PO.CL12.01 · 临床研究
将转录组膀胱癌亚型应用于国际队列中的上尿路尿路上皮癌（UTUC）揭示种族差异与转化局限性
Application of transcriptomic bladder-cancer subtypes to upper-tract urothelial carcinoma (UTUC) across international cohorts reveals racial differences and translational limitations
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摘要 Abstract
中文摘要
背景与目的：UTUC的管理遵循膀胱癌（BC）指南，但可以进一步优化。分子分型为肌层浸润性（MI）和非肌层浸润性（NMI）BC的肿瘤生物学和治疗应答/耐药提供了宝贵见解，对UTUC也可能具有类似价值。与NMIBC类似，UTUC在亚型上以腔面-乳头状（LumP）为主，这促使人们提出了更细致的UTUC特异性分类方案。在此，我们研究了MIBC和NMIBC分型是否可转化应用于UTUC。
方法：从Cedars-Sinai医学中心（美国洛杉矶）和近畿大学（日本大阪）回顾性收集组织学确诊的FFPE UTUC肾输尿管切除标本。对126例肿瘤进行RNA-seq，并使用consensus-MIBC和UROMOL2021-NMIBC框架进行分类。通过Kaplan-Meier分析估计无事件生存期（EFS），排除既往或同期患有BC的病例。
结果：在126例UTUC中，69例（54.8%）为NMI，55例（47.3%）为MI。LumP亚型最常见（57%），在NMI-UTUC中富集（75%）而在MI-UTUC中较低（36%），与NMIBC对比MIBC的情况相符。Cedars-Sinai的肿瘤主要为NMI（59%），而近畿的肿瘤大多为MI（58%），提示人群差异。Cedars-Sinai中LumP的富集（NMI的80%对MI的33%）与近畿更为均衡的分布（NMI 5/10，MI 7/15）形成对比，提示潜在的种族特异性变异。在LumP-UTUC中，四种UROMOL类别均有代表，而非LumP UTUC大多为UROMOL 2b。按LumP与其他分层显示，NMI-和MI-UTUC中呈现相反（但不显著）的生存趋势：LumP在NMI-UTUC中5年EFS较差，但在MI-UTUC中结局较好。对LumP NMI-UTUC按UROMOL类别进一步分层显示EFS无显著差异，尽管2b类肿瘤的结局与LumP MI-UTUC相当地差。病理T分期仍是最强的预后因素（EFS：Ta > T1 > T2 > T3/4；p < 0.05）。
结论：UTUC中LumP的高发主要由NMI肿瘤驱动，重现了NMIBC的生物学特征。亚型和分期分布在西方与亚洲队列间存在差异，提示种族相关的分子多样性。虽然源自BC的分类器可对UTUC进行归类，但其临床解读并不能直接转化。肿瘤分期作为结局的主要决定因素，其重要性超过分子亚型。
查看英文原文 English abstract
Background and Objectives: Management of UTUC follows bladder cancer (BC) guidelines but could be refined. Molecular subtyping has yielded valuable insights into tumor biology and therapy response/resistance for muscle-invasive (MI) and non-MI (NMI) BC and could have similar value for UTUC. Like NMIBC, UTUC is predominantly luminal-papillary (LumP) in subtype, which has spurred more granular UTUC-specific classification schemes. Here, we investigated whether MIBC and NMIBC subtyping could be translated to UTUC.
Methods: Histologically confirmed FFPE UTUC nephroureterectomy specimens were retrospectively collected from Cedars-Sinai Medical Center (Los Angeles, USA) and Kindai University (Osaka, Japan). RNA-seq was performed on 126 tumors, which were classified using consensus-MIBC and UROMOL2021-NMIBC frameworks. Event-free survival (EFS) was estimated by Kaplan-Meier analysis, excluding cases with prior or concurrent BC.
Results: Of 126 UTUCs, 69 (54.8%) were NMI and 55 (47.3%) MI. The LumP subtype was most common (57%), enriched in NMI-UTUC (75%) versus MI-UTUC (36%), mirroring NMIBC vs. MIBC. Cedars-Sinai tumors were mainly NMI (59%), while Kindai tumors were mostly MI (58%), suggesting population differences. LumP enrichment in Cedars-Sinai (80% of NMI vs. 33% of MI) contrasted with more balanced distributions in Kindai (5/10 NMI, 7/15 MI), indicating potential race-specific variation.Within LumP-UTUC, all four UROMOL classes were represented, whereas non-LumP UTUCs were mostly UROMOL 2b. Stratification by LumP vs. other revealed opposing (but not significant) survival trends in NMI- and MI-UTUC: LumP had poorer 5-year EFS in NMI-UTUC but better outcomes in MI-UTUC. Further stratification of LumP NMI-UTUC by UROMOL class showed no significant EFS differences, although Class 2b tumors had comparably poor outcomes to LumP MI-UTUC. Pathologic T stage remained the strongest prognostic factor (EFS: Ta > T1 > T2 > T3/4; p < 0.05).
Conclusions: LumP prevalence in UTUC is largely driven by NMI tumors, recapitulating NMIBC biology. Subtype and stage distributions vary between Western and Asian cohorts, implying race-related molecular diversity. While BC-derived classifiers can categorize UTUC, their clinical interpretation does not directly translate. Tumor stage outweighs molecular subtype as the principal determinant of outcome.
利益披露 Disclosure
J. M. Scurll, None..
H. Bahlburg, None..
T. Phung, None..
J. Heard, None..
M. Hashimoto, None..
K. Fujita, None..
D. Luthringer, None..
T. Sakatani, None..
K. Murakami, None.
C. J. Rosser,
Nonagen Bioscience Employment, Stock.
E. A. Gibb, None..
P. C. Black1, None..
H. Furuya, None.