• Understanding the role of hypoxia and PTEN loss in driving prostate cancer progression

      Suvac, Alexandru; Rebello, Richard; Lyons, Steve; Bristow, Robert G; Cancer Research UK Manchester Institute, Manchester (2021)
      Prostate cancer is the most commonly diagnosed cancer in the UK. Increased levels of prostate hypoxia have been shown to drive tumor aggression as an adverse prognostic factor following surgery or radiotherapy, especially when combined with tumor genetic instability. Our recent collaborative bioinformatic studies (Bhandari et al, Nat. Genetics 2019; Nat. Communications 2020) have shown various copy number changes to be enriched in hypoxic tumors, with mono- or bi-allelic loss of the PTEN being the most significant. To delineate a direct relationship between hypoxia and PTEN loss, we interrogated the impact of chronic hypoxia (1% O2, 0.2% O2; 72 h) on PTEN oncogenic signaling and asked whether this translates to improved fitness and survival in non-transformed and transformed PTEN isogenic cell lines. Despite increased oncogenic signaling (increased phospho-AKT) of PTEN-null 22Rv1 cells and hTERT-immortalized prostate epithelial cells (GHM) under chronic hypoxic gassing conditions, this did not lead to increased adaption and tumor clone survival. Differential survival for the PTEN isogenic cell lines following prostate cancer therapies (i.e. IR, PARPi, cDDP, taxols) under oxia and hypoxia are underway to further this work and determine a potential translational importance to clinical treatment. Independent evidence also points to hypoxia/PTEN loss in deregulating centrosome biology as a potential mechanism for genetic instability under hypoxia. Hence, we also hypothesized that the relationship between PTEN and hypoxia might be unearthed if aberrant unstable mitoses following deregulation of spindle poles under hypoxia selectively adapt and have a survival advantage. Quantitative immunofluorescence of centrosome aberrations, using antibodies to phospho-Histone H3 and Centrin-1, show significant increases in centriole numbers (p < 0.05) in mitotic cells under chronic hypoxic conditions and an increase in the incidence of micronuclei (p < 0.005), specifically in chronic hypoxic cells with PTEN loss, supporting our hypothesis. Current studies are investigating in situ staining of centrosomes as a readout of chromosomal instability (CIN) in primary prostate cancer tissues with variable PTEN status as a new biomarker for aggressiveness to link hypoxia-associated genetic instability with novel clinical trial development. (Funded by Cancer Research UK as a core grant to RGB).
    • Unexpected effects on bacterial phenotype induced by expression of a tumour-amplified human sequence.

      Heighway, Jim; Santibanez-Koref, Mauro F; Department of Cancer Genetics, Paterson Institute for Cancer Research, Christie Hospital, Manchester, UK. (1989-09-12)
      An amplified human sequence was isolated from a metastatic human lung carcinoma. A fragment of this sequence situated behind the lac promoter of pUC19 appeared to affect plasmid DNA supercoiling in certain E. coli strains. Subclones were constructed to identify the smallest region of the human insert that conferred the activity and a 369 bp fragment was identified, expression of which appeared to result in abnormal plasmid supercoiling. In order to study this phenotype, various constructs were introduced into the minicell-producing strain E. coli DS410 and an unexpected effect was observed. The bacteria, after normal early growth, clumped together in late log phase, leaving virtually clear medium. Other E. coli strains were also shown to be affected to a lesser degree. The sequence producing this effect was also mapped to the 369 bp fragment and a critical region of approximately 50 bp was identified using site-directed in vitro mutagenesis and Bal31 deletion analysis. The plasmid encoded product responsible for this phenotypic alteration did not appear to be a peptide and clumping was observed when the human DNA was expressed from several bacterial promoters. It would seem likely that this sequence encodes a biologically active RNA which affects gene expression in the host cell.
    • A unified haplotype-based method for accurate and comprehensive variant calling

      Cooke, D. P.; Wedge, David C; Lunter, G.; MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK (2021)
      Almost all haplotype-based variant callers were designed specifically for detecting common germline variation in diploid populations, and give suboptimal results in other scenarios. Here we present Octopus, a variant caller that uses a polymorphic Bayesian genotyping model capable of modeling sequencing data from a range of experimental designs within a unified haplotype-aware framework. Octopus combines sequencing reads and prior information to phase-called genotypes of arbitrary ploidy, including those with somatic mutations. We show that Octopus accurately calls germline variants in individuals, including single nucleotide variants, indels and small complex replacements such as microinversions. Using a synthetic tumor data set derived from clean sequencing data from a sample with known germline haplotypes and observed mutations in a large cohort of tumor samples, we show that Octopus is more sensitive to low-frequency somatic variation, yet calls considerably fewer false positives than other methods. Octopus also outputs realigned evidence BAM files to aid validation and interpretation.
    • United Kingdom Radiation Oncology 1 Conference (UKRO 1): accuracy and uncertainty in radiotherapy.

      Jones, B; Aird, E G; Colyer, H; Dobbs, J; Harris, R; Hoskin, P; McKenzie, A; West, Catharine M L; Oncology Centre, Hammersmith Hospital, London, UK. (2002-04)
    • Unsatisfactory quality of E. coli asparaginase biogenerics in India: Implications for clinical outcomes in acute lymphoblastic leukaemia

      Sidhu, J.; Gogoi, M. P.; Agarwal, P.; Mukherjee, T.; Saha, D.; Bose, P.; Roy, P.; Phadke, Y.; Sonawane, B.; Paul, Pritha; et al. (2021)
      Background: The biotherapeutic asparaginase is a cornerstone of therapy in acute lymphoblastic leukaemia (ALL). With limited access to the original native Escherichia coli-derived asparaginase (EcASNase), a variety of EcASNase biogenerics are used in low-middle-income countries (LMICs). The variable quality of these biogenerics potentially influences clinical outcomes. Procedure: Seven biogeneric EcASNases (P1-P7) marketed widely in India were evaluated, with P2 as an exemplar for in vivo monitoring. Therapeutic activity of P2 (10,000 IU/m2 /dose, intramuscular, every 72 hours) was monitored during induction therapy, and drug-related toxicities recorded. Molecular identity, purity and in vitro drug activity of seven biogenerics were characterised using multimodal analyses, and findings compared with reference EcASNase (R). Results: In patients (N = 62) receiving P2, subtherapeutic asparaginase activity (<100 U/L) was observed in 66% (46/70) of trough timepoints (72 hours postdose) during induction. Twelve patients (19%), 11 with high-risk ALL, developed hypersensitivity. Isoforms of EcASNase were identified in all seven biogenerics. All generic products contained impurities with batch-to-batch variability. These included high levels of protein aggregates and host cell protein contamination. In vitro assays of EcASNase activity and leukaemia cell line cytotoxicity were not discriminatory. Conclusions: Our findings confirm widespread concerns over the unsatisfactory quality and therapeutic activity of native EcASNase biogenerics marketed in LMICs. Appropriate use of these products requires monitored studies to identify clinical suitability and determine appropriate dosing and schedule. For large parts of the world, assured access to high-quality asparaginases remains an unmet therapeutic need.
    • Up-regulation of the embryonic self-renewal network through reversible polyploidy in irradiated p53-mutant tumour cells.

      Salmina, Kristine; Jankevics, Eriks; Huna, Anda; Perminov, Dmitry; Radovica, Ilze; Klymenko, Tetyana; Ivanov, Andrei; Jascenko, Elina; Scherthan, Harry; Cragg, Mark S; et al. (2010-08-01)
      We have previously documented that transient polyploidy is a potential cell survival strategy underlying the clonogenic re-growth of tumour cells after genotoxic treatment. In an attempt to better define this mechanism, we recently documented the key role of meiotic genes in regulating the DNA repair and return of the endopolyploid tumour cells (ETC) to diploidy through reduction divisions after irradiation. Here, we studied the role of the pluripotency and self-renewal stem cell genes NANOG, OCT4 and SOX2 in this polyploidy-dependent survival mechanism. In irradiation-resistant p53-mutated lymphoma cell-lines (Namalwa and WI-L2-NS) but not sensitive p53 wild-type counterparts (TK6), low background expression of OCT4 and NANOG was up-regulated by ionising radiation with protein accumulation evident in ETC as detected by OCT4/DNA flow cytometry and immunofluorescence (IF). IF analysis also showed that the ETC generate PML bodies that appear to concentrate OCT4, NANOG and SOX2 proteins, which extend into complex nuclear networks. These polyploid tumour cells resist apoptosis, overcome cellular senescence and undergo bi- and multi-polar divisions transmitting the up-regulated OCT4, NANOG and SOX2 self-renewal cassette to their descendents. Altogether, our observations indicate that irradiation-induced ETC up-regulate key components of germ-line cells, which potentially facilitate survival and propagation of the tumour cell population.
    • Update on thin melanoma: outcome of an international workshop.

      Mihic-Probst, D; Shea, C; Duncan, L; de la Fouchardiere, A; Landman, G; Landsberg, J; Ven den Oord, J; Lowe, L; Cook, Martin G; Jung Yun, S; et al. (2016-01)
      The following communication summarizes the proceedings of a 1-day Workshop of the International Melanoma Pathology Study Group, which was devoted to thin melanoma. The definitions and histologic criteria for thin melanoma were reviewed. The principal differential diagnostic problems mentioned included the distinction of thin melanoma from nevi, especially from nevi of special site, irritated nevi, inflamed and regressing nevi, and dysplastic nevi. Histologic criteria for this analysis were discussed and the importance of clinico-pathologic correlation, especially in acral sites, was emphasized. Criteria for the minimal definition of invasion were also discussed. In addition, a new technique of m-RNA expression profiling with 14 genes was presented and facilitated the distinction of thin melanomas from nevus in histologically obvious cases. However, for particular nevi, it was not obvious why the results indicated a malignant lesion. Despite many molecular and other ancillary investigations, Breslow thickness remains the most important prognostic factor in thin melanoma. The prognostic significance of radial (horizontal) and vertical growth phases, Clark level, regression, and mitotic rate were also discussed. Because of the increasing frequency of thin melanomas, there is a great need to develop more refined predictors of thin melanomas with worse clinical outcome.
    • Upregulation of meiosis-specific genes in lymphoma cell lines following genotoxic insult and induction of mitotic catastrophe.

      Kalejs, Martins; Ivanov, Andrei; Plakhins, Gregory; Cragg, Mark S; Emzinsh, Dzintars; Illidge, Timothy M; Erenpreisa, Jekaterina; Biomedical Research and Study Centre, Latvian University, Ratsupites 1, Riga, LV-1067, Latvia. m.kalejs@no.lv (2006)
      BACKGROUND: We have previously reported that p53 mutated radioresistant lymphoma cell lines undergo mitotic catastrophe after irradiation, resulting in metaphase arrest and the generation of endopolyploid cells. A proportion of these endopolyploid cells then undergo a process of de-polyploidisation, stages of which are partially reminiscent of meiotic prophase. Furthermore, expression of meiosis-specific proteins of the cancer/testis antigens group of genes has previously been reported in tumours. We therefore investigated whether expression of meiosis-specific genes was associated with the polyploidy response in our tumour model. METHODS: Three lymphoma cell lines, Namalwa, WI-L2-NS and TK6, of varying p53 status were exposed to a single 10 Gy dose of gamma radiation and their responses assessed over an extended time course. DNA flow cytometry and mitotic counts were used to assess the kinetics and extent of polyploidisation and mitotic progression. Expression of meiotic genes was analysed using RT-PCR and western blotting. In addition, localisation of the meiotic cohesin REC8 and its relation to centromeres was analysed by immunofluorescence. RESULTS: The principal meiotic regulator MOS was found to be significantly post-transcriptionally up-regulated after irradiation in p53 mutated but not p53 wild-type lymphoma cells. The maximum expression of MOS coincided with the maximal fraction of metaphase arrested cells and was directly proportional to both the extent of the arrest and the number of endopolyploid cells that subsequently emerged. The meiotic cohesin REC8 was also found to be up-regulated after irradiation, linking sister chromatid centromeres in the metaphase-arrested and subsequent giant cells. Finally, RT-PCR revealed expression of the meiosis-prophase genes, DMC1, STAG3, SYCP3 and SYCP1. CONCLUSION: We conclude that multiple meiotic genes are aberrantly activated during mitotic catastrophe in p53 mutated lymphoma cells after irradiation. Furthermore, we suggest that the coordinated expression of MOS and REC8 regulate the extent of arrested mitoses and polyploidy.
    • Upstream elements bestow T-cell and haemopoietic progenitor-specific activity on the granzyme B promoter.

      Johnson, Barbra A; John, Victoria A; Henschler, Reinhard; Hampson, Ian N; Heyworth, Clare M; Babichuk, Charolyn K; Bleackley, R Chris; Dexter, T Michael; Cross, Michael A; Section of Haemopoietic Cell and Gene Therapeutics, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester M20 4BX, UK. (1999-06-24)
      Cytotoxic T cells and early haemopoietic progenitors share the expression of a number of specific genes. Of these, granzyme B has attracted particular interest because of its role in inducing apoptosis during cytotoxic T cell-mediated target cell killing, and its potential role in the mobilisation and homeostasis of haemopoietic stem cells. Studies of granzyme B regulation should therefore yield valuable information concerning the molecular control of these processes, and also identify elements capable of directing gene expression to two cell types of relevance to gene therapy. Here we show that proximal regulatory elements already known to direct promoter activity in T cells are similarly active in haemopoietic progenitors. However, this activity is not strictly specific, since the promoter regions also direct low levels of reporter gene expression in fibroblasts. More importantly, we also report the presence of two previously unidentified clusters of DNaseI hypersensitive sites upstream from the murine granzyme B gene, and show that these regions impart both increased transcriptional activity and the appropriate cell type specificity on the granzyme B promoter. These upstream regulatory regions are therefore likely to play a key role in the coordination of granzyme B expression in vivo.
    • Uptake of alpha-(L)-iduronidase produced by retrovirally transduced fibroblasts into neuronal and glial cells in vitro.

      Stewart, K; Brown, O A; Morelli, A E; Fairbairn, Leslie J; Lashford, Linda S; Cooper, A; Hatton, C E; Dexter, T Michael; Castro, M G; Lowenstein, P R; et al. (1997-01)
      The uptake of recombinant alpha-(L)-iduronidase into glial and neuronal cells, produced by retrovirally transduced NIH3T3 fibroblasts, was studied. We demonstrate that: (1) neuronal and glial cells take up alpha-(L)-iduronidase released into the medium by retrovirally transduced fibroblasts expressing high levels of alpha-(L)-iduronidase; (2) both glial and neuronal cells express the cation independent mannose-6-phosphate receptor responsible for lysosomal enzyme uptake; and (3) uptake of the lysosomal enzyme can be blocked by excess free mannose-6-phosphate, but not glucose-6-phosphate. Thus, various brain cells take up alpha-(L)-iduronidase, possibly through a cation independent mannose-6-phosphate receptor mediated pathway, and this uptake is higher in actively dividing or immature brain cells. Consequently, (1) neuronal metabolism ought to be capable of cross correction by enzyme provided by genetically engineered and transplanted cells provided by bone marrow transplantation (BMT); (2) that BMT could have a more beneficial effect on neurological function if performed as early as possible; and (3) given that the uptake mechanism of glial cells has a higher capacity, it might be easier to target diseases like the leukodystrophies in which lysosomal enzymes are needed in glial cells, compared to diseases where lysosomal enzymes ought to be delivered into neurons.
    • Uptake of genetic testing for cancer predisposition.

