title: HER2 gene amplification occurs frequently in the micropapillary variant of urothelial carcinoma: analysis by dual-color in situ hybridization.
abstract: Human epidermal growth factor receptor-2 (HER2) is a well-recognized growth-promoting factor in cancer, although its application to urothelial carcinoma has been limited because of a low frequency of gene amplification. We evaluated HER2 protein expression and gene amplification in micropapillary carcinoma, a rare but highly aggressive variant of urothelial carcinoma by dual-color in situ hybridization. Gene amplification was defined by a HER2:CHR17 ratio of ≥2.2; low and high levels of amplification were further defined as <2.5 and ≥2.5, respectively. Immunohistochemistry was used to determine HER2 protein expression using the American Society of Clinical Oncology/College of American Pathologists Guidelines of HER2 staining. Protein expression, gene amplification, and chromosome 17 aneusomy were compared by Jonchkeere-Terpstra and Cochran-Armitage trend tests. In all, 19 of the 20 micropapillary carcinoma samples yielded usable dual-color in situ hybridization and immunohistochemistry results for evaluation. Overall, 68% (n=13) demonstrated HER2 protein expression of 2+ to 3+ staining. Gene amplification was present in 42% of samples (n=8), with 100% correlation with 2+ and 3+ protein expression. Gene amplification and protein expression were significantly associated (P=0.01). Overall, 53% of samples (n=10) had aneusomy of chromosome 17. Chromosome 17 aneusomy was present in approximately half of the samples evaluated, suggesting inherent genomic instability in this variant of urothelial carcinoma. However, increased HER2:CHR17 ratios demonstrate increased HER2 expression due to amplification in the majority of micropapillary carcinomas. These results suggest that HER2-targeted therapy may be successful on the genomic level in patients with this disease.
authors.affiliation: Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Christina B
authors.initials: CB
authors.lastname: Ching
authors.forename: Mahul B
authors.initials: MB
authors.lastname: Amin
authors.forename: Raymond R
authors.initials: RR
authors.lastname: Tubbs
authors.forename: Paul
authors.initials: P
authors.lastname: Elson
authors.forename: Eric
authors.initials: E
authors.lastname: Platt
authors.forename: Robert
authors.initials: R
authors.lastname: Dreicer
authors.forename: Amr
authors.initials: A
authors.lastname: Fergany
authors.forename: Donna E
authors.initials: DE
authors.lastname: Hansel
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000782:Aneuploidy; D002295:Carcinoma, Transitional Cell / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D005260:Female; D005784:Gene Amplification; D018734:Genes, erbB-2 / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D008875:Middle Aged; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics*; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases