Department of Pathology and Laboratory Medicine, The Warren Albert Medical School of Brown University, Lifespan Academic Medical Center, and the Legorreta Cancer Center at Brown University, Providence, Rhode Island; Laboratory of Systems Cancer Biology, The Rockefeller University, New York, New York.
Department of Pathology and Laboratory Medicine, The Warren Albert Medical School of Brown University, Lifespan Academic Medical Center, and the Legorreta Cancer Center at Brown University, Providence, Rhode Island.
Mod Pathol. 2024 Mar;37(3):100424. doi: 10.1016/j.modpat.2024.100424. Epub 2024 Jan 12.
The micropapillary subtype of urothelial carcinoma (MPUC) of the bladder is a very aggressive histological variant of urothelial bladder cancer (UBC). A high frequency of MPUC contains activating mutations in the extracellular domain (ECD) of ERBB2. We sought to further characterize ERBB2 ECD-mutated MPUC to identify additional genomic alterations that have been associated with tumor progression and therapeutic response. In total, 5,485 cases of archived formalin-fixed, paraffin-embedded UBC underwent comprehensive genomic profiling to identify ERBB2 ECD-mutated MPUC and evaluate the frequencies of genomic co-alterations. We identified 219 cases of UBC with ERBB2 ECD mutations (74% S310F and 26% S310Y), of which 63 (28.8%) were MPUC. Genomic analysis revealed that TERT, TP53, and ARID1A were the most common co-altered genes in ERBB2-mutant MPUC (82.5%, 58.7%, and 39.7%, respectively) and did not differ from ERBB2-mutant non-MPUC (86.5%, 51.9%, and 35.3%). The main differences between ERBB2 ECD-mutated MPUC compared with non-MPUC were KMT2D, RB1, and MTAP alterations. KMT2D and RB1 are tumor-suppressor genes. KMT2D frequency was significantly decreased in ERBB2 ECD-mutated MPUC (6.3%) in contrast to non-MPUC (27.6%; P < .001). RB1 mutations were more frequent in ERBB2 ECD-mutated MPUC (33.3%) than in non-MPUC (17.3%; P = .012). Finally, MTAP loss, an emerging biomarker for new synthetic lethality-based anticancer drugs, was less frequent in ERBB2 ECD-mutated MPUC (11.1%) than in non-MPUC (26.9%; P = .018). Characterizing the genomic landscape of MPUC may not only improve our fundamental knowledge about this aggressive morphological variant of UBC but also has the potential to identify possible prognostic and predictive biomarkers that may drive tumor progression and dictate treatment response to therapeutic approaches.
膀胱尿路上皮癌的微乳头状亚型（MPUC）是一种非常侵袭性的尿路上皮膀胱癌（UBC）组织学变体。高频 MPUC 含有 ERBB2 细胞外结构域（ECD）的激活突变。我们试图进一步描述 ERBB2 ECD 突变的 MPUC，以确定与肿瘤进展和治疗反应相关的其他基因组改变。总共对 5485 例存档的福尔马林固定、石蜡包埋的 UBC 进行了全面的基因组分析，以确定 ERBB2 ECD 突变的 MPUC，并评估基因组共改变的频率。我们鉴定出 219 例 UBC 存在 ERBB2 ECD 突变（74%为 S310F，26%为 S310Y），其中 63 例（28.8%）为 MPUC。基因组分析显示，TERT、TP53 和 ARID1A 是 ERBB2 突变型 MPUC 中最常见的共改变基因（分别为 82.5%、58.7%和 39.7%），与 ERBB2 突变型非 MPUC 无差异（分别为 86.5%、51.9%和 35.3%）。与非 MPUC 相比，ERBB2 ECD 突变的 MPUC 的主要区别在于 KMT2D、RB1 和 MTAP 的改变。KMT2D 和 RB1 是肿瘤抑制基因。在 ERBB2 ECD 突变的 MPUC 中，KMT2D 频率明显降低（6.3%），而非 MPUC 中则升高（27.6%；P<.001）。在 ERBB2 ECD 突变的 MPUC 中，RB1 突变更为常见（33.3%），而非 MPUC 中则较少见（17.3%；P=0.012）。最后，MTAP 缺失是新兴的基于合成致死的抗癌药物的生物标志物，在 ERBB2 ECD 突变的 MPUC 中较少见（11.1%），而非 MPUC 中则较常见（26.9%；P=0.018）。对 MPUC 的基因组图谱进行描述不仅可以提高我们对 UBC 这种侵袭性形态变体的基本认识，还有可能确定可能的预后和预测生物标志物，这些标志物可能会推动肿瘤进展，并决定对治疗方法的治疗反应。
