Assessment of hepatocyte growth factor in ovarian cancer mortality.
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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, Høgdall Estrid, Kjær Susanne Krüger, Fasching Peter A, Ekici Arif B, Lambrechts Diether, Despierre Evelyn, Høgdall Claus, Lundvall Lene, Karlan Beth Y, Gross Jenny, Brown Robert, Chien Jeremy, Duggan David J, Tsai Ya-Yu, Phelan Catherine M, Kelemen Linda E, Peethambaram Prema P, Schildkraut Joellen M, Shridhar Vijayalakshmi, Sutphen Rebecca, Couch Fergus J, Sellers Thomas A, Ovarian Cancer Association Consortium
Аннотация
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 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.