Regulating Epigenetics in Cancer; A Model for Regulating Epigenetics and all Diseases. jjyrkkanen76@outlook.com Jorma Jyrkkanen

Draft: Regulating Epigenetics in Cancer; A Model for Regulating Epigenetics and all Diseases Sep. 15th, 2019 at 9:02 AM

Introduction: Discussion Paper to Stimulate Inclusion of Epigenetics and Epigenetically active substances in Carcinogenicity Testing. This is a rough drafft under construction. Comments appreciated. Please email me directly. Jorma Jyrkkanen, BSc, PDP. Jyrkkanen Environmental Consulting JEC jormabio@hotmail.com Abstract: Recent developments in epigenetics, knowledge of lateral gene transfer, impacts of antibiotics on mitochondria, antibiotic induced cancers, antibiotic resistance, technologies that enable easy weaponization of lethal viruses, highlight the need for pre-approval testing of pollutants, industrial chemicals including pesticides, biological pesticides, GMOs, antibiotics and drugs in general and engineered microbes; for carcinogenicity, epigenetic profiles, impacts on mitochondria, LGT potential of introduced or altered genes, effects on tumor suppressor genes, effect on DNA methylation, DNA repair genes, promoters, microRNA up or down regulation, hypomethylation, hypermethylation, genes found silenced in cancer or deleterious genes activated, impacts on the ubiquitin-proteasome pathway(UPP)and on imopacgts on the innate immune system. There is a need for registration and UN oversight of lethal technologies and substances. Diagnosis of cancer causing infectious agents should result in rules to prevent transmission. We need to take them more seriously than previously. Background The ability to manipulate genetic material has undergone a quantum leap in recent years such that a large variety of altered genes and genetic products and means of manipulation of those genes as well as delivery mechanisms has been developed. Our understanding of the epigenetic determinants of cancer has also grown immensely in recent times (Stephen B Baylin and Peter A Jones. Epigenetic Determinants of Cancer. Cold Spring Harb Perspect Biol. 2016 Sep; 8(9): a019505.) Cancer causing infectious agents that have epigenetic components and are potential targets for cut and paste technologies have been reviewed by IARC recently (https://gco.iarc.fr/causes/infections/help). Carcinogenic Infectious agents Ten infectious agents that have been classified as well-established (Group 1) carcinogenic agents in humans by the International Agency for Research on Cancer (IARC) were considered, namely: Helicobacter pylori, hepatitis B virus (HBV), hepatitis C virus (HCV), human papillomavirus (HPV; types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59 — known collectively as high-risk types), Epstein–Barr virus (EBV), human herpesvirus type 8 (HHV-8; also known as Kaposi sarcoma-associated herpesvirus), human T-cell lymphotropic virus type 1 (HTLV-1), Opisthorchis viverrini, Clonorchis sinensis, and Schistosoma haematobium. Prevention of contagion should be a consquence of the knowledge of their serious potential. As well, synergisms and promoters need to be identified. The search for their epigenetic action potential needs elaboration and classification and opportunities for pharmaceutical targeting to reset methylation tags and develop potential vaccines. Population attributable fraction (PAF) of cancer incidence attributable to infections The PAF for carcinogenic infections is an estimate of the proportion of new cancer cases that would have been prevented in a population if all infections had been avoided or successfully treated before they caused cancer. The number of cancer cases that would have been prevented in a population if all infections had been avoided or successfully treated was calculated by multiplying the PAF by the total cancer burden (i.e. the total number of all cancers in the population). Infection-related cancers Cancers for which there is well-established evidence of a causal link with the above-mentioned infectious agents; these include carcinoma of the oral cavity, oropharynx including tonsil and base of tongue, larynx, anus, cervix, vulva, vagina, and penis (HPV); adult T-cell leukaemia and lymphoma (HTLV-1); Kaposi sarcoma (HHV-8); Hodgkin