Assessment of hepatocyte growth factor in ovarian cancer mortality
| Autor: | Michele M. Schmidt, Thomas A. Sellers, Jeremy Chien, Robert A. Vierkant, Estrid Høgdall, Rebecca Sutphen, Jenny Gross, Joellen M. Schildkraut, Julie M. Cunningham, Kristin L. White, Hugues Sicotte, Robert S. Brown, Jonathan Beesley, Prema P. Peethambaram, Linda E. Kelemen, Gary L. Keeney, Xiaoqing Chen, Melissa C. Larson, Brooke L. Fridley, Ya Yu Tsai, David N. Rider, Georgia Chenevix-Trench, Kimberly R. Kalli, Ellen L. Goode, Katelyn E. Goodman, Beth Y. Karlan, Sebastian M. Armasu, Lynn C. Hartmann, Elaine A. Elliott, Susanne K. Kjaer, Claus Høgdall, Catherine M. Phelan, Trynda N. Oberg, Sharon E. Johnatty, Arif B. Ekici, Evelyn Despierre, Fergus J. Couch, Vijayalakshmi Shridhar, David Duggan, Lene Lundvall, Diether Lambrechts, Peter A. Fasching |
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| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Oncology
medicine.medical_specialty Candidate gene Genotype Epidemiology Single-nucleotide polymorphism Disease Bioinformatics Polymorphism Single Nucleotide Article Internal medicine medicine SNP Humans Ovarian Neoplasms Tissue microarray business.industry Hepatocyte Growth Factor medicine.disease Immunohistochemistry United States Hepatocyte growth factor Female Ovarian cancer business medicine.drug Signal Transduction |
| Popis: | 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 (r2 = 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. Cancer Epidemiol Biomarkers Prev; 20(8); 1638–48. ©2011 AACR. |
| Databáze: | OpenAIRE |
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