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The objective of this study was to evaluate cancer mortality in pulp and paper industry workers exposed to chlorinated organic compounds. We assembled a multinational cohort of workers employed between 1920 and 1996 in 11 countries. Exposure to both volatile and nonvolatile organochlorine compounds was estimated at the department level using an exposure matrix. We conducted a standardized mortality ratio (SMR) analysis based on age and calendar-period-specific national mortality rates and a Poisson regression analysis. The study population consisted of 60,468 workers. Workers exposed to volatile organochlorines experienced a deficit of all-cause [SMR = 0.91; 95% confidence interval (CI), 0.89–0.93] and all-cancer (SMR = 0.93; 95% CI, 0.89–0.97) mortality, with no evidence of increased risks for any cancer of a priori interest. There was a weak, but statistically significant, trend of increasing risk of all-cancer mortality with increasing weighted cumulative exposure. A similar deficit in all-cause (SMR = 0.94; 95% CI, 0.91–0.96) and all-cancer (SMR = 0.94; 95% CI, 0.89–1.00) mortality was observed in those exposed to nonvolatile organochlorines. No excess risk was observed in cancers of a priori interest, although mortality from Hodgkin disease was elevated (SMR = 1.76; 95% CI, 1.02–2.82). In this study we found little evidence that exposure to organochlorines at the levels experienced in the pulp and paper industry is associated with an increased risk of cancer, apart from a weak but significant association between all-cancer mortality and weighted cumulative volatile organochlorine exposure. [ABSTRACT FROM AUTHOR]

Gallbladder cancer (GBC) is an aggressive disease with limited treatment options but high prevention potential. GBC tumours take 10-20 years to develop, a timeframe that holds potential for early detection. MicroRNAs (miRNAs) play a central role in abnormal cell processes, and circulating miRNAs may constitute valuable biomarkers of early disease. We used microarray data to pre-select differentially expressed miRNAs in formalin-fixed paraffin-embedded (FFPE) gallbladder tissue samples (GBC n = 40, normal n = 8). We then applied small-RNA sequencing to screen for miRNA expression differences in serum samples from three European prospective cohorts (n = 37 GBC case-control pairs), and validated the most promising candidates in three independent cohorts (n = 36 GBC case- control pairs). Statistical analyses included robust linear regression, pathway and meta-analysis, and examination of expression correlation between miRNAs and target genes. MiR-4533 and miR-671-5p were overexpressed in GBC tissue and serum samples, and meta-analysis confirmed the overexpression of miR-4533 in GBC serum samples from the prospective cohorts (p-value = 4.1×10 -4 ), especially in individuals of female sex, under 63.5 years, or with a BMI below 26.2 kg/m 2 . Pathway and correlation analyses revealed that miR-4533 targets SIPA1L2 in the Rap1 signalling pathway, and SIPA1L2 was downregulated in GBC serum samples. Our study highlights the advantage of integrating small-RNA sequencing results from different types of samples and independent datasets, and the need for international research collaborations to identify and validate biomarkers for secondary prevention of rare tumours such as GBC. The function of miR-4533 and its interaction with SIPA1L2 in GBC development need to be further investigated., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Endometrial cancer (EC) is one of the most common female cancers and there is currently no routine screening strategy for early detection. An altered abundance of circulating microRNAs (miRNAs) and other RNA classes have the potential as early cancer biomarkers. We analyzed circulating RNA levels using small RNA sequencing, targeting RNAs in the size range of 17-47 nucleotides, in EC patients with samples collected prior to diagnosis compared to cancer-free controls. The analysis included 316 cases with samples collected 1-11 years prior to EC diagnosis, and 316 matched controls, both from the Janus Serum Bank cohort in Norway. We identified differentially abundant (DA) miRNAs, isomiRs, and small nuclear RNAs between EC cases and controls. The top EC DA miRNAs were miR-155-5p, miR-200b-3p, miR-589-5p, miR-151a-5p, miR-543, miR-485-5p, miR-625-p, and miR-671-3p. miR-200b-3p was previously reported to be among one of the top miRNAs with higher abundance