lymphoma, Burkitt lymphoma, and nasopharyngeal carcinoma (EBV); non-cardia and cardia gastric carcinoma, and gastric non-Hodgkin lymphoma (H. pylori); liver cancer (HBV); liver cancer and non-Hodgkin lymphomas (HCV); bile duct cancer (Opisthorchis viverrini and Clonorchis sinensis); and bladder carcinoma (Schistosoma haematobium). These were discussed further by myself at the Second Annual Conference on Genetics, Genetic Diseases and Stem Cells in Copenhagen in May 2019. From GMO technologies of pesticide corporations (Bt by Monsanto) to CRISPR and epigenetic drugs and creation of killer strains deliberately by military weaponization. The latter might create more lethal gene profiles by pharmacological alteration of methylation, hypomethylation or hypermethylation of DNA or microRNA as well as creating denovo new viruses or pathogens by in vivo or vitro hybridization. These could be used to turn genes off found silenced in various cancers. The following genes have been found turned off epigenetically in cancer by European Researchers. Epigenetic inactivation of tumour suppressor coding and non-coding genes in human cancer: an update. Pere Llinàs-Arias and Manuel Esteller. Published: 20 September 2017 https://doi.org/10.1098/rsob.170152 Silenced genes in cancer: 14-3-3 rho, Apaf-1, APC, ATM, BAX, BIM, BRCA1, CADM1, Casp 8, CBS, CDH11, CDO1, CHK2, CXXC4, DACH1, DACT2, DERL3, DNA-PKc, DR4, DUSP1, ERCC1, FADD, FASR, GP3, GS, HACE1, HHIP, HIC1, HOXA10, ITGA2, ITGA5, KISS1, KLF4, Ku80, Let-7a, MAT1, MBD4, MGMT, miR-124a, miR-129, miR-137, miR-145, miR-200, miR-214, miR-345, miR-34a, miR-373, miR-375, miR-7, miR-9, miR1-1, MLH1, MTHFR, NDRG2, NEIL1, NKD2, Notch L, Notch R, NUDT16, OGG1, OLFM4, P14/ARF, P15INK4b/CDKN2B, P16INK4a/CDKN2A, PLCD1, PTCD, PTRR, RAD23B, RAD51, RAD51B, RASSF1, RB1, RECK, Reprimo, RIPK3, ROR2, SFRP1, SFRP2, SFRP3, SLFN11, SOD2, SOX1, SPINT2, SRBC, TFPI-2, TMS1/ASC, TP53TG1, TSC1/TSC2, VHL, WIF1, WNT5A, WNT7A, WRN, XPC, XRCC3, ZIC1, ZIC4. Carcinogenesis. 2011 Jul;32(7):1033-42. doi: 10.1093/carcin/bgr081. Epub 2011 May 11. MicroRNA-342 inhibits colorectal cancer cell proliferation and invasion by directly targeting DNA methyltransferase 1. Wang H1, Wu J, Meng X, Ying X, Zuo Y, Liu R, Pan Z, Kang T, Huang W. These abnormally methylation altered DNA and miRNA genes raise the need for regulatory reform that recognizes that substances which can affect genes epigenetically and can contribute to cancers. These developments imply that a wide panoply of newly synthesized means exist to alter genomic transcription and translation and this creates the potential for errors deliberate or by ignorance to be introduced into genomes which may have unforeseen deleterious consequences. Genes can also be transferred laterally between organisms (Ed Yong, The Scientist, June 20 2013; Crisp et al. Genome Biology 2015 16:50), (University of Illinois at Urbana-Champaign. "Microbes in the human body swap genes, even across tissue boundaries, study indicates. (ScienceDaily, 11 April 2019). Retroviruses Ex: (HIV, herv-k (hml-2), HTLV) are of course the quintessential gene transfer agents for humans. Lateral gene transfer risks need evaluation and especially retroviral risks call for special investigation and oversight and more stringent rules for public health . Life-time exposures to pathogens, carcinogens, mutagens, methylators, alkylators, phosphorylators, damage to our bodies is often multi-factorial, cumulative, synergistic, genetic, epigenetic, potentially heritable, different for everybody. There will be folks whose immune systems having been compromised who will be susceptible to these diseases much more than others and genetics plays a large role as well. Example AIDS patients, scleroderma pigmentosum patients, patients with genetic defects, epigenetic defects. A questionnaire may help identify these cumulative risk factors. Synergies exist between drugs, pesticides, pathogens and the strength of these will vary also from person to person depending on history of exposure. Cancers exhibit epigenetic on/off switching. Special Case of Mitochondrial Contribution to Cancer via Antibiotics. Another problem has raised its head. Antibiotics induce mitochondrial dysfunction leading to increased