Relationships between Chromosome 7 Gain, MET Gene Copy Number Increase and MET Protein Overexpression in Chinese Papillary Renal Cell Carcinoma Patients

PLoS One. 2015 Dec 4;10(12):e0143468. doi: 10.1371/journal.pone.0143468. eCollection 2015.

Abstract

To investigate the relationships between Chromosome 7 gain, mesenchymal-epithelial transition factor (MET) gene copy number increase and MET protein overexpression in Chinese patients with papillary renal cell carcinoma (PRCC), immunohistochemistry (IHC), immunofluorescence (IF) and fluorescence in situ hybridization (FISH) were performed on 98 formalin-fixed, paraffin-embedded (FFPE) PRCC samples. Correlations between MET gene copy number increase, Chromosome 7 gain and MET protein overexpression were analyzed statistically. A highly significant correlation was observed between the percentage of tumor cells with MET gene copy number ≥3 and CEP7 copy number ≥3 (R2 = 0.90, p<0.001) across two subtypes of PRCC. In addition, the percentage of tumor cells with MET gene copy number ≥3 was found to increase along with increases in MET IHC score. This correlation was further confirmed in those PRCC tumor cells with average MET gene copy number >5 using combined IF and FISH methodology. Overall, this study provides evidence that Chromosome 7 gain drives MET gene copy number increase in PRCC tumors, and appears to subsequently lead to an increase in MET protein overexpression in these tumor cells. This supports MET activation as a potential therapeutic target in sporadic PRCC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Asian People / genetics
  • Carcinoma, Renal Cell / genetics*
  • Carcinoma, Renal Cell / metabolism
  • Carcinoma, Renal Cell / pathology
  • China
  • Chromosomes, Human, Pair 7 / genetics*
  • Female
  • Gene Amplification*
  • Gene Expression Regulation, Neoplastic
  • Genetic Predisposition to Disease
  • Humans
  • In Situ Hybridization, Fluorescence
  • Kidney Neoplasms / genetics*
  • Kidney Neoplasms / metabolism*
  • Male
  • Prognosis
  • Proto-Oncogene Proteins c-met / genetics*
  • Up-Regulation

Substances

  • MET protein, human
  • Proto-Oncogene Proteins c-met

Grants and funding

Authors affiliated with AstraZeneca are full-time employees and/or stakeholders of AstraZeneca. This study is fully funded by AstraZeneca. The funder provided support in the form of salaries for authors (YX, ZT, SX, JY, YP, FH, FS, GP and GY). The specific roles of these authors are articulated in the "author contributions" section. In addition to the salaries, this study was completed in AstraZeneca’s facility and using AstraZeneca’s resources.