Background
Childhood cancer is a rare but leading cause of morbidity and mortality. Established risk factors, accounting for <10% of incidence, have been identified primarily from case‐control ...studies. However, recall, selection and other potential biases impact interpretations particularly, for modest associations. A consortium of pregnancy and birth cohorts (I4C) was established to utilise prospective, pre‐diagnostic exposure assessments and biological samples.
Methods
Eligibility criteria, follow‐up methods and identification of paediatric cancer cases are described for cohorts currently participating or planning future participation. Also described are exposure assessments, harmonisation methods, biological samples potentially available for I4C research, the role of the I4C data and biospecimen coordinating centres and statistical approaches used in the pooled analyses.
Results
Currently, six cohorts recruited over six decades (1950s‐2000s) contribute data on 388 120 mother‐child pairs. Nine new cohorts from seven countries are anticipated to contribute data on 627 500 additional projected mother‐child pairs within 5 years. Harmonised data currently includes over 20 “core” variables, with notable variability in mother/child characteristics within and across cohorts, reflecting in part, secular changes in pregnancy and birth characteristics over the decades.
Conclusions
The I4C is the first cohort consortium to have published findings on paediatric cancer using harmonised variables across six pregnancy/birth cohorts. Projected increases in sample size, expanding sources of exposure data (eg, linkages to environmental and administrative databases), incorporation of biological measures to clarify exposures and underlying molecular mechanisms and forthcoming joint efforts to complement case‐control studies offer the potential for breakthroughs in paediatric cancer aetiologic research.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Four sesquiterpene lactones were isolated from
Achillea falcata, through bioassay-guided fractionation, based on their differential ability to affect HaCaT cell growth. Identified ...seco-tanapartholides: 3-β-methoxy-iso-seco-tanapartholide (
1), tanaphillin (
2), iso-seco-tanapartholide (
3), and 8-hydroxy-3-methoxy-iso-seco-tanaparatholide (
4) were found to differentially decrease keratinocyte cell viability. In addition, the stereoselectivity, lipophilicity, and number and position of hydroxyl groups present in these compounds were correlated with their biological activities for HaCaT cell growth inhibition. Statistical analyses confirmed an enhanced potency of the β-OH iso-seco-tanapartholide over the α:β-OH diastereoisomeric mixture. The highest potency, however, was mainly the function of the enhanced lipophilicity of the molecule.
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50 values of four seco-tanapartholides differing in chemical properties and number and position of substituents showed that 3-β-methoxy-iso-seco-tanapartholide most potently inhibits keratinocyte cell proliferation due to its enhanced lipophilicity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
In a number of human cancers, NTN1 upregulation inhibits apoptosis induced by its so‐called dependence receptors DCC and UNC5H, thus promoting tumor progression. In other cancers however, the ...selective inhibition of this dependence receptor death pathway relies on the silencing of pro‐apoptotic effector proteins. We show here that a substantial fraction of human breast tumors exhibits simultaneous DNA methylation‐dependent loss of expression of NTN1 and of DAPK1, a serine threonine kinase known to transduce the netrin‐1 dependence receptor pro‐apoptotic pathway. The inhibition of DNA methylation by drugs such as decitabine restores the expression of both NTN1 and DAPK1 in netrin‐1‐low cancer cells. Furthermore, a combination of decitabine with NTN1 silencing strategies or with an anti‐netrin‐1 neutralizing antibody potentiates tumor cell death and efficiently blocks tumor growth in different animal models. Thus, combining DNA methylation inhibitors with netrin‐1 neutralizing agents may be a valuable strategy for combating cancer.
Synopsis
Inhibition of DNA methylation with decitabine restores expression of netrin‐1 (NTN1) and DAPK1 in human breast tumors. Combining decitabine with NTN1 neutralization potentiates tumor cell death and blocks tumor growth in various animal models.
NTN1 and DAPK1 are frequently hypermethylated and lost in human breast cancers.
NTN1 and DAPK1 loss of expression is associated with a loss of apoptosis induction upon netrin‐1 targeting antibody treatment.
Epigenetic drugs such as decitabine (DAC) induce demethylation and upregulation of DAPK1 and NTN1 in tumor cells, thus leading to cell resensitization to netrin‐1 targeting antibodies.
Combinatorial DAC + net1‐mAb treatment triggers cell death in vitro and tumor growth inhibition in mice.
