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Assessment of hepatocyte growth factor in ovarian cancer mortality.

Publication ,  Journal Article
Goode, EL; Chenevix-Trench, G; Hartmann, LC; Fridley, BL; Kalli, KR; Vierkant, RA; Larson, MC; White, KL; Keeney, GL; Oberg, TN; Cunningham, JM ...
Published in: Cancer Epidemiol Biomarkers Prev
August 2011

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.

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Published In

Cancer Epidemiol Biomarkers Prev

DOI

EISSN

1538-7755

Publication Date

August 2011

Volume

20

Issue

8

Start / End Page

1638 / 1648

Location

United States

Related Subject Headings

  • United States
  • Signal Transduction
  • Polymorphism, Single Nucleotide
  • Ovarian Neoplasms
  • Immunohistochemistry
  • Humans
  • Hepatocyte Growth Factor
  • Genotype
  • Female
  • Epidemiology
 

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Goode, E. L., Chenevix-Trench, G., Hartmann, L. C., Fridley, B. L., Kalli, K. R., Vierkant, R. A., … Ovarian Cancer Association Consortium. (2011). Assessment of hepatocyte growth factor in ovarian cancer mortality. Cancer Epidemiol Biomarkers Prev, 20(8), 1638–1648. https://doi.org/10.1158/1055-9965.EPI-11-0455
Goode, Ellen L., Georgia Chenevix-Trench, Lynn C. Hartmann, Brooke L. Fridley, Kimberly R. Kalli, Robert A. Vierkant, Melissa C. Larson, et al. “Assessment of hepatocyte growth factor in ovarian cancer mortality.Cancer Epidemiol Biomarkers Prev 20, no. 8 (August 2011): 1638–48. https://doi.org/10.1158/1055-9965.EPI-11-0455.
Goode EL, Chenevix-Trench G, Hartmann LC, Fridley BL, Kalli KR, Vierkant RA, et al. Assessment of hepatocyte growth factor in ovarian cancer mortality. Cancer Epidemiol Biomarkers Prev. 2011 Aug;20(8):1638–48.
Goode, Ellen L., et al. “Assessment of hepatocyte growth factor in ovarian cancer mortality.Cancer Epidemiol Biomarkers Prev, vol. 20, no. 8, Aug. 2011, pp. 1638–48. Pubmed, doi:10.1158/1055-9965.EPI-11-0455.
Goode EL, Chenevix-Trench G, Hartmann LC, Fridley BL, Kalli KR, Vierkant RA, Larson MC, White KL, Keeney GL, Oberg TN, Cunningham JM, Beesley J, Johnatty SE, Chen X, Goodman KE, Armasu SM, Rider DN, Sicotte H, Schmidt MM, Elliott EA, Høgdall E, Kjær SK, Fasching PA, Ekici AB, Lambrechts D, Despierre E, Høgdall C, Lundvall L, Karlan BY, Gross J, Brown R, Chien J, Duggan DJ, Tsai Y-Y, Phelan CM, Kelemen LE, Peethambaram PP, Schildkraut JM, Shridhar V, Sutphen R, Couch FJ, Sellers TA, Ovarian Cancer Association Consortium. Assessment of hepatocyte growth factor in ovarian cancer mortality. Cancer Epidemiol Biomarkers Prev. 2011 Aug;20(8):1638–1648.

Published In

Cancer Epidemiol Biomarkers Prev

DOI

EISSN

1538-7755

Publication Date

August 2011

Volume

20

Issue

8

Start / End Page

1638 / 1648

Location

United States

Related Subject Headings

  • United States
  • Signal Transduction
  • Polymorphism, Single Nucleotide
  • Ovarian Neoplasms
  • Immunohistochemistry
  • Humans
  • Hepatocyte Growth Factor
  • Genotype
  • Female
  • Epidemiology