Chu Carissa E, Chen Ziyu, Whiting Karissa, Ostrovnaya Irina, Lenis Andrew T, Clinton Timothy N, Rammal Rayan, Ozcan Gamze Gokturk, Akbulut Dilara, Basar Merve, Chen Jie-Fu, Chen Ying-Bei, Gopalan Anuradha, Fine Samson W, Tickoo Satish K, Arcila Maria, Brannon A Rose, Berger Michael F, Cha Eugene K, Goh Alvin C, Donahue Timothy F, Bajorin Dean F, Teo Min Yuen, Rosenberg Jonathan E, Iyer Gopa, Pietzak Eugene J, Bochner Bernard H, Reuter Victor E, Sarungbam Judy, Solit David B, Al-Ahmadie Hikmat
Department of Urology, University of California, San Francisco, CA, USA; Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA.
Physiology, Biophysics and Systems Biology Program, Weill Cornell Medicine, New York, NY, USA; Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Eur Urol. 2025 Apr 26. doi: 10.1016/j.eururo.2025.04.008.
Divergent differentiation and histologic subtypes are common findings in urothelial carcinoma (UC). Clinically relevant genomic alterations and oncogenic drivers of individual subtypes remain poorly defined. We characterized surgical outcomes and the genomic landscape of UC with aberrant histology (UCAH), with a focus on biomarkers and targetable alterations.
The clinical cohort comprised 3052 patients who underwent radical cystectomy (RC) with or without neoadjuvant chemotherapy. Targeted exon sequencing was performed for a genomic cohort of 1060 bladder tumors from RC or transurethral resection specimens. We characterized the frequency of oncogenic mutations and targetable alterations, and the tumor mutational burden (TMB) of each subtype. We defined the clonal relatedness of morphologically distinct regions of tumors with mixed histology.
Patients with plasmacytoid, micropapillary, sarcomatoid, or mixed-histology tumors had worse cancer-specific survival than patients with pure urothelial histology. ERBB2, FGFR3, and PTEN alterations were most frequent in micropapillary, nested/squamous, and sarcomatoid UC, respectively. TMB was highest in plasmacytoid, neuroendocrine, and micropapillary tumors. Regions of mixed histology had shared clonal origins, but exceptions were observed. The retrospective design and potential for selection bias are limitations of our study.
UCAH tumors have distinct patterns of genomic alterations, which may be targetable via novel therapies and have implications for clinical trial inclusion. Biomarker-driven systemic therapy should be explored in patients with histologic subtypes that are associated with worse clinical outcomes.
尿路上皮癌（UC）常出现分化差异和组织学亚型。各亚型临床相关的基因组改变和致癌驱动因素仍未明确界定。我们对具有异常组织学表现的尿路上皮癌（UCAH）的手术结果和基因组格局进行了特征分析，重点关注生物标志物和可靶向改变。
临床队列包括3052例行根治性膀胱切除术（RC）且接受或未接受新辅助化疗的患者。对来自RC或经尿道切除标本的1060例膀胱肿瘤的基因组队列进行靶向外显子测序。我们对致癌突变和可靶向改变的频率以及各亚型的肿瘤突变负荷（TMB）进行了特征分析。我们确定了具有混合组织学表现的肿瘤形态学不同区域的克隆相关性。
浆细胞样、微乳头、肉瘤样或混合组织学肿瘤患者的癌症特异性生存率低于纯尿路上皮组织学患者。ERBB2、FGFR3和PTEN改变分别在微乳头、巢状/鳞状和肉瘤样UC中最为常见。TMB在浆细胞样、神经内分泌和微乳头肿瘤中最高。混合组织学区域具有共同的克隆起源，但也观察到了例外情况。我们研究的局限性在于回顾性设计和存在选择偏倚的可能性。
UCAH肿瘤具有独特的基因组改变模式，可能可通过新疗法靶向治疗，并对临床试验纳入有影响。对于临床结局较差的组织学亚型患者，应探索生物标志物驱动的全身治疗。
