Dataset Information

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.

Impact

Our study shows the utility of multiple data types and multiple data sets in observational studies.

SUBMITTER: Goode EL

PROVIDER: S-EPMC3153603 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Publications

Assessment of hepatocyte growth factor in ovarian cancer mortality.

Goode Ellen L EL Chenevix-Trench Georgia G Hartmann Lynn C LC Fridley Brooke L BL Kalli Kimberly R KR Vierkant Robert A RA Larson Melissa C MC White Kristin L KL Keeney Gary L GL Oberg Trynda N TN Cunningham Julie M JM Beesley Jonathan J Johnatty Sharon E SE Chen Xiaoqing X Goodman Katelyn E KE Armasu Sebastian M SM Rider David N DN Sicotte Hugues H Schmidt Michele M MM Elliott Elaine A EA Høgdall Estrid E Kjær Susanne Krüger SK Fasching Peter A PA Ekici Arif B AB Lambrechts Diether D Despierre Evelyn E Høgdall Claus C Lundvall Lene L Karlan Beth Y BY Gross Jenny J Brown Robert R Chien Jeremy J Duggan David J DJ Tsai Ya-Yu YY Phelan Catherine M CM Kelemen Linda E LE Peethambaram Prema P PP Schildkraut Joellen M JM Shridhar Vijayalakshmi V Sutphen Rebecca R Couch Fergus J FJ Sellers Thomas A TA

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20110701 8

<h4>Background</h4>Invasive ovarian cancer is a significant cause of gynecologic cancer mortality.<h4>Methods</h4>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 tis ...[more]

PMID: 21724856

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Project description:BACKGROUND:Although many reports show that various kinds of stem cells have the ability to recover function in premature ovarian aging, few studies have looked at stem cell treatment of natural ovarian aging (NOA). We designed this experimental study to investigate whether human amniotic mesenchymal stem cells (hAMSCs) retain the ability to restore ovarian function, and how hAMSCs work in this process. METHODS:To build the NOA mouse model, the mice were fed for 12-14 months normally with young fertile female mice as the normal control group (3-5 months old). Hematoxylin and eosin staining permitted follicle counting and showed the ovarian tissue structure. An enzyme-linked immunosorbent assay was used to detect the serum levels of the sex hormones estradiol (E2), anti-mullerian hormone (AMH), and follicle-stimulating hormone (FSH). The proliferation rate and marker expression level of human ovarian granule cells (hGCs) (ki67, AMH, FSH receptor, FOXL2, and CYP19A1) were measured by flow cytometry (FACS). Cytokines (growth factors) were measured by a protein antibody array methodology. After hepatocyte growth factor (HGF) and epidermal growth factor (EGF) were co-cultured with hGCs, proliferation (ki67) and apoptosis (Annexin V) levels were analyzed by FACS. After HGF and EGF were injected into the ovaries of natural aging mice, the total follicle numbers and hormone levels were tested. RESULTS:After the hAMSCs were transplanted into the NOA mouse model, the hAMSCs exerted a therapeutic activity on mouse ovarian function by improving the follicle numbers over four stages. In addition, our results showed that hAMSCs significantly promoted the proliferation rate and marker expression level of ovarian granular cells that were from NOA patients. Meanwhile, we found that the secretion level of EGF and HGF from hAMSCs was higher than other growth factors. A growth factor combination (HGF with EGF) improved the proliferation rate and inhibited the apoptosis rate more powerfully after a co-culture with hGCs, and total follicle numbers and hormone levels were elevated to a normal level after the growth factor combination was injected into the ovaries of the NOA mouse model. CONCLUSIONS:These findings provide insight into the notion that hAMSCs play an integral role in resistance to NOA. Furthermore, our present study demonstrates that a growth factor combination derived from hAMSCs plays a central role in inhibiting ovarian aging. Therefore, we suggest that hAMSCs improve ovarian function in natural aging by secreting HGF and EGF.

Dataset Information

Assessment of hepatocyte growth factor in ovarian cancer mortality.

Background

Methods

Results

Conclusions

Impact

Publications

Assessment of hepatocyte growth factor in ovarian cancer mortality.

Similar Datasets

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