Inhibition of DNA methylation with decitabine restores expression of netrin‐1 (NTN1) and DAPK1 in human breast tumors. Combining decitabine with NTN1 neutralization potentiates tumor cell death and blocks tumor growth in various animal models.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Abstract
Pulmonary grade-1 typical (TC) and grade-2 atypical (AC) carcinoids share molecular characteristics with grade-3 large-cell neuroendocrine carcinoma (LCNEC) despite the distinct clinical ...behaviors. Most carcinoids can be surgically resected, however, limited treatment options exist for metastatic disease, present in 10-23% of TC and 40-50% of AC. Comprehensive genomic studies could help identify better therapeutic opportunities, novel diagnostic markers, and provide insight on the mechanisms responsible for the increased aggressiveness of AC versus TC. Such studies are rare due to the limited availability of suitable material.
We have established a multi-center collaboration that has given us access to a unique collection of samples. We have already characterized 40 TC and 60 LCNEC genomes/exomes, and 61 TC, 8 AC and 69 LCNEC trancriptomes (published data). In the present study, we have performed whole-exome and transcriptome sequencing on 20 AC patients. Methylation data from 850K Illumina arrays were also generated for these samples, and for a subset of 20 TC and 20 LCNEC previously mentioned.
When comparing the mutational data on AC with that of TC and LCNEC, we have found that similar to TC, AC harbor recurrent alterations in chromatin remodeling genes (such as MEN1 and ARID1A). They also carry alterations in genes involved in other cancer-related pathways (based on STRING), such as cell motility and cell death explaining their more aggressive phenotype. Integrative clustering analysis (MOFA and iCLUSTER) based on expression and methylation data tends to classify carcinoids into four groups: groups 1 and 2 are mostly composed of females with TC, and differ by their age composition and smoking status (Fisher's exact test p=0.008 and 0.03, respectively). Groups 3 and 4 are mostly composed of males with AC (Fisher's exact test for tumor type p=8x10-5). When including the LCNEC data, the samples from group 3 cluster with LCNEC, suggesting that AC can display a variety of expression and methylation patterns that may be linked to aggressiveness. This result was supported by the better survival of groups 1 and 2 compared to groups 3 and 4 (log-rank p=0.02), for which survival was similar to that of patients with LCNEC.
Here, we present for the first time: (i) a multi-omics study on AC; (ii) the methylome characterization of TC, AC, and LCNEC; and (iii) the results of a comparative analysis of TC, AC, and LCNEC based on their molecular characteristics. We have identified the genes and pathways that might explain the progression from low-grade TC to intermediate-grade AC. Our expression and methylation data also supports the existence of a “super-AC” group, which clusters with LCNEC. Finally, we have identified a panel of molecular alterations that may help pathologist distinguishing between these three entities.
NL and NA contributed equally. LFC and MF jointly supervised this work.
Citation Format: Noémie Leblay, Nicolas Alcala, David Hervás Marin, Tiffany M. Delhomme, Théo Giffon, Akram Ghantous, Amélie Chabrier, Cyrille Cuenin, Janine Altmueller, Geoffroy Durand, Catherine Voegele, Philippe Lorimier, Anne-Claire Toffart, Jules Derks, Odd Terje Brustugun, Joachim H. Clement, Joerg Saenger, John K. Field, Alex Soltermann, Gavin M. Wright, Luca Roz, Lucia Anna Muscarella, Paolo Graziano, Zdenko Herceg, Ernst-Jan Speel, Peter Nuernberg, James McKay, Nicolas Girard, Sylvie Lantuejoul, Juan Sandoval, Elisabeth Brambilla, Matthieu Foll, Lynnette Fernandez-Cuesta. Multi-omics comparative analyses of pulmonary typical carcinoids, atypical carcinoids, and large-cell neuroendocrine carcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5358.
Background: Bisphenol A (BPA), an estrogen-like endocrine disruptor, has been associated with breast carcinogenesis in multiple studies, so plastic manufacturers shifted towards the less-studied and ...potentially less toxic BPA analogues, bisphenol F (BPF) and bisphenol S (BPS). Estrogen receptor (ER) is involved in the upregulation of global DNA methylation and telomerase expression, which have been associated with breast cancer development. However, the role of endocrine disruptors in the regulation of DNA methylation and telomerase expression has not been fully elucidated. Aims: We aimed to evaluate the metabolic activity, viability and mobility, as well as the DNA methylation and telomerase-linked mechanisms of BPA and its analogues (BPF and BPS) on breast cancer cell lines (ER positive: MCF-7 and ER negative: MDA-MB-231).Methods: We assessed metabolic activity, viability and mobility of MCF-7 and MDA-MB-231 cells after treatment with BPA, BPF and BPS with/without ER inhibitor. At day 1 of treatment of MCF-7 cells, RNA expression of genes involved in DNA methylation (DNMT1, DNMT3a, DNMT3b) and demethylation (APOBEC3B and TET 2 and 3 enzymes) was quantified. Telomerase expression and relative telomere length (RTL) were also evaluated. Cell invasion assay and LINE1 methylation (as a surrogate marker for global methylation) are in progress for both cell lines. Similar assays will be performed on normal-like breast epithelial cells.Results: In MCF-7 cells, BPA, BPF and BPS caused a dose- and ER-dependent increase in cell metabolic activity and viability, with BPS being 10 times less potent than BPA and BPF. All three endocrine disruptors increased MCF-7 cell mobility over 24 hours. As expected, MDA-MB-231 cells, being ER negative, did not show changes in these parameters. In MCF-7 cells, the three endocrine disruptors increased the expression of DNMT1 and telomerase (but without affecting RTL); TET2 expression was increased by both BPA and BPS while TET3 expression was increased by only BPA. Similarly to the phenotypic changes, these molecular alterations were ER-dependent (Figure1).Conclusions: DNA methylation and telomerase are potentially involved in the effects of BPA and its analogues on MCF-7 cells. Our results hopefully set the basis for studies aiming to evaluate the mechanism of endocrine disruptors.
Abstract
Purpose of the study: This study was aimed at identifying epigenome signature associated with risk of pediatric leukemia and uncovering molecular precursors of leukemia at birth in the blood ...of children before they develop the disease. Pediatric cancer is the leading cause of disease-related mortality in children and adolescents, with increasing incidence worldwide and lifelong sequelae in survivors. The most common form is leukemia, the causes of which are largely unknown. Growing evidence points to an origin in utero, when global redistribution of the epigenome modifications occurs driving tissue differentiation. Here, we sought to identify genome-wide differentially methylated genes at birth in newborns who later developed pediatric precursor B-cell ALL (pre-B ALL), compared with those who did not.
Experimental procedures: Epigenome-wide DNA methylation was profiled in neonatal blood, with follow-up to pediatric pre-B ALL, using double-blinded analyses between prospective cohorts extending from birth to diagnosis and retrospective studies backtracking from clinical disease to birth. Validation was done using an independent technology and population (totaling 317 cases and 483 control) and complemented with pan-tissue methylation-stability (n=5,023 tissues; 30 types) and methylation-expression (n=2,294 tissues; 26 types) analyses. At diagnosis, methylation analysis was performed in leukemia tissues from pre-B ALL patients (n=644) with at least ten-year follow-up.
Results: We found a limited number of loci (among which an imprinted tumor suppressor gene) as being significantly hypermethylated at birth in nested cases relative to controls in all tested populations, including European and Hispanic ancestries. Some DMRs were found to be stable over follow-up years after birth and across surrogate blood and target bone marrow tissues. Differential methylation was found to be associated with a change in gene expression and with worse pre-B ALL patient survival, supporting a functional and translational role for differential methylation.
Conclusions: Our results provide proof-of-concept to detect at birth epigenetic alterations predisposing to childhood leukemia, reproducible in three continents and two ethnicities. DNA methylation alterations evident before diagnosis could be precursors of pediatric pre-B ALL development and actionable targets for risk assessment and prognosis.
Citation Format: Akram Ghantous, Semira Gonseth Nusslé, Farah Nassar, Natalia Spitz, Alexei Novoloaca, Olga Krali, Ritu Roy, Shaobo Li, Maxime Caron, Lilys Lam, Peter Daniel Fransquet, John Casement, John Strathdee, Mark S. Pearce, Helen M. Hansen, Adam J. De Smith, Daniel Sinnett, Siri Eldevik Håberg, Jill McKay, Jessica Nordlund, Per Magnus, Terence Dwyer, Richard Saffery, Joseph Leo Wiemels, Monica Cheng Munthe-Kaas, Zdenko Herceg. Epigenome-wide DNA methylation alterations precede diagnosis since birth and affect prognosis of pediatric B-cell acute lymphoblastic leukemia abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB362.
Sesquiterpene lactones (SL) are plant secondary metabolites that are known for their anti-fungal, anti-bacterial, anti-inflammatory, and anti-tumor properties. Considering that several SL-derived ...drugs are currently in cancer clinical trials, we have tested two SL molecules, 3-β-methoxy-iso-seco-tanapartholide (β-tan) isolated from Achillea falcata and salograviolide A (Sal A) isolated from Centaurea ainetensis, for their anti-tumor properties. We used the mouse epidermal JB6P + cells as a model for tumor promotion and cellular transformation. Key players that are involved in cellular transformation and tumorigenesis are the AP-1 and NF-κB transcription factors; therefore, we assessed how β-tan and Sal A modulate their signaling pathways in JB6P + cells.
The effects of β-tan and Sal A on the growth of normal and neoplastic keratinocytes and on the tumor promotion-responsive JB6P + cells were determined using the MTT assay. Anchorage-independent cell growth transformation assays were used to evaluate the anti-tumor promoting properties of these SL molecules in JB6P + cells and dual luciferase reporter assays and western blot analysis were used to investigate their effects on tumor promoter-induced AP-1 and NF-κB activities and protein levels of key AP-1 and NF-кB target genes.
β-tan and Sal A selectively inhibited tumor promoter-induced cell growth and transformation of JB6P + cells at concentrations that do not affect JB6P + and primary keratinocytes basal cell growth. In addition, both molecules reduced basal and tumor promoter-induced NF-κB transcriptional activities, differentially regulated basal and tumor promoter-induced AP-1 transcriptional activities, and modulated key players of the AP-1 and NF-κB signaling pathways.
These results highlight the anti-tumor promoting properties of β-tan and Sal A. These SL molecules isolated from two plant species native to the Middle East may provide opportunities for complementary medicine practices.
HTLV-I associated adult T-cell leukemia/lymphoma (ATL) carries a dismal prognosis due to chemo-resistance and immuno-compromised micro-environment. The combination of zidovudine and interferon-alpha ...(IFN) significantly improved survival in ATL. Promising results were reported by adding arsenic trioxide to zidovudine and IFN.
Here we assessed Th1/Th2/T(reg) cytokine gene expression profiles in 16 ATL patients before and 30 days after treatment with arsenic/IFN/zidovudine, in comparison with HTLV-I healthy carriers and sero-negative blood donors. ATL patients at diagnosis displayed a T(reg)/Th2 cytokine profile with significantly elevated transcript levels of Foxp3, interleukin-10 (IL-10), and IL-4 and had a reduced Th1 profile evidenced by decreased transcript levels of interferon-γ (IFN-γ) and IL-2. Most patients (15/16) responded, with CD4⁺CD25⁺ cells significantly decreasing after therapy, paralleled by decreases in Foxp3 transcript. Importantly, arsenic/IFN/zidovudine therapy sharply diminished IL-10 transcript and serum levels concomittant with decrease in IL-4 and increases in IFN-γ and IL-2 mRNA, whether or not values were adjusted to the percentage of CD4⁺CD25⁺ cells. Finally, IL-10 transcript level negatively correlated with clinical response at Day 30.
The observed shift from a T(reg)/Th2 phenotype before treatment toward a Th1 phenotype after treatment with arsenic/IFN/zidovudine may play an important role in restoring an immuno-competent micro-environment, which enhances the eradication of ATL cells and the prevention of opportunistic infections.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Kaposi sarcoma-associated herpesvirus (KSHV) is the etiologic agent of primary effusion lymphomas (PEL). PEL cell lines infected with KSHV, but negative for Epstein-Barr virus have a tumorigenic ...potential in non-obese diabetic/severe combined immunodeficient mice and result in efficient engraftment and formation of malignant ascites with notable abdominal distension, consistent with the clinical manifestations of PEL in humans.
Using this preclinical mouse model, we demonstrate that the combination of arsenic trioxide and interferon-alpha (IFN) inhibits proliferation, induces apoptosis and downregulates the latent viral transcripts LANA-1, v-FLIP and v-Cyc in PEL cells derived from malignant ascites. Furthermore, this combination decreases the peritoneal volume and synergistically increases survival of PEL mice.
These results provide a promising rationale for the therapeutic use of arsenic/IFN in PEL patients.
No relevant conflicts of interest to declare.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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