Incidence of KRAS G12C mutations in genitourinary malignancies; emerging target in precision medicine.

Q2 Medicine

Oncotarget Pub Date : 2026-08-19 DOI:10.18632/oncotarget.28912

Kelly Crane, K R Seetharam Bhat, P Grivas, Andrea Necchi, Gennady Bratslavsky, Oleg Shapiro, Joseph M Jacob, Hanan Goldberg, Rebecca Sager, Jeffery S Ross

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Abstract

Copyright: © 2026 Crane et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Purpose: The discovery of KRAS G12C as a therapeutic target has transformed oncology with the development of specific inhibitors. This study aimed to characterize the prevalence and clinicogenomic features of KRAS G12C mutations in genitourinary malignancies, an area with limited prior data despite recent FDA approvals of KRAS G12C-targeted therapies.

Materials and methods: Comprehensive genomic profiling was performed on 13,654 formalin-fixed paraffin-embedded specimens, including 1,453 renal clear cell carcinomas (RCCC), 3,879 urothelial bladder carcinomas (UBC), and 8,322 prostate acinar adenocarcinomas (PAAC). Tumor mutational burden (TMB), microsatellite instability (MSI), and PD-L1 expression (Dako 22C3) were also assessed.

Results: KRAS alterations were identified in 7 RCCC (<1%), 202 UBC (5.2%), and 158 PAAC (1.9%) cases. KRAS G12C variants were detected in 0 RCCC (0%), 24 UBC (12%), and 1 PAAC (<1%) cases. No KRAS G12C-mutated tumors showed MSI-high status. In UBC, KRAS G12C-positive cases demonstrated significantly lower TERT co-mutations and higher KDM6A alterations compared to KRAS G12C-negative cases (both p < 0.05). Age and sex distributions were similar across subtypes. Predominant co-alterations included VHL, SETD2, and PBRM1 in RCCC, and TP53, CDKN2A, and TERT in UBC.

Conclusions: KRAS G12C mutations occur infrequently in major genitourinary malignancies. However, given the expanding therapeutic landscape of KRAS G12C inhibitors and potential for basket trials, further investigation in bladder and prostate cancers is warranted. These agents may offer meaningful benefit to the small subset of patients harboring this actionable alteration.

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KRAS G12C突变在泌尿生殖系统恶性肿瘤中的发生率精准医疗的新目标。

版权所有：2026 Crane et al。这是一篇在知识共享署名许可（CC BY 4.0）条款下发布的开放获取文章，该许可允许在任何媒体上不受限制地使用、分发和复制，前提是要注明原作者和来源。目的：KRAS G12C作为治疗靶点的发现，随着特异性抑制剂的开发，改变了肿瘤学。本研究旨在表征KRAS G12C突变在泌尿生殖系统恶性肿瘤中的患病率和临床基因组学特征，尽管最近FDA批准了KRAS G12C靶向治疗，但该领域的先前数据有限。材料与方法：对13654例福尔马林固定石蜡包埋标本进行了全面的基因组图谱分析，其中肾透明细胞癌（RCCC） 1453例，尿路上皮膀胱癌（UBC） 3879例，前列腺腺泡癌（PAAC） 8322例。肿瘤突变负荷（TMB）、微卫星不稳定性（MSI）和PD-L1表达（Dako 22C3）也进行了评估。结果：在7例RCCC （<1%）、202例UBC（5.2%）和158例PAAC（1.9%）中发现了KRAS改变。在0例RCCC（0%）、24例UBC（12%）和1例PAAC（1%）病例中检测到KRAS G12C变异。没有KRAS g12c突变的肿瘤显示msi -高状态。在UBC，与KRAS g12c阴性病例相比，KRAS g12c阳性病例的TERT共突变显著降低，KDM6A改变显著增加（p < 0.05）。不同亚型的年龄和性别分布相似。主要的共改变包括RCCC中的VHL、SETD2和PBRM1，以及UBC中的TP53、CDKN2A和TERT。结论：KRAS G12C突变在主要的泌尿生殖系统恶性肿瘤中并不常见。然而，考虑到KRAS G12C抑制剂不断扩大的治疗前景和篮子试验的潜力，进一步研究膀胱癌和前列腺癌是有必要的。这些药物可能为一小部分有这种可操作改变的患者提供有意义的益处。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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