Inherited variants in regulatory T cell genes and outcome of ovarian cancer.

Although ovarian cancer is the most lethal of gynecologic malignancies, wide variation in outcome following conventional therapy continues to exist. The presence of tumor-infiltrating regulatory T cells (Tregs) has a role in outcome of this disease, and a growing body of data supports the existence of inherited prognostic factors. However, the role of inherited variants in genes encoding Treg-related immune molecules has not been fully explored. We analyzed expression quantitative trait loci (eQTL) and sequence-based tagging single nucleotide polymorphisms (tagSNPs) for 54 genes associated with Tregs in 3,662 invasive ovarian cancer cases. With adjustment for known prognostic factors, suggestive results were observed among rarer histological subtypes; poorer survival was associated with minor alleles at SNPs in RGS1 (clear cell, rs10921202, p = 2.7×10(-5)), LRRC32 and TNFRSF18/TNFRSF4 (mucinous, rs3781699, p = 4.5×10(-4), and rs3753348, p = 9.0×10(-4), respectively), and CD80 (endometrioid, rs13071247, p = 8.0×10(-4)). Fo0r the latter, correlative data support a CD80 rs13071247 genotype association with CD80 tumor RNA expression (p = 0.006). An additional eQTL SNP in CD80 was associated with shorter survival (rs7804190, p = 8.1×10(-4)) among all cases combined. As the products of these genes are known to affect induction, trafficking, or immunosuppressive function of Tregs, these results suggest the need for follow-up phenotypic studies

Assessment of Multifactor Gene-Environment Interactions and Ovarian Cancer Risk: Candidate Genes, Obesity and Hormone-Related Risk Factors

BACKGROUND: Many epithelial ovarian cancer (EOC) risk factors relate to hormone exposure and elevated estrogen levels are associated with obesity in postmenopausal women. Therefore, we hypothesized that gene-environment interactions related to hormone-related risk factors could differ between obese and non-obese women. METHODS: We considered interactions between 11,441 SNPs within 80 candidate genes related to hormone biosynthesis and metabolism and insulin-like growth factors with six hormone-related factors (oral contraceptive use, parity, endometriosis, tubal ligation, hormone replacement therapy, and estrogen use) and assessed whether these interactions differed between obese and non-obese women. Interactions were assessed using logistic regression models and data from 14 case-control studies (6,247 cases; 10,379 controls). Histotype-specific analyses were also completed. RESULTS: SNPs in the following candidate genes showed notable interaction: IGF1R (rs41497346, estrogen plus progesterone hormone therapy, histology = all, P = 4.9 × 10(-6)) and ESR1 (rs12661437, endometriosis, histology = all, P = 1.5 × 10(-5)). The most notable obesity-gene-hormone risk factor interaction was within INSR (rs113759408, parity, histology = endometrioid, P = 8.8 × 10(-6)). CONCLUSIONS: We have demonstrated the feasibility of assessing multifactor interactions in large genetic epidemiology studies. Follow-up studies are necessary to assess the robustness of our findings for ESR1, CYP11A1, IGF1R, CYP11B1, INSR, and IGFBP2 Future work is needed to develop powerful statistical methods able to detect these complex interactions. IMPACT: Assessment of multifactor interaction is feasible, and, here, suggests that the relationship between genetic variants within candidate genes and hormone-related risk factors may vary EOC susceptibility

High pre-diagnosis inflammation-related risk score associated with decreased ovarian cancer survival

BACKGROUND: There is suggestive evidence that inflammation is related to ovarian cancer survival. However, more research is needed to identify inflammation-related factors that are associated with ovarian cancer survival and to determine their combined effects. METHODS: This analysis used pooled data on 8,147 women with invasive epithelial ovarian cancer from the Ovarian Cancer Association Consortium. Pre-diagnosis inflammatory-related exposures of interest included alcohol use, aspirin use, other nonsteroidal anti-inflammatory drug use, body mass index, environmental tobacco smoke exposure, history of pelvic inflammatory disease, polycystic ovarian syndrome, and endometriosis, menopausal hormone therapy use, physical inactivity, smoking status, and talc use. Using Cox proportional hazards (PH) models, the relationship between each exposure and survival was assessed in 50% of the data. A weighted inflammation-related risk score (IRRS) was developed and its association with survival was assessed using Cox PH models in the remaining 50% of the data. RESULTS: There was a statistically significant trend of increasing risk of death per quartile of the IRRS (HR=1.09, 95% CI 1.03-1.14). Women in the upper quartile of the IRRS had 31% higher death rate compared to the lowest quartile (95% CI 1.11-1.54). CONCLUSIONS: A higher pre-diagnosis IRRS was associated with increased mortality risk after an ovarian cancer diagnosis. Further investigation is warranted to evaluate whether post-diagnosis exposures are also associated with survival. IMPACT: Given that pre- and post-diagnosis exposures are often correlated and many are modifiable, our study results can ultimately motivate the development of behavioral recommendations to enhance survival among ovarian cancer patients