in EC cases. We observed 47, 41, and 32 DA miRNAs for EC interacting with BMI, smoking status, and physical activity, respectively, including two miRNAs (miR-223-3p and miR-29b-3p) interacting with all three factors. The circulating RNAs are altered and show temporal dynamics prior to EC diagnosis. Notably, DA miRNAs for EC had the lowest q-value 4.39-6.66 years before diagnosis. Enrichment analysis of miRNAs showed that signaling pathways Fc epsilon RI, prolactin, toll-like receptor, and VEGF had the strongest associations., (© 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Introduction: Effective strategies for early detection of epithelial ovarian cancer are lacking. We evaluated whether a panel of 14 previously established circulating microRNAs could discriminate between cases diagnosed <2 years after serum collection and those diagnosed 2-7 years after serum collection. miRNA sequencing data from subsequent ovarian cancer cases were obtained as part of the ongoing multi-cancer JanusRNA project, utilizing pre-diagnostic serum samples from the Janus Serum Bank and linked to the Cancer Registry of Norway for cancer outcomes., Methods: We included a total of 80 ovarian cancer cases contributing 80 serum samples and compared 40 serum samples from cases with samples collected <2 years prior to diagnosis with 40 serum samples from cases with sample collection ≥2 to 7 years. We employed the extreme gradient boosting (XGBoost) algorithm to train a binary classification model using 70% of the available data, while the model was tested on the remaining 30% of the dataset., Results: The performance of the model was evaluated using repeated holdout validation. The previously established set of miRNAs achieved a median area under the receiver operating characteristic curve (AUC) of 0.771 in the test sets. Four out of 14 miRNAs (hsa-miR-200a-3p, hsa-miR-1246, hsa-miR-203a-3p, hsa-miR-23b-3p) exhibited higher expression levels closer to diagnosis, consistent with the previously reported upregulation in cancer cases, with statistical significance observed only for hsa-miR-200a-3p (beta=0.14; p=0.04)., Discussion: The discrimination potential of the selected models provides evidence of the robustness of the miRNA signature for ovarian cancer., Competing Interests: K.S., K.E., and W.F.. are co-inventors of patent US201762444085P/EP3565903A1 (title “Circulating microrna signatures for ovarian cancer”), which relates to the use of circulating miRNAs for ovarian cancer diagnosis. The authors remaining declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Stawiski, Fortner, Pestarino, Umu, Kaaks, Rounge, Elias, Fendler and Langseth.)

Background: It has been hypothesized that poorly functioning Leydig and/or Sertoli cells of the testes, indicated by higher levels of serum gonadotropins and lower levels of androgens, are related to the development of testicular germ cell tumors (TGCT). To investigate this hypothesis, we conducted a nested case-control study within the Janus Serum Bank cohort., Methods: Men who developed TGCT (n = 182) were matched to men who did not (n = 364). Sex steroid hormones were measured using LC/MS. Sex hormone binding globulin, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were quantified by direct immunoassay. Multivariable logistic regression was used to calculate ORs and 95% confidence intervals (CI) for associations between hormone levels and TGCT risk., Results: Higher FSH levels [tertile (T) 3 vs. T2: OR = 2.89, 95% CI = 1.83-4.57] were associated with TGCT risk, but higher LH levels were not (OR = 1.26, 95% CI = 0.81-1.96). The only sex steroid hormone associated with risk was androstane-3α, 17β-diol-3G (3α-diol-3G; OR = 2.37, 95% CI = 1.46-3.83). Analysis by histology found that increased FSH levels were related to seminoma (OR = 3.55, 95% CI = 2.12-5.95) but not nonseminoma (OR = 1.19, 95% CI = 0.38-3.13). Increased levels of 3α-diol-3G were related to seminoma (OR = 2.29, 95% CI = 1.35-3.89) and nonsignificantly related to nonseminoma (OR = 2.71, 95% CI = 0.82-8.92)., Conclusions: Higher FSH levels are consistent with the hypothesis that poorly functioning Sertoli cells are related to the development of TGCT. In contrast, higher levels of 3α-diol-3G do not support the hypothesis that insufficient androgenicity is related to risk of TGCT., Impact: Clarifying the role of sex hormones in the development of TGCT may stimulate new research hypotheses., (©2023 American Association for Cancer Research.)

