Olsson, Håkan

Abstract DNA methylation is instrumental for gene regulation. Global changes in the epigenetic landscape have been recognized as a hallmark of cancer. However, the role of DNA methylation in epithelial ovarian cancer (EOC) remains unclear. In this study, high-density genetic and DNA methylation data in white blood cells from the Framingham Heart Study (N = 1,595) were used to build genetic models to predict DNA methylation levels. These prediction models were then applied to the summary statistics of a genome-wide association study (GWAS) of ovarian cancer including 22,406 EOC cases and 40,941 controls to investigate genetically predicted DNA methylation levels in association with EOC risk. Among 62,938 CpG sites investigated, genetically predicted methylation levels at 89 CpG were significantly associated with EOC risk at a Bonferroni-corrected threshold of P < 7.94 × 10−7. Of them, 87 were located at GWAS-identified EOC susceptibility regions and two resided in a genomic region not previously reported to be associated with EOC risk. Integrative analyses of genetic, methylation, and gene expression data identified consistent directions of associations across 12 CpG, five genes, and EOC risk, suggesting that methylation at these 12 CpG may influence EOC risk by regulating expression of these five genes, namely MAPT, HOXB3, ABHD8, ARHGAP27, and SKAP1. We identified novel DNA methylation markers associated with EOC risk and propose that methylation at multiple CpG may affect EOC risk via regulation of gene expression. Significance: Identification of novel DNA methylation markers associated with EOC risk suggests that methylation at multiple CpG may affect EOC risk through regulation of gene expression.

Abstract Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P < 2.2 × 10−6, we identified 35 genes, including FZD4 at 11q14.2 (Z = 5.08, P = 3.83 × 10−7, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P < 1.47 × 10−3). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis. Significance: Transcriptomic analysis of a large cohort confirms earlier GWAS loci and reveals FZD4 as a novel locus associated with EOC risk. Cancer Res; 78(18); 5419–30. ©2018 AACR.

Abstract Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10−8 seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type–specific expression quantitative trait locus and enhancer–gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10−5 in the three-cancer meta-analysis. Significance: We demonstrate that combining large-scale GWA meta-analysis findings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identification of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers. Cancer Discov; 6(9); 1052–67. ©2016 AACR. This article is highlighted in the In This Issue feature, p. 932

Abstract Purpose: To analyze the effect of germline mutations in BRCA1 and BRCA2 on mortality in patients with ovarian cancer up to 10 years after diagnosis. Experimental Design: We used unpublished survival time data for 2,242 patients from two case–control studies and extended survival time data for 4,314 patients from previously reported studies. All participants had been screened for deleterious germline mutations in BRCA1 and BRCA2. Survival time was analyzed for the combined data using Cox proportional hazard models with BRCA1 and BRCA2 as time-varying covariates. Competing risks were analyzed using Fine and Gray model. Results: The combined 10-year overall survival rate was 30% [95% confidence interval (CI), 28%–31%] for non-carriers, 25% (95% CI, 22%–28%) for BRCA1 carriers, and 35% (95% CI, 30%–41%) for BRCA2 carriers. The HR for BRCA1 was 0.53 at time zero and increased over time becoming greater than one at 4.8 years. For BRCA2, the HR was 0.42 at time zero and increased over time (predicted to become greater than 1 at 10.5 years). The results were similar when restricted to 3,202 patients with high-grade serous tumors and to ovarian cancer–specific mortality. Conclusions: BRCA1/2 mutations are associated with better short-term survival, but this advantage decreases over time and in BRCA1 carriers is eventually reversed. This may have important implications for therapy of both primary and relapsed disease and for analysis of long-term survival in clinical trials of new agents, particularly those that are effective in BRCA1/2 mutation carriers. Clin Cancer Res; 21(3); 652–7. ©2014 AACR.

Abstract Rare germline mutations in the breast and ovarian cancer predisposition genes BRCA1 and BRCA2 are present in roughly 5 percent of ovarian cancer patients. Both genes play key roles in DNA damage repair but appear to have distinct, although often complementary, functions. The risks of breast and ovarian cancer have been shown to differ between BRCA1 and BRCA2 carriers, and mutation-specific effects have also been suggested for both groups. Published reports comparing the survival of ovarian cancer patients with and without BRCA1/2 mutations generally show a survival advantage among mutation carriers. This is thought to be related to an improved response of carriers to platinum-based therapies. Since it is not known whether BRCA1 and BRCA2 carriers show similar survival patterns, we have performed a large, multicenter study to investigate the impact of germline BRCA1 and BRCA2 mutations on ovarian cancer survival. 3,531 invasive epithelial ovarian cancer cases (1,178 BRCA1, 367 BRCA2 and 1,986 BRCA-negative) with survival time data from twenty-four studies in the U.S.A, Europe, Israel and Asia were included. In our main analysis, we excluded patients who were known or who were likely to have not received platinum-based therapy. Compared to non-carriers, BRCA1 and BRCA2 carriers were more likely to present with advanced stage (BRCA1; p=2×10−4, BRCA2; p=4×10−6), high grade (BRCA1; p=4×10−9, BRCA2; p=1×10−4), serous disease (BRCA1; p=3×10−6, BRCA2; p=0.003). BRCA1 carriers were younger at diagnosis (p=2×10−9) and BRCA2 slightly older at diagnosis (p=0.002) than non-carriers. BRCA1 and BRCA2 carriers did not differ in terms of tumor stage, grade or histology but did show differences in the age at diagnosis (p=2×10−14). In an unadjusted analysis, neither BRCA1 nor BRCA2 carriers differed from non-carriers in overall survival (BRCA1: HR=1.02, p=0.77, BRCA2: HR=0.89, p=0.36). After adjusting for stage, grade, histology and age at diagnosis, BRCA1 carriers showed a modest, non-significant, survival advantage (HR=0.84, p=0.12) while BRCA2 carriers showed a marked improvement (HR=0.57, p=6×10−4) compared to non-carriers. This survival advantage was also seen when comparing BRCA2 carriers to BRCA1 carriers after adjustment for age at diagnosis (HR=0.69, p=5×10−4). Similar results were obtained when we restricted the analysis to high grade, advanced stage, serous cases. The survival differences we observed between BRCA1 and BRCA2 carriers could be related to differences in tumor biology or chemo-sensitivity. Additional analyses investigating the later will be presented in addition to mutation-specific effects within BRCA1 and BRCA2. In this study, we provide strong evidence for genetic heterogeneity of survival effects in ovarian cancer patients with BRCA mutations. This could be applied to both clinical prediction and to aid our understanding of the complex biology of BRCA mutations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2752. doi:10.1158/1538-7445.AM2011-2752