Identification of ALK gene alterations in urothelial carcinoma

PLoS One. 2014 Aug 1;9(8):e103325. doi: 10.1371/journal.pone.0103325. eCollection 2014.

Abstract

Background: Anaplastic lymphoma kinase (ALK) genomic alterations have emerged as a potent predictor of benefit from treatment with ALK inhibitors in several cancers. Currently, there is no information about ALK gene alterations in urothelial carcinoma (UC) and its correlation with clinical or pathologic features and outcome.

Methods: Samples from patients with advanced UC and correlative clinical data were collected. Genomic imbalances were investigated by array comparative genomic hybridization (aCGH). ALK gene status was evaluated by fluorescence in situ hybridization (FISH). ALK expression was assessed by immunohistochemistry (IHC) and high-throughput mutation analysis with Oncomap 3 platform. Next generation sequencing was performed using Illumina Genome Analyzer IIx, and Illumina HiSeq 2000 in the FISH positive case.

Results: 70 of 96 patients had tissue available for all the tests performed. Arm level copy number gains at chromosome 2 were identified in 17 (24%) patients. Minor copy number alterations (CNAs) in the proximity of ALK locus were found in 3 patients by aCGH. By FISH analysis, one of these samples had a deletion of the 5'ALK. Whole genome next generation sequencing was inconclusive to confirm the deletion at the level of the ALK gene at the coverage level used. We did not observe an association between ALK CNA and overall survival, ECOG PS, or development of visceral disease.

Conclusions: ALK genomic alterations are rare and probably without prognostic implications in UC. The potential for testing ALK inhibitors in UC merits further investigation but might be restricted to the identification of an enriched population.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Anaplastic Lymphoma Kinase
  • Carcinoma / genetics*
  • Carcinoma / metabolism
  • Carcinoma / mortality
  • Carcinoma / pathology
  • Chromosome Aberrations
  • Comparative Genomic Hybridization
  • DNA Copy Number Variations
  • Female
  • Gene Deletion
  • Genetic Variation*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization, Fluorescence
  • Male
  • Middle Aged
  • Mutation
  • Neoplasm Staging
  • Prognosis
  • Receptor Protein-Tyrosine Kinases / genetics*
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Urologic Neoplasms / genetics*
  • Urologic Neoplasms / metabolism
  • Urologic Neoplasms / mortality
  • Urologic Neoplasms / pathology

Substances

  • ALK protein, human
  • Anaplastic Lymphoma Kinase
  • Receptor Protein-Tyrosine Kinases

Grant support

This work has been supported by PI061513 (Spanish Health Ministry Grant “Fondo de Investigacion Sanitaria”) and RTICC 06/0020/19 grants. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.