title: A high frequency of activating extracellular domain ERBB2 (HER2) mutation in micropapillary urothelial carcinoma.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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).
  
  
  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.
authors.affiliation: Authors' Affiliations: Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York; and Foundation Medicine, Inc., Cambridge, Massachusetts.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Ross
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.forename: Laurie M
authors.initials: LM
authors.lastname: Gay
authors.forename: Rami N
authors.initials: RN
authors.lastname: Al-Rohil
authors.forename: Tipu
authors.initials: T
authors.lastname: Nazeer
authors.forename: Christine E
authors.initials: CE
authors.lastname: Sheehan
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Jennings
authors.forename: Geoff A
authors.initials: GA
authors.lastname: Otto
authors.forename: Amy
authors.initials: A
authors.lastname: Donahue
authors.forename: Jie
authors.initials: J
authors.lastname: He
authors.forename: Gary
authors.initials: G
authors.lastname: Palmer
authors.forename: Siraj
authors.initials: S
authors.lastname: Ali
authors.forename: Michelle
authors.initials: M
authors.lastname: Nahas
authors.forename: Geneva
authors.initials: G
authors.lastname: Young
authors.forename: Elaine
authors.initials: E
authors.lastname: Labrecque
authors.forename: Garrett
authors.initials: G
authors.lastname: Frampton
authors.forename: Rachel
authors.initials: R
authors.lastname: Erlich
authors.forename: John A
authors.initials: JA
authors.lastname: Curran
authors.forename: Kristina
authors.initials: K
authors.lastname: Brennan
authors.forename: Sean R
authors.initials: SR
authors.lastname: Downing
authors.forename: Roman
authors.initials: R
authors.lastname: Yelensky
authors.forename: Doron
authors.initials: D
authors.lastname: Lipson
authors.forename: Matthew
authors.initials: M
authors.lastname: Hawryluk
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Stephens
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D017434:Protein Structure, Tertiary; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D017422:Sequence Analysis, DNA; D001749:Urinary Bladder Neoplasms / Q000235:genetics*
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human