Ages at menarche- and menopause-related genetic variants in relation to terminal duct lobular unit involution in normal breast tissue

PURPOSE: Reduced levels of terminal duct lobular unit (TDLU) involution, as reflected by higher numbers of TDLUs and acini per TDLU, have been associated with higher breast cancer risk. Younger age at menarche and older age at menopause have been previously related to lower levels of TDLU involution. To determine a possible genetic link, we examined whether single nucleotide polymorphisms (SNPs) previously established in genome-wide association studies (GWAS) for ages at menarche and menopause are associated with TDLU involution. METHODS: We conducted a pooled analysis of 862 women from two studies. H&E tissue sections were assessed for numbers of TDLUs and acini/TDLU. Poisson regression models were used to estimate associations of 36 menarche- and 21 menopause-SNPs with TDLU counts, acini counts/TDLU, and the product of these two measures, adjusting for age and study site. RESULTS: Fourteen percent of evaluated SNPs (8 SNPs) were associated with TDLU counts at p<0.05, suggesting an enrichment of associations with TDLU counts. However, only menopause-SNPs had >50% that were either significantly or nonsignficantly associated with TDLU measures in the directions consistent with their relationships shown in GWAS. Among 10 SNPs that were statistically significantly associated with at least one TDLU involution measure (p<0.05), seven SNPs (rs466639: RXRG; rs2243803: SLC14A2; rs2292573: GAB2; rs6438424: 3q13.32; rs7606918: METAP1D; rs11668344: TMEM150B; rs1635501: EXO1) were associated in the consistent directions. CONCLUSIONS: Our data suggest that the loci associated with ages at menarche and menopause may influence TDLU involution, suggesting some shared genetic mechanisms. However, larger studies are needed to confirm the results

Investigation of Exomic Variants Associated with Overall Survival in Ovarian Cancer

BACKGROUND: While numerous susceptibility loci for epithelial ovarian cancer (EOC) have been identified, few associations have been reported with overall survival. In the absence of common prognostic genetic markers, we hypothesize that rare coding variants may be associated with overall EOC survival and assessed their contribution in two exome-based genotyping projects of the Ovarian Cancer Association Consortium (OCAC). METHODS: The primary patient set (Set 1) included 14 independent EOC studies (4,293 patients) and 227,892 variants, and a secondary patient set (Set 2) included six additional EOC studies (1,744 patients) and 114,620 variants. Because power to detect rare variants individually is reduced, gene-level tests were conducted. Sets were analyzed separately at individual variants and by gene, and then combined with meta-analyses (73,203 variants and 13,163 genes overlapped). RESULTS: No individual variant reached genome-wide statistical significance. A SNP previously implicated to be associated with EOC risk and, to a lesser extent, survival, rs8170, showed the strongest evidence of association with survival and similar effect size estimates across sets (Pmeta = 1.1E-6, HRSet1 = 1.17, HRSet2 = 1.14). Rare variants in ATG2B, an autophagy gene important for apoptosis, were significantly associated with survival after multiple testing correction (Pmeta = 1.1E-6; Pcorrected = 0.01). CONCLUSIONS: Common variant rs8170 and rare variants in ATG2B may be associated with EOC overall survival, although further study is needed. IMPACT: This study represents the first exome-wide association study of EOC survival to include rare variant analyses, and suggests that complementary single variant and gene-level analyses in large studies are needed to identify rare variants that warrant follow-up study

Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk

BACKGROUND: Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by coexpression may also be enriched for additional EOC risk associations. METHODS: We selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly coexpressed with each selected TF gene in the unified microarray dataset of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this dataset were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls). RESULTS: Gene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P < 0.05 and FDR < 0.05). These results were replicated (P < 0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network. CONCLUSION: We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development. IMPACT: Network analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization

Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer

BACKGROUND: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer. METHODS: In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients. RESULTS: The most significant global associations for all genes in the pathway were seen in endometrioid (p = 0.082) and clear cell (p = 0.083), with the most significant gene level association seen with TGFBR2 (p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 (p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA (p = 0.035, endometrioid and mucinous), LGALS1 (p = 0.03, mucinous), STAT5B (p = 0.022, clear cell), TGFBR1 (p = 0.021 endometrioid) and TGFBR2 (p = 0.017 and p = 0.025, endometrioid and mucinous, respectively). CONCLUSIONS: Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients