Citations 2
Assessment of Hepatocyte Growth Factor in Ovarian Cancer Mortality
Goode, Ellen L. , Chenevix‐Trench, Georgia , Hartmann, Lynn C. , Kalli, Kimberly R., Vierkant, Robert A. , White, Kristin L., Keeney, Gary L., Oberg, Trynda N., Cunningham, Julie M. , Johnatty, Sharon E. , Chen, Xiaoqing, Goodman, Katelyn E., Armasu, Sebastian M. , Rider, David N., Sicotte, Hugues , Schmidt, Michele M. , Elliott, Elaine A., Høgdall, Estrid , Kjær, Susanne K. , Fasching, Peter A. , Ekici, Arif B. , Lambrechts, Diether , Despierre, Evelyn, Høgdall, Claus , Lundvall, Lene, Gross, Jenny , Brown, Robert , Chien, Jeremy , Duggan, David , Phelan, Catherine M., Kelemen, Linda E. , Peethambaram, Prema P. , Schildkraut, Joellen M. , Shridhar, Vijayalakshmi, Sutphen, Rebecca , Sellers, Thomas A. , Lambrechts, Diether , Fridley, Brooke L. , Larson, Melissa C. , Beesley, Jonathan , Chen, Xiaoqing, Karlan, Beth Y. , Tsai, Ya-Yu , Couch, Fergus J. , Lambrechts, Diether , Kjaer, Susanne K , Vierkant, Robert A , Chien, Jeremey , Brown, Robert , Lambrechts, Diether , Ekici, Arif B , Chenevix-Trench, Georgia , Høgdall, Estrid , Høgdall, Claus K
Cancer Epidemiology, Biomarkers & Prevention | August 8, 2011 | Volume: 20 | Issue: 8 | Pages: 1638-1648
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 (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.
Abstract 4718: Inherited variants in relapse-associated genes and risk of ovarian cancer
Hartmann, Lynn C. , Fredericksen, Zachary S., White, Kristin L., Elliott, Elaine A., Phelan, Catherine M., Iversen, Edwin S. , Peethambaram, Prema P. , Kalli, Kimberly R., Kosel, Matthew , Shridhar, Vijayalakshmi, Rider, David N., Liebow, Mark , Cunningham, Julie M. , Schildkraut, Joellen M. , Sellers, Thomas A. , Goode, Ellen L. , Peedicayil, Abraham , Vierkant, Robert A. , Fridley, Brooke L. , Tsai, Ya-Yu , Berchuck, Andrew , Couch, Fergus J. , Larson, Melissa C.
Cancer Research | February 25, 2011 | Volume: 70 | Issue: 8_Supplement | Pages: 4718-4718
Abstract Background: We previously identified a panel of genes associated with outcome of ovarian cancer. The purpose of the current study was to assess whether variants in these genes correlated with ovarian cancer risk. Methods and Findings: Women with and without invasive ovarian cancer (749 cases, 1,041 controls) were genotyped at 136 single nucleotide polymorphisms (SNPs) within 13 candidate genes. Risk was estimated for each SNP and for overall variation within each gene. At the gene-level, variation within MSL1 (male-specific lethal-1 homolog) was associated with risk of serous cancer (p=0.03); haplotypes within PRPF31 (PRP31 pre-mRNA processing factor 31 homolog) were associated with risk of invasive disease (p=0.03). MSL1 rs7211770 was associated with decreased risk of serous disease (OR 0.81, 95% CI 0.66-0.98; p=0.03). SNPs in MFSD7, BTN3A3, ZNF200, PTPRS, and CCND1A were inversely associated with risk (p<0.05), and there was increased risk at HEXIM1 rs1053578 (p=0.04, OR 1.40, 95% CI 1.02-1.91). Conclusions: Tumor studies can reveal novel genes worthy of follow-up for cancer susceptibility. Here, we found that inherited markers in the gene encoding MSL1, part of a complex that modifies the histone H4, may decrease risk of invasive serous ovarian cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4718.