A High Frequency of Activating Extracellular Domain ERBB2 (HER2) Mutation in Micropapillary Urothelial Carcinoma

作者：Ross Jeffrey S^*; Wang Kai; Gay Laurie M; Al Rohil Rami N; Nazeer Tipu; Sheehan Christine E; Jennings Timothy A; Otto Geoff A; Donahue Amy; He Jie; Palmer Gary; Ali Siraj; Nahas Michelle; Young Geneva; LaBrecque Elaine; Frampton Garrett; Erlich Rachel; Curran John A; Brennan Kristina; Downing Sean R; Yelensky Roman; Lipson Doron; Hawryluk Matthew; Miller Vincent A; Stephens Philip J

来源：Clinical Cancer Research, 2014, 20(1): 68-75.

DOI：10.1158/1078-0432.CCR-13-1992

Purpose: Micropapillary urothelial carcinoma (MPUC) is a rare and aggressive form of bladder cancer. We conducted genomic analyses [next-generation sequencing (NGS)] of MPUC and non-micropapillary urothelial bladder carcinomas (non-MPUC) to characterize the genomic landscape and identify targeted treatment options. %26lt;br%26gt;Experimental Design: DNA was extracted from 40 mm of formalin-fixed paraffin-embedded sections from 15 MPUC and 64 non-MPUC tumors. Sequencing (NGS) was performed on hybridization-captured, adaptor ligation-based libraries to high coverage for 3,230 exons of 182 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer. The results were evaluated for all classes of genomic alteration. %26lt;br%26gt;Results: Mutations in the extracellular domain of ERBB2 were identified in 6 of 15 (40%) of MPUC: S310F (four cases), S310Y (one case), and R157W (one case). All six cases of MPUC with ERBB2 mutation were negative for ERBB2 amplification and Erbb2 overexpression. In contrast, 6 of 64 (9.4%) non-MPUC harbored an ERBB2 alteration, including base substitution (three cases), amplification (two cases), and gene fusion (one case), which is higher than the 2 of 159 (1.3%) protein-changing ERBB2 mutations reported for urinary tract cancer in COSMIC. The enrichment of ERBB2 alterations in MPUC compared with non-MPUC is significant both between this series (P %26lt; 0.0084) and for all types of urinary tract cancer in COSMIC (P %26lt; 0.001). %26lt;br%26gt;Conclusions: NGS of MPU Crevealed a high incidence of mutation in the extracellular domain of ERBB2, a gene for which there are five approved targeted therapies. NGS can identify genomic alteration, which inform treatment options for the majority of MPUC patients.

• 出版日期2014-1-1