The blood transcriptome prior to ovarian cancer diagnosis: A case-control study in the NOWAC postgenome cohort

Abstract

Epithelial ovarian cancer (EOC) has a 5-year relative survival of 50%, partly because markers of early-stage disease are not available in current clinical diagnostics. The aim of the present study was to investigate whether EOC is associated with transcriptional profiles in blood collected up to 7 years before diagnosis. For this, we used RNA-stabilized whole blood, which contains circulating immune cells, from a sample of EOC cases from the population-based Norwegian Women and Cancer (NOWAC) postgenome cohort. We explored case-control differences in gene expression in all EOC (66 case-control pairs), as well as associations between gene expression and metastatic EOC (56 pairs), serous EOC (45 pairs, 44 of which were metastatic), and interval from blood sample collection to diagnosis (≤3 or >3 years; 34 and 31 pairs, respectively). Lastly, we assessed differential expression of genes associated with EOC in published functional genomics studies that used blood samples collected from newly diagnosed women. After adjustment for multiple testing, this nested case-control study revealed no significant case-control differences in gene expression in all EOC (false discovery rate q>0.96). With the exception of a few probes, the log2 fold change values obtained in gene-wise linear models were below ±0.2. P-values were lowest in analyses of metastatic EOC (80% of which were serous EOC). No common transcriptional profile was indicated by interval to diagnosis; when comparing the 100 genes with the lowest p-values in gene-wise tests in samples collected ≤3 and >3 years before EOC diagnosis, no overlap in these genes was observed. Among 86 genes linked to ovarian cancer in previous publications, our data contained expression values for 42, and of these, tests of LIME1, GPR162, STAB1, and SKAP1, resulted in unadjusted p<0.05. Although limited by sample size, our findings indicated less variation in blood gene expression between women with similar tumor characteristics.

Associations of gene expression in blood with BMI and weight changes among women in the Norwegian Women and Cancer postgenome cohort

“…The estimated proportions of WBCs in our study deviated from the expected range, but this deviation also has been observed in other recent studies based on the NOWAC postgenome cohort [41, 42]. This indicated a bias that could be explained by the deconvolution technique or data preprocessing [41, 43]. Still, absolute differences in estimated WBCs across BMI categories were modest, and the top‐ranked genes identified in our models were very similar, indicating that these genes were not substantially influenced by distributions of WBCs.…”

“…As skewed WBC proportions due to differences in BMI could have influenced our BMI analyses, we included these estimated cell proportions in our fully adjusted models [40]. The estimated proportions of WBCs in our study deviated from the expected range, but this deviation also has been observed in other recent studies based on the NOWAC postgenome cohort [41,42]. This indicated a bias that could be explained by the deconvolution technique or data preprocessing [41,43].…”