Mutational Analysis of 472 Urothelial Carcinoma Across Grades and Anatomic Sites
Mutational Analysis of 472 Urothelial Carcinoma Across Grades and Anatomic Sites
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DOI：
10.1158/1078-0432.ccr-18-3147
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发表时间：
2019-04-15
影响因子：
11.5
通讯作者：
Kwiatkowski, David J.
中科院分区：
文献类型：
--
作者：
Nassar, Amin H.;Umeton, Renato;Kwiatkowski, David J.
目的：本研究的目的是描述整个尿路上皮癌（UC）谱的突变景观，以确定突变特征和潜在的治疗靶点。使用靶向外显子组测序（n = 237个基因），我们分析了82例低度非肌层浸润性膀胱癌的突变谱，结果：126例高级别（HG）NMIBC，199例肌肉浸润性膀胱癌（MIBC），10例LG上尿路上皮癌（LG-UTUC）和55例HG-UTUC。FGFR 3和KDM 6A突变在LG-NMIBC中（分别为72%和44%）比其他膀胱亚型更常见。FGFR 3改变也在LG-UTUC与HG-UTUC肿瘤中富集（80%与16%）。相比之下，TP 53和RB 1突变在所有3种HG尿路上皮癌亚型中比在LG-NIMBC中显著更频繁（分别为45%-58%对4%; 9%-22%对0）。在LG-NMIBC肿瘤中，KDM 6A突变在女性中比男性更常见（71% vs. 38%）。HGNMIBC和MIBC的肿瘤突变负荷（TMB）高于LG-NMIBC（分别为P = 0.001和P < 0.01）。DNA损伤修复（DDR）改变与HG-NMIBC和MIBC肿瘤中更高的TMB相关，与LG-NMIBC和HG-UTUC相比，这两种肿瘤类型也富含APOBEC突变特征。FGFR 3，PIK 3CA和EP 300的改变与HG-UTUC的总体生存率较差相关，并且同时发生。结论：我们的分析表明，一部分MIBC可能来自LG-NMIBC以外的前驱病变。KDM 6A突变在LG-NIMBC女性中的发生率是男性的两倍。DDR基因突变和APOBEC诱变驱动HG-NMIBC和MIBC中的突变。UTUC具有与膀胱癌不同的突变谱。
Purpose: The purpose of this study is to characterize the mutational landscape across the spectrum of urothelial carcinoma (UC) to identify mutational features and potential therapeutic targets.Experimental Design: Using targeted exome sequencing (n = 237 genes), we analyzed the mutation spectra of 82 lowgrade nonmuscle-invasive bladder cancers (LG-NMIBC), 126 high-grade (HG) NMIBC, 199 muscle-invasive bladder cancers (MIBC), 10 LG-upper tract urothelial cancers (LG-UTUC), and 55 HG-UTUC.Results: FGFR3 and KDM6A mutations were significantly more common in LG-NMIBC (72% and 44%, respectively) versus other bladder subtypes. FGFR3 alterations were also enriched in LG-UTUC versus HG-UTUC tumors (80% vs. 16%). In contrast, TP53 and RB1 mutations were significantly more frequent in all 3 HG urothelial carcinoma subtypes than in LG-NIMBC (45%-58% vs. 4%; 9%-22% vs. 0; respectively). Among LG-NMIBC tumors, KDM6A mutations were more common in women than in men (71% vs. 38%). HGNMIBC and MIBC had higher tumor mutational burden (TMB) than LG-NMIBC (P = 0.001 and P < 0.01, respectively). DNA-damage repair (DDR) alterations were associated with a higher TMB in HG-NMIBC and MIBC tumors, and these two tumor types were also enriched for an APOBEC mutational signature compared with LG-NMIBC and HG-UTUC. Alterations in FGFR3, PIK3CA, and EP300 correlated with worse overall survival in HG-UTUC and occurred concurrently.Conclusions: Our analysis suggests that a fraction of MIBCs likely arise from precursor lesions other than LG-NMIBC. KDM6A mutations are twice as common in women with LG-NIMBC than those in men. DDR gene mutations and APOBEC mutagenesis drive mutations in HG-NMIBC and MIBC. UTUC has a distinct mutation profile from bladder cancer.