Previous studies had limited power to assess the associations of testosterone with aggressive disease as a primary endpoint. Further, the association of genetically predicted testosterone with aggressive disease is not known. We investigated the associations of calculated free and measured total testosterone and sex hormone-binding globulin (SHBG) with aggressive, overall and early-onset prostate cancer. In blood-based analyses, odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer were estimated using conditional logistic regression from prospective analysis of biomarker concentrations in the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group (up to 25 studies, 14 944 cases and 36 752 controls, including 1870 aggressive prostate cancers). In Mendelian randomisation (MR) analyses, using instruments identified using UK Biobank (up to 194 453 men) and outcome data from PRACTICAL (up to 79 148 cases and 61 106 controls, including 15 167 aggressive cancers), ORs were estimated using the inverse-variance weighted method. Free testosterone was associated with aggressive disease in MR analyses (OR per 1 SD = 1.23, 95% CI = 1.08-1.40). In blood-based analyses there was no association with aggressive disease overall, but there was heterogeneity by age at blood collection (OR for men aged <60 years 1.14, CI = 1.02-1.28; P het  = .0003: inverse association for older ages). Associations for free testosterone were positive for overall prostate cancer (MR: 1.20, 1.08-1.34; blood-based: 1.03, 1.01-1.05) and early-onset prostate cancer (MR: 1.37, 1.09-1.73; blood-based: 1.08, 0.98-1.19). SHBG and total testosterone were inversely associated with overall prostate cancer in blood-based analyses, with null associations in MR analysis. Our results support free testosterone, rather than total testosterone, in the development of prostate cancer, including aggressive subgroups., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: IgA antibodies against few Epstein-Barr virus (EBV) proteins are established serological markers for nasopharyngeal carcinoma (NPC). We recently validated a novel, comprehensive EBV marker panel and showed that IgA, but also IgG antibodies against multiple EBV proteins are highly sensitive and specific for EBV-positive NPC at diagnosis. However, data about these novel biomarkers as prospective markers for NPC are sparse., Methods: This study included 30 incident NPC cases and 60 matched controls from the Norwegian Janus Serum Bank. For 21 NPCs, molecular EBV and human papillomavirus (HPV) status were assessed by EBER-ISH and HPV DNA/RNA testing by PCR, respectively. IgA and IgG serum antibodies against 17 EBV antigens were analyzed in prediagnostic sera of cases (median lead time 14 years) and controls using multiplex serology. Sensitivities were calculated using receiver operating characteristic analysis pre-specified to yield 90% specificity in the control group. From 10 cases, serial samples were available., Results: Quantitative EBV antibody levels were significantly elevated among all cases (p < 0.05) for three IgA and six IgG antibodies. The highest sensitivities for defining 12 EBER-ISH-positive NPCs were observed for BGLF2 IgA (67%) and BGLF2 IgG (83%). Increased IgA and IgG antibody levels between the first and last draw before diagnosis were observed for EBER-ISH positive, but not for EBER-ISH negative NPCs. Among 21 molecularly analyzed NPCs, 4 EBER-ISH negative NPCs showed concomitant positivity to HPV type-specific DNA and RNA; 3 NPCs were HPV16 and 1 NPC was HPV18 positive., Conclusion: Both, EBV IgA and IgG antibody levels are significantly elevated many years before diagnosis of EBV-positive NPCs in Norway, an NPC low-incidence region. This study provides insights into one of the largest available prospective sample collections of NPCs in a non-endemic country., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

While genotyping studies are scavenging for suitable samples to analyze, large serum collections are currently left unused as they are assumed to provide insufficient amounts of DNA for array-based genotyping. Long-term stored serum is considered to be difficult to genotype since preanalytical treatments and storage effects on DNA yields are not well understood. Successful genotyping of such samples has the potential to activate large biobanks for future genome-wide association studies (GWAS). We aimed to evaluate genotyping of ultralow amounts of DNA from samples stored up to 45 years in the Janus Serum Bank with two commercially available platforms. 64 samples, with various preanalytical treatments, were genotyped on the Axiom Array from Thermo Fisher Scientific and a subset of 24 samples with slightly higher yield were genotyped on the HumanCoreExome array from Illumina. Our results showed that about 80% of the serum samples produced call rates with the Axiom arrays that would be satisfactory in GWAS. The mean DNA yield was 5.8 ng as measured with PicoGreen, 3-6% of recommended yield. The failed samples had on average lower input amounts of DNA. All serum samples genotyped on the HumanCoreExome with a standard and FFPE protocol produced GWAS satisfactory call rates, with mean 97.57% and 98.35% call rates, respectively. The mean yield was 10.65 ng, 6% of the recommendations. Successful array-based genotyping of ultralow DNA yields from serum samples stored up to 45 years is possible. These results demonstrate the potential to activate large serum biobank collections for future studies.

