.4%), PIK3CA (25.9%), and TP53 (22.2%). APOBEC and CpG were the most common mutational signatures. UCHC of RNAseq data segregated samples into four molecular subtypes with the following characteristics. Cluster 1: no PIK3CA mutations, nonsmokers, high-grade <pT2 tumors, high recurrences. Cluster 2: 100% FGFR3 mutations, low-grade tumors, tobacco use, noninvasive disease, no bladder recurrences. Cluster 3: 100% FGFR3 mutations, 71% PIK3CA, no TP53 mutations, five bladder recurrences, tobacco use, tumors all <pT2. Cluster 4: KMT2D (62.5%), FGFR3 (50%), TP53 (50%) mutations, no PIK3CA mutations, high-grade pT2+ disease, tobacco use, carcinoma in situ, shorter survival. We identified a novel SH3KBP1-CNTNAP5 fusion.

Conclusions

Mutations in UTUC occur at differing frequencies from bladder cancer, with four unique molecular and clinical subtypes. A novel SH3KBP1 fusion regulates RTK signaling. Further studies are needed to validate the described subtypes, explore their responses to therapy, and better define the novel fusion mutation.

Patient summary

We conducted a comprehensive study of the genetics of upper urinary tract urothelial cancer by evaluating DNA, RNA and protein expression in 31 tumors. We identified four molecular subtypes with distinct behaviors. Future studies will determine if these subtypes appear to have different responses to treatments.

中文翻译：

---

上尿道上皮癌的综合基因组学表征

背景

与膀胱癌相比，上尿路尿路上皮癌（UTUC）可能具有独特的病因和基因组因素。

客观的

使用全面的综合基因组分析来表征UTUC的基因组景观并提供对其生物学的见解。

设计，设置和参与者

我们从两个机构收集了31个未经处理的速冻UTUC样品，并进行了DNA的全外显子测序（WES），RNA测序（RNAseq）和蛋白质分析。

成果测量和统计分析

调整批处理效果后，来自独立管道的共有突变调用确定了DNA突变，使用无监督共有层次聚类（UCHC）的基因表达簇以及与相关临床变量，《癌症基因组图谱》和其他已发表数据相关的蛋白质表达水平。

结果与局限性

WES在FGFR3（74.1％; 92％低等级，60％高等级），KMT2D（44.4％），PIK3CA（25.9％）和TP53（22.2％）中鉴定出突变。APOBEC和CpG是最常见的突变特征。RNAseq数据的UCHC将样品分为具有以下特征的四个分子亚型。聚类1：无PIK3CA突变，不吸烟者，高度<pT2肿瘤，高复发率。第2组：100％FGFR3突变，低度肿瘤，吸烟，无创性疾病，无膀胱复发。第3类：100％FGFR3突变，71％PIK3CA，无TP53突变，五次膀胱癌复发，吸烟，肿瘤均<pT2。集群4：KMT2D（62.5％），FGFR3（50％），TP53（50％）突变，无PIK3CA突变，高度pT2 +疾病，吸烟，原位癌，生存期较短。我们确定了一种新颖的SH3KBP1-CNTNAP5融合体。

结论

UTUC的突变与膀胱癌的发生频率不同，具有四种独特的分子和临床亚型。一种新颖的SH3KBP1融合调节RTK信号。需要进一步的研究来验证所描述的亚型，探索其对治疗的反应，并更好地定义新型融合突变。

病人总结

我们通过评估31种肿瘤中的DNA，RNA和蛋白质表达，对上尿路尿路上皮癌的遗传学进行了全面研究。我们确定了具有不同行为的四种分子亚型。未来的研究将确定这些亚型对治疗的反应是否不同。