      Evans, D Gareth R; Maher, E R; Macleod, R; Davies, D R; Craufurd, D; CRC Department of Cancer Genetics, Paterson Institute for Cancer Research, Christie Hospital, Manchester, UK. (1997-09)
      Although there has been much debate about the uptake and effects of predictive testing for common cancers, such as breast and colon cancer, little has been published on the more classical tumour predisposing conditions, such as von Hippel-Lindau disease and familial adenomatous polyposis. Since 1990 the genetics departments in Manchester and Cambridge have had a genetic register for cancer predisposing syndromes and presymptomatic testing for these conditions has been offered once this has become possible. To investigate the factors that might influence uptake of genetic testing in familial cancer syndromes we have reviewed our experience. Demand for predictive testing has generally been high, but men had a lower uptake (77%) than a comparable group of women (93%) (p < 0.01).
    • The uptake of porphyrin and zinc-metalloporphyrin by the primate prostate.

      Pantelides, M L; Moore, James V; Forbes, E; Truscott, T G; Blacklock, N J; University Department of Urology, University Hospital of South Manchester, West Didsbury, U.K. (1993-05)
      The relative distribution of sensitizer drugs in the prostate and its contiguous organs is of importance in the treatment of localized prostatic cancer with photodynamic therapy. Using the primate model, whose prostate is both morphologically and physiologically homologous with its human counterpart, the distribution of hematoporphyrin derivative (HpD) amongst organs of urological interest was determined. Hematoporphyrin derivative levels were comparatively low in both caudal and cranial prostatic lobes (0.93-1.77 micrograms/g) and were similar to those in rectum, urethra and the skin. The reticuloendothelial organs, liver, spleen and also the kidney accumulated the highest quantities of porphyrin (4.76-9.8 micrograms/g, liver > spleen > kidney). Despite a high avidity of prostatic tissue for zinc, a zinc-metalloporphyrin (Zn-HpD) did not concentrate selectively in the prostate. The results are of clinical value in view of the homology between the primate and the human.
    • Urocortin suppresses endometrial cancer cell migration via CRFR2 and its system components are differentially modulated by estrogen.

      Owens, Gemma L; Lawrence, Kevin M; Jackson, Tom R; Crosbie, E; Sayan, Berna S; Kitchener, H; Townsend, Paul A; Division of Molecular & Clinical Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine & Health, Manchester Cancer Research Centre, University of Manchester, Wilmslow Road, Manchester, M20 4QL (2017-02)
      Urocortin (UCN1) peptide shares structural and functional homology with corticotropin-releasing factor (CRF). UCN1 is significantly reduced in endometrial adenocarcinoma compared to healthy controls. However, there are no data which evaluate the effects of UCN1 in the endometrium, or how it is modulated. We used proliferation and transwell assays to determine the effect of UCN1 on the proliferation and migration of Ishikawa and HEC1A cells. We also determined the expression levels of UCN1 and its receptors produced by estrogen receptor agonists, and the effect of UCN1 on estrogen receptor expression, using quantitative polymerase chain reaction. UCN1 suppressed migration of endometrial cancer cells in vitro. This effect appears to be specific to CRF receptor 2 (CRFR2), as selective antagonism of CRFR2 but not CRFR1 completely eliminated suppression of migration. Activation of ERA reduced UCN1 expression, but only had a small effect on the expression of CRFR1. However, expression of CRFR2 was more notably reduced at both the mRNA and protein levels by activation of ERB. UCN1 in turn reduced both ERA and ERB expression, as assessed by real-time quantitative PCR. We demonstrate that UCN1 significantly suppresses the migration of endometrial cancer cells but has no effect on their proliferation. Thus, loss of UCN1 in endometrial cancer may promote invasion and metastatic spread. There is a complex relationship between the UCN1 system and estrogen receptors, which may provide insights into endometrial carcinogenesis, a disease known to be driven by estrogen excess.
    • Urothelial proliferation in growing mice.