Objectives: Sex hormones have been hypothesized to explain the strong male predominance in esophageal adenocarcinoma, but evidence is needed. This study examined how circulating sex hormone levels influence future risk of esophageal adenocarcinoma., Methods: This case-control study was nested in a prospective Norwegian cohort (Janus Serum Bank Cohort), including 244 male patients with esophageal adenocarcinoma and 244 male age-matched control participants. Associations between prediagnostic circulating levels of 12 sex hormones and risk of esophageal adenocarcinoma were assessed using conditional logistic regression. In addition, a random-effect meta-analysis combined these data with a similar prospective study for 5 sex hormones., Results: Decreased odds ratios (ORs) of esophageal adenocarcinoma were found comparing the highest with lowest quartiles of testosterone (OR = 0.44, 95% confidence interval [CI] 0.22-0.88), testosterone:estradiol ratio (OR = 0.37, 95% CI 0.19-0.72), and luteinizing hormone (OR = 0.50, 95% CI 0.30-0.98), after adjustment for tobacco smoking and physical activity. These associations were attenuated after further adjustment for body mass index (OR = 0.56, 95% CI 0.27-1.13 for testosterone; OR = 0.46, 95% CI 0.23-0.91 for testosterone:estradiol ratio; OR = 0.55, 95% CI 0.29-1.08 for luteinizing hormone). No associations were observed for sex hormone-binding globulin, dehydroepiandrosterone sulfate, follicle-stimulating hormone, prolactin, 17-OH progesterone, progesterone, androstenedione, or free testosterone index. The meta-analysis showed an inverse association between testosterone levels and risk of esophageal adenocarcinoma (pooled OR for the highest vs lowest quartile = 0.60, 95% CI 0.38-0.97), whereas no associations were identified for androstenedione, sex hormone-binding globulin, estradiol, or testosterone:estradiol ratio., Discussion: Higher circulating testosterone levels may decrease the risk of esophageal adenocarcinoma in men.

Background: Although glioma etiology is poorly understood in general, growing evidence indicates a genetic component. Four large genome-wide association studies (GWAS) have linked common genetic variants with an increased glioma risk. However, to date, these studies are based largely on a case-control design, where cases have been recruited at the time of or after diagnosis. They may therefore suffer from a degree of survival bias, introduced when rapidly fatal cases are not included., Methods: To confirm glioma risk variants in a prospective setting, we have analyzed 11 previously identified risk variants in a set of prediagnostic serum samples with 598 cases and 595 matched controls. Serum samples were acquired from The Janus Serum Bank, a Norwegian population-based biobank reserved for cancer research., Results: We confirmed the association with glioma risk for variants within five genomic regions: 8q24.21 (CCDC26), 9p21.3 (CDKN2B-AS1), 11q23.3 (PHLDB1), 17p13.1 (TP53), and 20q13.33 (RTEL1). However, previously identified risk variants within the 7p11.2 (EGFR) region were not confirmed by this study., Conclusions: Our results indicate that the risk variants that were confirmed by this study are truly associated with glioma risk and may, consequently, affect gliomagenesis. Though the lack of positive confirmation of EGFR risk variants may be attributable to relatively limited statistical power, it nevertheless raises the question whether they truly are risk variants or markers for glioma prognosis., Impact: Our findings indicate the need for further studies to clarify the role of glioma risk loci with respect to prolonged survival versus etiology., (©2015 American Association for Cancer Research.)