Assessment of Hepatocyte Growth Factor in Ovarian Cancer Mortality

作者：Goode Ellen L^*; Chenevix Trench Georgia; Hartmann Lynn C; Fridley Brooke L; Kalli Kimberly R; Vierkant Robert A; Larson Melissa C; White Kristin L; Keeney Gary L; Oberg Trynda N; Cunningham Julie M; Beesley Jonathan; Johnatty Sharon E; Chen Xiaoqing; Goodman Katelyn E; Armasu Sebastian M; Rider David N; Sicotte Hugues; Schmidt Michele M; Elliott Elaine A; Hogdall Estrid; Kjaer Susanne Krueger; Fasching Peter A; Ekici Arif B; Lambrechts Diether

来源：Cancer Epidemiology Biomarkers & Prevention, 2011, 20(8): 1638-1648.

DOI：10.1158/1055-9965.EPI-11-0455

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 x 10(-5)) and with overall variation in HGF (gene-level test, P = 3.7 x 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 x 10(-3); Mayo Clinic + TCGA HR = 1.6, CI = 1.3-1.9, P = 7.0 x 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.

• 出版日期2011-8
• 单位河北医科大学