      Jost, S; Potten, Christopher S; Paterson Laboratories, Christie Hospital & Holt Radium Institute, Manchester, M20 9BX, U.K. (1986-03)
      Developing murine urothelium undergoes pronounced proliferation until at least 10 days after birth. Thereafter, both mitotic and [3H]TdR-labelling indices fall sharply with age. The ratio of labelling to mitotic indices also alters dramatically during development, which is probably due to both endoreduplication and changes in the relative durations of the DNA synthesis and mitotic phases. This ratio reaches stability at 5 weeks of age. The adult labelling and mitotic indices were 0.11 and 0.019% respectively, indicating a very slow turnover.
    • The use of a fluorescent methotrexate probe to monitor the effects of three vinca alkaloids on a mixed population of parental L1210 and gene-amplified methotrexate-resistant cells by flow cytometry

      Poppitt, David G; McGown, Alan T; Fox, Brian W; Paterson Laboratories, Christie Hospital and Holt Radium Institute, Withington, Manchester, M20 9BX, UK (1984)
    • Use of adenoviruses encoding CD40L or IL-2 against B cell lymphoma.

      Meziane, El-Kahina; Bhattacharyya, Tapan; Armstrong, Anne C; Qian, Cheng; Hawkins, Robert E; Stern, Peter L; Dermime, Said; CRUK Immunology Group, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, United Kingdom. (2004-10-10)
      Some B cell lymphomas lack important costimulatory properties that could prevent them from being used as cell based vaccines. Infection of A20 B lymphoma cells with a replication-defective adenovirus encoding murine (m) CD40L, but not mIL-2, produces an antigen presentation phenotype with upregulation of MHC Class I/II, induction of B7-1/2 molecules and production of MIL-12 and MIP-1alpha. Subcutaneous vaccination with irradiated Ad-mCD40L-infected- or Ad-mIL-2-infected-A20 cells generated A20-specific CD8+ T cell responses and cross reactive A20 Ig antibodies. Only vaccination with Ad-mCD40L-infected A20 cells produced a significant delay in tumor growth and long-term survival (p = 0.0039). Stronger protective immunity to A20 challenge was generated by intravenous priming with A20 cells infected with Ad-mCD40L, Ad-mIL-2 or their combination followed by a boost immunization with A20 cells activated with syngeneic fibroblasts expressing CD40L. Compared to Ad-LacZ-infected A20 priming, the combination priming was most effective followed by Ad-mCD40L and Ad-mIL-2 (p = 0.0027, p = 0.0027, p = 0.0163 respectively). Significant A20-specific CD8+ T cell-mediated cytotoxicity was only demonstrated in splenocytes from these groups of vaccinated animals. By contrast, ELISPOT assay of splenocytes from all A20 prime/boosted vaccinated groups demonstrated increases in gamma-interferon release by T cells elicited by in vitro stimulation either with A20 cells or another syngeneic 2PK-3 lymphoma, indicating the presence of cross reactive immunity. Similarly anti-A20 immunoglobulin antibodies generated after vaccination were not necessarily A20 idiotype-specific. Direct therapy of pre-established tumors was achieved with the combination of Ad-mCD40L and Ad-mIL-2 given at Days 4 and 8 at the tumor site with a significant long-term survival of 85% of tumor-bearing mice (p = 0.0001). Our study strongly supports the use of Ad-CD40L and Ad-IL-2 combination therapy for the treatment of patients with B cell lymphoma.
    • Use of an internal standard in comparative measurements of the intrinsic radiosensitivities of human T-lymphocytes.

