Assessment of hepatocyte growth factor in ovarian cancer mortality.

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.

Polymorphisms in ABCB1 and ERCC2 associated with ovarian cancer outcome.

Using the most comprehensive approach to selecting polymorphisms to date, we sought to examine whether time to recurrence in ovarian cancer was associated with common inherited variation in eight genes involved in drug metabolism, multi-drug resistance, or DNA repair, namely ABCB1, CYP2C8, CYP3A4, ERCC1, ERCC2, GSTM1, XPC, and XRCC1. Invasive epithelial ovarian cancer patients (N=445) seen at the Mayo Clinic from 1999 to 2009 with 275 observed recurrences or deaths were analyzed at 94 SNPs in these candidate genes. Cox regression was used to estimate hazard ratios and 95% confidence intervals for each single nucleotide polymorphism (SNP) and outcome (defined as time to recurrence or death). Analyses were conducted at the gene level and on case subsets defined by histopathology and chemotherapeutic agent. At ABCB1, minor alleles at several SNPs were associated with outcome, with the most significant being the intronic SNP rs12334183 (HR=0.65, 95% Cl 0.51-0.83; p=0.0005). Overall variation in ABCB1 was predictive of outcome as well (p=0.003). At ERCC2, minor alleles at several SNPs were associated with outcome among women with high-grade serous disease (e.g., rs238417, HR 0.74, 95% Cl 0.59-0.92; p=0.006). No associations with outcome were observed in GSTM1, CYP2C8, CYP3A4, ERCC1, XPC, or XRCC1. In summary, inherited variation in ABCB1 and ERCC2 was associated with outcome in patients with ovarian cancer seen at the Mayo Clinic. As the associated SNPs have not been studied previously in ovarian cancer, these findings suggest novel sites of variation which may, in part, explain the range of treatment responses seen in this disease.

Risk of ovarian cancer and inherited variants in relapse-associated genes.

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.