Citations 1
Assessment of Hepatocyte Growth Factor in Ovarian Cancer Mortality
Goode, Ellen L. , Chenevix‐Trench, Georgia , Hartmann, Lynn C. , Kalli, Kimberly R., Vierkant, Robert A. , White, Kristin L., Keeney, Gary L., Oberg, Trynda N., Cunningham, Julie M. , Johnatty, Sharon E. , Chen, Xiaoqing, Goodman, Katelyn E., Armasu, Sebastian M. , Rider, David N., Sicotte, Hugues , Schmidt, Michele M. , Elliott, Elaine A., Høgdall, Estrid , Kjær, Susanne K. , Fasching, Peter A. , Ekici, Arif B. , Lambrechts, Diether , Despierre, Evelyn, Høgdall, Claus , Lundvall, Lene, Gross, Jenny , Brown, Robert , Chien, Jeremy , Duggan, David , Phelan, Catherine M., Kelemen, Linda E. , Peethambaram, Prema P. , Schildkraut, Joellen M. , Shridhar, Vijayalakshmi, Sutphen, Rebecca , Sellers, Thomas A. , Lambrechts, Diether , Fridley, Brooke L. , Larson, Melissa C. , Beesley, Jonathan , Chen, Xiaoqing, Karlan, Beth Y. , Tsai, Ya-Yu , Couch, Fergus J. , Lambrechts, Diether , Kjaer, Susanne K , Vierkant, Robert A , Chien, Jeremey , Brown, Robert , Lambrechts, Diether , Ekici, Arif B , Chenevix-Trench, Georgia , Høgdall, Estrid , Høgdall, Claus K
Cancer Epidemiology, Biomarkers & Prevention | August 8, 2011 | Volume: 20 | Issue: 8 | Pages: 1638-1648
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 (r2 = 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 mRNA levels (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: We conclude 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. Cancer Epidemiol Biomarkers Prev; 20(8); 1638–48. ©2011 AACR.