9p21 号染色体杂合性缺失常见于尿路上皮癌 (UC)，通常涉及 CDKN2A 和 MTAP 基因的缺失。 MTAP 丢失正在成为 UC 的一个有前途的治疗靶点和预测生物标志物。这项单中心回顾性研究检查了肌层浸润性膀胱癌 (MIBC) 和转移性尿路上皮癌 (mUC) 中 CDKN2A 缺失和 MTAP 缺失的发生率，调查了它们与临床、病理和基因组特征以及患者预后的相关性。对 302 例 MIBC 标本和 63 例活检证实的异时性尿路上皮转移进行荧光原位杂交 (FISH) 和免疫组织化学 (IHC)，以评估 CDKN2A 缺失和 MTAP 蛋白表达。在 30.3% 的 MIBC 中发现 CDKN2A 纯合性缺失 (HD)，并且28.8% 的 MIBC 中发现 MTAP 丢失，且与 luminal-URO 亚型、FGFR3 突变和正常/野生型 p53 IHC 显着相关 (P<0.05)。 MTAP 表达缺失与 CDKN2A HD 显着相关，敏感性为 84.0%，阴性预测值 (NPV) 为 92.3%，特异性为 96.3%，阳性预测值 (PPV) 为 91.9%。原发肿瘤和淋巴结转移之间的 MTAP 表达 100% 一致。与骨/软组织 (35.7%) 和淋巴结 (14.3%) 相比，MTAP 缺失的患者内脏转移 (50%) 的发生率更高。 MTAP 缺失的患者的平均无进展生存期和总生存期较短，尽管没有统计学意义。我们的研究结果强调 CDKN2A HD 和 MTAP 缺失是 MIBC 和 mUC 中普遍存在的基因改变，特别是在 luminal-URO 亚型和 FGFR3 突变的情况下， p53-正常/野生型肿瘤。 MTAP IHC 可作为 9p21.3 HD 的替代标记物，突出其临床相关性以及作为 MIBC 治疗靶点和预测生物标记物的潜力。© 2024 作者。组织病理学由约翰·威利出版

Loss of heterozygosity in chromosome 9p21, common in urothelial carcinoma (UC), typically involves deletion of CDKN2A and MTAP genes. MTAP loss is emerging as a promising therapeutic target and predictive biomarker in UC. This single-centrre retrospective study examined the incidence of CDKN2A deletions and MTAP loss in muscle-invasive bladder cancer (MIBC) and metastatic urothelial carcinoma (mUC), investigating their correlations with clinical, pathological, and genomic features, as well as patient outcomes.Fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) were performed on 302 MIBC specimens and 63 biopsy-proven metachronous urothelial metastases to assess CDKN2A deletions and MTAP protein expression.CDKN2A homozygous deletion (HD), identified in 30.3% of MIBCs, and MTAP loss, found in 28.8% of MIBCs, were both significantly associated with the luminal-URO subtype, FGFR3 mutations, and normal/wildtype p53 IHC (P < 0.05). Loss of MTAP expression was significantly correlated with CDKN2A HD, with 84.0% sensitivity, 92.3% negative predictive value (NPV), 96.3% specificity, and 91.9% positive predictive value (PPV). MTAP expression was 100% concordant between primary tumours and nodal metastases. Patients with MTAP loss had a higher incidence of visceral metastases (50%) compared to bone/soft tissue (35.7%) and nodes (14.3%). Mean progression-free survival and overall survival were shorter for patients with MTAP loss, although not statistically significant.Our findings highlight CDKN2A HD and MTAP loss as prevalent genetic alterations in MIBC and mUC, particularly within the luminal-URO subtype and FGFR3-mutated, p53-normal/wildtype tumours. MTAP IHC can serve as a surrogate marker for 9p21.3 HD, highlighting its clinical relevance and potential as a therapeutic target and predictive biomarker in MIBC.© 2024 The Author(s). Histopathology published by John Wiley & Sons Ltd.