ROS, lipid peroxidation both raising cancer risk and reduced glutathione (Kalghatigi, S. Et al . Antibiotic harms mammalian mitochondria. Sci Trans Med Sept 3 2013). Antibiotics can increase the likelihood of cancer particularly with repeat courses of exposure (Tim Newman. Medical News Today, Antibiotics may increase the risk of bowel cancer. April 5, 2017). Dietary sources of antibiotic treated meat products fall into this category of repeated exposure as might some pesticides. Mitochondrial health is associated with cancers. I postulate that antibiotic induced cancers may do so by the lipid peroxidation route the same as they do for red and treated meats. Why this matters is because we are entering an era where antibiotic resistance is a huge issue and we need to know that those we produce will not harm the mitochondria. Antibiotics will of course be considered for therapeutic use in infections by carcinogens such as Helicobacter pylori. Pesticides Impacts on Mitochondria Newly Identified. Nine commonly used pesticides in China, 9 were found to have affect mitochondria and have effects on the ubiquitin-proteasome UPS system at low concentrations which prevents normal recycling of proteins by blocking their breakdown into amino acid constituents. Seven induced mitochondrial fragmentation (T. Chen et al. Int J Mol Sci Nov 23;18(12) at low concentrations. I postulate that this may also increase cancer risk by a novel mechanism, lipid peroxide production, the same as in red and treated meat. Ben Boursi MD et al, Eur J Cancer. 2015 Nov; 51(17): 2655–2664 (Published online 2015 Aug 31) found among 125,441 cases and 490,510 matched controls were analyzed. For gastro-intestinal malignancies, the use of penicillin was associated with an elevated risk of esophageal, gastric, and pancreatic cancers. The association increased with the number of antibiotic courses and reached 1.4 for gastric cancers associated with >5 courses of penicillin (95%CI 1.2–1.8). Lung cancer risk increased with the use of penicillin, cephalosporines, or macrolides (AOR for >5 courses of penicillin: 1.4 95%CI 1.3–1.6). The risk of prostate cancer increased modestly with the use of penicillin, quinolones, sulphonamides and tetracyclines. The risk for breast cancer was modestly associated with exposure to sulphonamides. Because antibiotics and pesticides can affect the same genetic systems that are linked to increased cancer risk via ROS, lipid peroxide and the ubiquitin proteasome system and the SVIPgen both need to be included in regulatory monitoring and cancer prevention management. SVIP gen Mutation in Squamous cell cancer found that facilitates aerobic glycolysis and prevents Protein breakdown disrupting normal metabolism. Blocking it w drugs against glucose receptor starves the cancer. Trials underway. https://www.ub.edu/…/en/menu_eines/noticies/2019/03/029.html). Risk of Oversight or Deliberate Regulatory Mischief In 2008 I reported the following contaminants of 2,4-D. Amongst the dioxins there are the following found by Federal Researchers in Canada: 2,7-dichlorodibenzodioxin, 1,3,7-trichlorodibenzodioxin, 1,3,6,8-tetrachlorodibenzodioxin, 1,3,7,9-tetrachlorodibenzodioxin (Cochran, et. al. 1981, Agriculture Canada). Other contaminants revealed by the USA Government House Senate Oversight Committee to the International Agent Orange Committee of which I was a member are: octachlorobisfirone, xanthen-9-ones (Coddling Moth Ovicide), mono, di, tri, and tetradioxins (repeat of above), n-nitrosomethylamines, n-nitrosodiethylamines, ortho and para monochlorophenol isomers, (2,6-Di, 2,4,6 tri-) chloromethoxy phenol isomers, n-nitrosodiethanolamine, 3 chlorophenoxymethanes. These were kindly provided to me by my deceased friend, Joe Cole, Chairman of the IAOC. RIP Old buddy and thanks for your service to humanity. http://pr-rp.hc-sc.gc.ca/pi-ip/result-eng.php… FDA abd NCI have both been found to attempt patent theft in recent years of a Doctors effective remedy for certain cancers. Major Governent agencies cannot be trusted without independent oversight. Clearly there needs to be independent environmentalist led oversight at the technical level of active ingredients, inerts, surfactants and contaminants or a complete