| 1. |
- Kanerva, Anna, et al.
(author)
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Case-control estimation of the impact of oncolytic adenovirus on the survival of patients with refractory solid tumors.
- 2015
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In: Molecular Therapy. - : Elsevier BV. - 1525-0024 .- 1525-0016. ; 23:2, s. 321-329
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Journal article (peer-reviewed)abstract
- Oncolytic immunotherapy with cytokine armed replication competent viruses is an emerging approach in cancer treatment. In a recent randomized trial an increase in response rate was seen but the effect on overall survival is not known with any virus. To facilitate randomized trials, we performed a case-control study assessing the survival of 270 patients treated in an Advanced Therapy Access Program (ATAP), in comparison to matched concurrent controls from the same hospital. The overall survival of all virus treated patients was not increased over controls. However, when analysis was restricted to GMCSF-sensitive tumor types treated with GMSCF-coding viruses, a significant improvement in median survival was present (From 170 to 208 days, P = 0.0012, N=148). An even larger difference was seen when analysis was restricted to good performance score patients (193 versus 292 days, P = 0.034, N=90). The survival of ovarian cancer patients was especially promising as median survival nearly quadrupled (P = 0.0003, N=37). These preliminary data lend support to initiation of randomized clinical trials with GMCSF-coding oncolytic adenoviruses.Molecular Therapy (2014); doi:10.1038/mt.2014.218.
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| 2. |
- Frank, C, et al.
(author)
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Population Landscape of Familial Cancer.
- 2015
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 5
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Journal article (peer-reviewed)abstract
- Public perception and anxiety of familial cancer have increased demands for clinical counseling, which may be well equipped for gene testing but less prepared for counseling of the large domain of familial cancer with unknown genetic background. The aim of the present study was to highlight the full scope of familial cancer and the variable levels of risk that need to be considered. Data on the 25 most common cancers were obtained from the Swedish Family Cancer Database and a Poisson regression model was applied to estimate relative risks (RR) distinguishing between family histories of single or multiple affected first-degree relatives and their diagnostic ages. For all cancers, individual risks were significantly increased if a parent or a sibling had a concordant cancer. While the RRs were around 2.00 for most cancers, risks were up to 10-fold increased for some cancers. Familial risks were even higher when multiple relatives were affected. Although familial risks were highest at ages below 60 years, most familial cases were diagnosed at older ages. The results emphasized the value of a detailed family history as a readily available tool for individualized counseling and its preventive potential for a large domain of non-syndromatic familial cancers.
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| 3. |
- Freitag, Daniel F., et al.
(author)
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Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: a Mendelian randomisation analysis
- 2015
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In: The Lancet Diabetes & Endocrinology. - 2213-8595. ; 3:4, s. 243-253
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Journal article (peer-reviewed)abstract
- Background To investigate potential cardiovascular and other effects of long-term pharmacological interleukin 1 (IL-1) inhibition, we studied genetic variants that produce inhibition of IL-1, a master regulator of inflammation. Methods We created a genetic score combining the effects of alleles of two common variants (rs6743376 and rs1542176) that are located upstream of IL1RN, the gene encoding the IL-1 receptor antagonist (IL-1Ra; an endogenous inhibitor of both IL-1 alpha and IL-1 beta); both alleles increase soluble IL-1Ra protein concentration. We compared effects on inflammation biomarkers of this genetic score with those of anakinra, the recombinant form of IL-1Ra, which has previously been studied in randomised trials of rheumatoid arthritis and other inflammatory disorders. In primary analyses, we investigated the score in relation to rheumatoid arthritis and four cardiometabolic diseases (type 2 diabetes, coronary heart disease, ischaemic stroke, and abdominal aortic aneurysm; 453 411 total participants). In exploratory analyses, we studied the relation of the score to many disease traits and to 24 other disorders of proposed relevance to IL-1 signalling (746 171 total participants). Findings For each IL1RN minor allele inherited, serum concentrations of IL-1Ra increased by 0.22 SD (95% CI 0.18-0.25; 12.5%; p=9.3 x 10(-33)), concentrations of interleukin 6 decreased by 0.02 SD (-0.04 to -0.01; -1,7%; p=3.5 x 10(-3)), and concentrations of C-reactive protein decreased by 0.03 SD (-0.04 to -0.02; -3.4%; p=7.7 x 10(-14)). We noted the effects of the genetic score on these inflammation biomarkers to be directionally concordant with those of anakinra. The allele count of the genetic score had roughly log-linear, dose-dependent associations with both IL-1Ra concentration and risk of coronary heart disease. For people who carried four IL-1Ra-raising alleles, the odds ratio for coronary heart disease was 1.15 (1.08-1.22; p=1.8 x 10(-6)) compared with people who carried no IL-1Ra-raising alleles; the per-allele odds ratio for coronary heart disease was 1.03 (1.02-1.04; p=3.9 x 10(-10)). Perallele odds ratios were 0.97 (0.95-0.99; p=9.9 x 10(-4)) for rheumatoid arthritis, 0.99 (0.97-1.01; p=0.47) for type 2 diabetes, 1.00 (0.98-1.02; p=0.92) for ischaemic stroke, and 1.08 (1.04-1.12; p=1.8 x 10(-5)) for abdominal aortic aneurysm. In exploratory analyses, we observed per-allele increases in concentrations of proatherogenic lipids, including LDL-cholesterol, but no clear evidence of association for blood pressure, glycaemic traits, or any of the 24 other disorders studied. Modelling suggested that the observed increase in LDL-cholesterol could account for about a third of the association observed between the genetic score and increased coronary risk. Interpretation Human genetic data suggest that long-term dual IL-1 alpha/beta inhibition could increase cardiovascular risk and, conversely, reduce the risk of development of rheumatoid arthritis. The cardiovascular risk might, in part, be mediated through an increase in proatherogenic lipid concentrations. Copyright (C) The Interleukin 1 Genetics Consortium. Open Access article distributed under the terms of CC-BY-NC-ND.
