Document Detail

Assessment of hepatocyte growth factor in ovarian cancer mortality.
MedLine Citation:
PMID:  21724856     Owner:  NLM     Status:  MEDLINE    
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.
IMPACT: Our study shows the utility of multiple data types and multiple data sets in observational studies.
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 Elliott; Estrid 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;
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-07-01
Journal Detail:
Title:  Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology     Volume:  20     ISSN:  1538-7755     ISO Abbreviation:  Cancer Epidemiol. Biomarkers Prev.     Publication Date:  2011 Aug 
Date Detail:
Created Date:  2011-08-09     Completed Date:  2012-02-01     Revised Date:  2014-09-12    
Medline Journal Info:
Nlm Unique ID:  9200608     Medline TA:  Cancer Epidemiol Biomarkers Prev     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1638-48     Citation Subset:  IM    
Copyright Information:
©2011 AACR.
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MeSH Terms
Hepatocyte Growth Factor / genetics*,  metabolism
Ovarian Neoplasms / genetics*,  mortality*
Polymorphism, Single Nucleotide
Signal Transduction
United States / epidemiology
Grant Support
13086//Cancer Research UK; P50 CA136393/CA/NCI NIH HHS; R01 CA106414/CA/NCI NIH HHS; R01 CA106414-06/CA/NCI NIH HHS; R01 CA122443/CA/NCI NIH HHS; R01 CA122443-06/CA/NCI NIH HHS; R01-CA122443/CA/NCI NIH HHS; R01-CA86888/CA/NCI NIH HHS
Reg. No./Substance:
67256-21-7/Hepatocyte Growth Factor

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