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A high frequency of activating extracellular domain ERBB2 (HER2) mutation in micropapillary urothelial carcinoma.
- Source :
-
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2014 Jan 01; Vol. 20 (1), pp. 68-75. Date of Electronic Publication: 2013 Nov 05. - Publication Year :
- 2014
-
Abstract
- 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.<br />Experimental Design: DNA was extracted from 40 μm 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.<br />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 < 0.0084) and for all types of urinary tract cancer in COSMIC (P < 0.001).<br />Conclusions: NGS of MPUC revealed 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.
- Subjects :
- Aged
Aged, 80 and over
Case-Control Studies
DNA Mutational Analysis
Female
Gene Frequency
Genetic Association Studies
Genetic Predisposition to Disease
High-Throughput Nucleotide Sequencing
Humans
Male
Middle Aged
Protein Structure, Tertiary
Sequence Analysis, DNA
Receptor, ErbB-2 genetics
Urinary Bladder Neoplasms genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1557-3265
- Volume :
- 20
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Publication Type :
- Academic Journal
- Accession number :
- 24192927
- Full Text :
- https://doi.org/10.1158/1078-0432.CCR-13-1992