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| 4. |
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| 5. |
- Chen, Tianhui, et al.
(author)
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Distribution and risk of the second discordant primary cancers combined after a specific first primary cancer in German and Swedish cancer registries.
- 2015
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In: Cancer Letters. - : Elsevier BV. - 1872-7980 .- 0304-3835. ; 369:1, s. 152-166
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Journal article (peer-reviewed)abstract
- We aimed at investigating the distribution and risk of all second discordant primary cancers (SDPCs) after a specific first primary cancer in Germany and Sweden to provide etiological understanding of SDPCs and insight into their incidence rates and recording practices. Among 1,537,004 survivors of first primary cancers in Germany and 588,103 in Sweden, overall 80,162 and 32,544 SDPCs were recorded, respectively. Standardized incidence ratios (SIRs) of all SDPCs were elevated at levels between 1.1 and 2.1 after 23 (out of overall 29) cancers in Germany and at levels between 1.1 and 1.6 after 24 cancers in Sweden, and among them, elevated SIRs were found after 19 cancers in both populations. Decreased SIRs at levels ranging from 0.5 to 0.9 were found for some cancers with poor prognosis in Germany only. We found elevated risk after 19 out of 29 cancers in both countries, suggesting common etiology of SDPCs after most of first cancers and registration similarity. Decreased risks after some fatal cancers were found only in Germany, which may be attributed to reporting practices or missed death data in Germany.
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| 7. |
- Denisova, Evgeniya, et al.
(author)
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Frequent DPH3 promoter mutations in skin cancers.
- 2015
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In: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 6:34, s. 35922-35930
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Journal article (peer-reviewed)abstract
- Recent reports suggested frequent occurrence of cancer associated somatic mutations within regulatory elements of the genome. Based on initial exome sequencing of 21 melanomas, we report frequent somatic mutations in skin cancers in a bidirectional promoter of diphthamide biosynthesis 3 (DPH3) and oxidoreductase NAD-binding domain containing 1 (OXNAD1) genes. The UV-signature mutations occurred at sites adjacent and within a binding motif for E-twenty six/ternary complex factors (Ets/TCF), at -8 and -9 bp from DPH3 transcription start site. Follow up screening of 586 different skin lesions showed that the DPH3 promoter mutations were present in melanocytic nevi (2/114; 2%), melanoma (30/304; 10%), basal cell carcinoma of skin (BCC; 57/137; 42%) and squamous cell carcinoma of skin (SCC; 12/31; 39%). Reporter assays carried out in one melanoma cell line for DPH3 and OXNAD1 orientations showed statistically significant increased promoter activity due to -8/-9CC > TT tandem mutations; although, no effect of the mutations on DPH3 and OXNAD1 transcription in tumors was observed. The results from this study show occurrence of frequent somatic non-coding mutations adjacent to a pre-existing binding site for Ets transcription factors within the directional promoter of DPH3 and OXNAD1 genes in three major skin cancers. The detected mutations displayed typical UV signature; however, the functionality of the mutations remains to be determined.
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| 8. |
- Figlioli, Gisella, et al.
(author)
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Novel genetic variants in differentiated thyroid cancer and assessment of the cumulative risk.
- 2015
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 5
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Journal article (peer-reviewed)abstract
- A genome-wide association study (GWAS) performed on a high-incidence Italian population followed by replications on low-incidence cohorts suggested a strong association of differentiated thyroid cancer (DTC) with single nucleotide polymorphisms (SNPs) at 9q22.33, 2q35, 20q11.22-q12 and 14q24.3. Moreover, six additional susceptibility loci were associated with the disease only among Italians. The present study had two aims, first to identify loci involved in DTC risk and then to assess the cumulative effect of the SNPs identified so far in the Italian population. The combined analysis of the previous GWAS and the present Italian study provided evidence of association with rs7935113 (GALNTL4, OR = 1.36, 95%CI 1.20-1.53, p-value = 7.41 × 10(-7)) and rs1203952 (FOXA2, OR = 1.29, 95%CI 1.16-1.44, p-value = 4.42 × 10(-6)). Experimental ENCODE and eQTL data suggested that both SNPs may influence the closest genes expression through a differential recruitment of transcription factors. The assessment of the cumulative risk of eleven SNPs showed that DTC risk increases with an increasing number of risk alleles (p-trend = 3.13 × 10(-47)). Nonetheless, only a small fraction (about 4% on the disease liability scale) of DTC is explained by these SNPs. These data are consistent with a polygenic model of DTC predisposition and highlight the importance of association studies in the discovery of the disease hereditability.
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