      Elyan, S A; West, Catharine M L; Roberts, Stephen A; Hunter, Robin D; Cancer Research Campaign Department of Experimental Radiation Oncology, Paterson Institute for Cancer Research, Manchester, UK. (1993-10)
      A study has been made of the intrinsic radiosensitivity of peripheral blood lymphocytes from normal individuals. Cell survival following in vitro high (1.55 Gy min-1) and low (0.0098 Gy min-1) dose-rate irradiation was obtained for single lymphocyte samples from three individuals in six experiments. Despite wide interexperimental variability the ranking of intrinsic radiosensitivity for these individuals was reproducible. Further studies were carried out using low dose-rate irradiation only, on: (1) single lymphocyte samples from 18 people; (2) 14 samples taken on different occasions from one of these donors over a period of 5 months; and (3) a large store of lymphocytes from another individual. The latter was assayed in every experiment and served as an internal standard to which results could be normalized. In comparison with uncorrected values, the normalized results for the 14 samples from the single individual showed a reduction in the spread of data while those for the 18 different donors were unchanged. An analysis of variance was carried out on a larger data set of 38 measurements which included repeat assays on several of the samples (two samples from the multiply-sampled individual and five samples from other donors were assayed twice). In comparison with the uncorrected values, the normalized results showed a reduction in experimental variability such that the coefficient of variation (CV) for surviving fraction at 4 Gy for the multiple samples from a single individual decreased from 41 to 19%. In contrast, there was little change in the variation between 18 individuals with CVs of 56 and 62%, respectively, for uncorrected and normalized results. These data suggest that the use of an internal standard for the determination of the intrinsic radiosensitivity of individuals using peripheral blood lymphocytes should aid the development and evaluation of predictive tests for the radiotherapy of cancer.
    • The use of an intestinal epithelial cell line as a biological assay system of growth factor activity.

      Cove, Frances L; Evans, Gareth S; CRC Dept. of Epithelial Biology, Paterson Institute for Cancer Research, Manchester. (1992-05)
    • Use of antidepressants and risk of cutaneous melanoma: a prospective registry-based case-control study

      Berge, LAM; Andreassen, BK; Stenehjem, JS; Heir, T; Furu, K; Juzeniene, A; Roscher, I; Larsen, IK; Green, Adèle C; Veierod, MB; et al. (2020)
      PURPOSE: Melanoma is the cancer with the most rapidly rising incidence rate in Norway. Although exposure to ultraviolet radiation (UVR) is the major environmental risk factor, other factors may also contribute. Antidepressants have cancer inhibiting and promoting side effects, and their prescription rates have increased in parallel with melanoma incidence. Thus, we aimed to prospectively examine the association between use of antidepressants and melanoma by using nation-wide data from the Cancer Registry of Norway, the National Registry, the Norwegian Prescription Database and the Medical Birth Registry of Norway. PATIENT AND METHODS: All cases aged 18-85 with a primary cutaneous invasive melanoma diagnosed during 2007-2015 (n=12,099) were matched to population controls 1:10 (n=118,467) by sex and year of birth using risk-set sampling. We obtained information on prescribed antidepressants and other potentially confounding drug use (2004-2015). Conditional logistic regression was used to estimate adjusted rate ratios (RRs) and 95% confidence intervals (CIs) for the association between overall and class-specific use of antidepressants and incident melanoma. RESULTS: Compared with ≤1 prescription, ≥8 prescriptions of antidepressants overall were negatively associated with melanoma (RR 0.81 CI 0.75-0.87). Class-specific analyses showed decreased RRs for selective serotonin reuptake inhibitors (RR 0.82 CI 0.73-0.93) and mixed antidepressants (RR 0.77 CI 0.69-0.86). The negative association was found for both sexes, age ≥50 years, residential regions with medium and highest ambient UVR exposure, all histological subtypes, trunk, upper and lower limb sites and local disease. CONCLUSION: Use of antidepressants was associated with decreased risk of melanoma. There are at least two possible explanations for our results; cancer-inhibiting actions induced by the drug and less UVR exposure among the most frequent users of antidepressants.
    • The use of counter-current distribution to examine the effect of damaging agents on DNA.

      Jeney, A; Fox, Brian W; Paterson Laboratories, Christie Hospital and Holt Radium Institute, Manchester (1973-11)