title: Assessment of hepatocyte growth factor in ovarian cancer mortality.
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 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.
  
  
  CONCLUSIONS
  Our study shows the utility of multiple data types and multiple data sets in observational studies.
authors: Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. egoode@mayo.edu
authors: Ellen L
authors: EL
authors: Goode
authors: Georgia
authors: G
authors: Chenevix-Trench
authors: Lynn C
authors: LC
authors: Hartmann
authors: Brooke L
authors: BL
authors: Fridley
authors: Kimberly R
authors: KR
authors: Kalli
authors: Robert A
authors: RA
authors: Vierkant
authors: Melissa C
authors: MC
authors: Larson
authors: Kristin L
authors: KL
authors: White
authors: Gary L
authors: GL
authors: Keeney
authors: Trynda N
authors: TN
authors: Oberg
authors: Julie M
authors: JM
authors: Cunningham
authors: Jonathan
authors: J
authors: Beesley
authors: Sharon E
authors: SE
authors: Johnatty
authors: Xiaoqing
authors: X
authors: Chen
authors: Katelyn E
authors: KE
authors: Goodman
authors: Sebastian M
authors: SM
authors: Armasu
authors: David N
authors: DN
authors: Rider
authors: Hugues
authors: H
authors: Sicotte
authors: Michele M
authors: MM
authors: Schmidt
authors: Elaine A
authors: EA
authors: Elliott
authors: Estrid
authors: E
authors: Høgdall
authors: Susanne Krüger
authors: SK
authors: Kjær
authors: Peter A
authors: PA
authors: Fasching
authors: Arif B
authors: AB
authors: Ekici
authors: Diether
authors: D
authors: Lambrechts
authors: Evelyn
authors: E
authors: Despierre
authors: Claus
authors: C
authors: Høgdall
authors: Lene
authors: L
authors: Lundvall
authors: Beth Y
authors: BY
authors: Karlan
authors: Jenny
authors: J
authors: Gross
authors: Robert
authors: R
authors: Brown
authors: Jeremy
authors: J
authors: Chien
authors: David J
authors: DJ
authors: Duggan
authors: Ya-Yu
authors: YY
authors: Tsai
authors: Catherine M
authors: CM
authors: Phelan
authors: Linda E
authors: LE
authors: Kelemen
authors: Prema P
authors: PP
authors: Peethambaram
authors: Joellen M
authors: JM
authors: Schildkraut
authors: Vijayalakshmi
authors: V
authors: Shridhar
authors: Rebecca
authors: R
authors: Sutphen
authors: Fergus J
authors: FJ
authors: Couch
authors: Thomas A
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authors: Sellers
mesh_terms: D005260:Female; D005838:Genotype; D017228:Hepatocyte Growth Factor / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000401:mortality*; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction; D014481:United States / Q000453:epidemiology
chemical_list: D017228:Hepatocyte Growth Factor