Assessment of hepatocyte growth factor in ovarian cancer mortality

Ellen L. Goode, Georgia Chenevix-Trench, Lynn C. Hartmann, Brooke L. Fridley, Kimberly R. Kalli, Robert A. Vierkant, Melissa C. Larson, Kristin L. White, Gary L. Keeney, Trynda N. Oberg, Julie M. Cunningham, Jonathan Beesley, Sharon E. Johnatty, Xiaoqing Chen, Katelyn E. Goodman, Sebastian M. Armasu, David N. Rider, Hugues Sicotte, Michele M. Schmidt, Elaine A. ElliottEstrid Høgdall, Susanne Krüger Kjær, Peter A. Fasching, Arif B. Ekici, Diether Lambrechts, Evelyn Despierre, Claus Høgdall, Lene Lundvall, Beth Y. Karlan, Jenny Gross, Robert Brown, Jeremy Chien, David J. Duggan, Ya Yu Tsai, Catherine M. Phelan, Linda E. Kelemen, Prema P. Peethambaram, Joellen M. Schildkraut, Vijayalakshmi Shridhar, Rebecca Sutphen, Fergus J. Couch, Thomas A. Sellers

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Background: Invasive ovarian cancer is a significant cause of gynecologic cancer mortality. Methods: We examined whether this mortality was associated with inherited variation in approximately 170 candidate genes/regions [993 single-nucleotide polymorphisms (SNPs)] in a multistage analysis based initially on 312 Mayo Clinic cases (172 deaths). Additional analyses used The Cancer Genome Atlas (TCGA; 127 cases, 62 deaths). For the most compelling gene, we immunostained Mayo Clinic tissue microarrays (TMA, 326 cases) and conducted consortium-based SNP replication analysis (2,560 cases, 1,046 deaths). Results: The strongest initial mortality association was in HGF (hepatocyte growth factor) at rs1800793 (HR = 1.7, 95% CI = 1.3-2.2, P = 2.0 × 10 -5) and with overall variation in HGF (gene-level test, P = 3.7 × 10 -4). Analysis of TCGA data revealed consistent associations [e.g., rs5745709 (r 2 = 0.96 \with rs1800793): TCGA HR = 2.4, CI = 1.4-4.1, P = 2.2 × 10 -3; Mayo Clinic + TCGA HR = 1.6, CI = 1.3-1.9, P = 7.0 × 10 -5] and suggested genotype correlation with reduced HGF mRNAlevels (P = 0.01). In Mayo Clinic TMAs, protein levels of HGF, its receptor MET (C-MET), and phospho-MET were not associated with genotype and did not serve as an intermediate phenotype; however, phospho-MET was associated with reduced mortality (P = 0.01) likely due to higher expression in early-stage disease. In eight additional ovarian cancer case series, HGF rs5745709 was not associated with mortality (HR = 1.0, CI = 0.9-1.1, P = 0.87). Conclusions: Weconclude that although HGF signaling is critical to migration, invasion, and apoptosis, it is unlikely that HGF genetic variation plays a major role in ovarian cancer mortality. Furthermore, any minor role is not related to genetically-determined expression. Impact: Our study shows the utility of multiple data types and multiple data sets in observational studies.

Original languageEnglish (US)
Pages (from-to)1638-1648
Number of pages11
JournalCancer Epidemiology Biomarkers and Prevention
Volume20
Issue number8
DOIs
StatePublished - Aug 1 2011
Externally publishedYes

ASJC Scopus subject areas

  • Epidemiology
  • Oncology

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  • Cite this

    Goode, E. L., Chenevix-Trench, G., Hartmann, L. C., Fridley, B. L., Kalli, K. R., Vierkant, R. A., Larson, M. C., White, K. L., Keeney, G. L., Oberg, T. N., Cunningham, J. M., Beesley, J., Johnatty, S. E., Chen, X., Goodman, K. E., Armasu, S. M., Rider, D. N., Sicotte, H., Schmidt, M. M., ... Sellers, T. A. (2011). Assessment of hepatocyte growth factor in ovarian cancer mortality. Cancer Epidemiology Biomarkers and Prevention, 20(8), 1638-1648. https://doi.org/10.1158/1055-9965.EPI-11-0455