accounting of the final products contents. Weaponization of Pathogens Risk to Global Health and Regulation. Cambridge Working Group Recommendations. Working with Hazardous Pandemic Organisms July 14 2014 www.cambridgeworkinggroup.org Laboratory creation of highly transmissible, novel strains of dangerous viruses, especially but not limited to influenza, poses substantially increased risks. An accidental infection in such a setting could trigger outbreaks that would be difficult or impossible to control. Experiments involving the creation of potential pandemic pathogens should be curtailed until there has been a quantitative, objective and credible assessment of the risks, potential benefits, and opportunities for risk mitigation, as well as comparison against safer experimental approaches. A modern version of the Asilomar process, which engaged scientists in proposing rules to manage research on recombinant DNA, could be a starting point to identify the best approaches to achieve the global public health goals of defeating pandemic disease and assuring the highest level of safety. REPLACE with World Wide Ban on Weaponization [make more lethal, contagious, useful for military assassinations] of organisms. Its time has come. CRISPR and Epigenetic Manipulation has made it too dangerous. Too easy to create cut and paste pandemic lethals. LGT also means creations have lateral transfer potential. Proposed Regulatory Reforms 1. A UN imposed worldwide ban on weaponization of genetic material or organisms for military use. Global UN Convention ban requiring signatures from all participating countries on weaponizing disease vectors or production of any substance that affects methylation profiles and uses GM technologies for said purposes. 2. I propose that all carcinogens in Proposition 65, known mutagens, endocrine disrupters, pesticides, inerts, pesticide contaminants, GMO’s be tested for their ability to turn DNA and microRNA genes off in cancers or altered in expression and any future genes added to this list and those that do have this effect alert users by listing this on the MSDS sheets. 3. Test antibiotics and all other drugs for potential to produce ROS and lipid peroxide in mitochondria and or to rupture mitochondrial cells and their effects on epigenetic cancer profiles. 4. To existing regulatory approval requirements add assays of biological pesticides, phthalates, flame retardants, to DNA, RNA(s) including microRNA’s to epigenetic impact challenge testing for both methylating and alkylation. 5. Testing of all pollutants, industrial chemicals, food additives for epigenetic profiles in both DNA and microRNA. 6. Product or substance effects on tumor suppressor genes, DNA repair genes, microRNA deleterious disease genes activated, impacts on the ubiquitin-proteasome system(UPS). 7. Examine lateral gene transfer potential of introduced modified genes in the microbiome and in human cells. 8. Examine heritability of epigenetic results found for at least 3 generations. 9. Agency policy. i). Stop the revolving door of corporate executives in government regulatory jobs. ii). Prohibit lobbying for laws Any such use to suit chemical companies and pharmaceuticals. 10. Those infected with cancer causing infectious agents are to seek isolation during acute infective stages and recurrent outbreaks as carriers if that is applicable and are required to inform intimate partners and associates who might become contaminated of their condition. They need to avoid situations where the may contaminate others or take necessary precautions as per the best medical advice available. 11. It is deemed a War Crime and a violation of human rights to use any disease causing infectious agent, natural or genetically engineered, or mutation or epigenetic modification thereof or synthetic to kill, harm or alter the health or mind of any persons foreign or domestic or to introduce any such agent into any environment so as to cause harm including hunger, deliberate or by carelessness. Any such use for domestic purposes shall be deemed domestic terrorism. 12. The growing epigenetic Database needs to be included in this regulatory framework. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4494013/?fbclid=IwAR2cJGNPjPxo2rVEhXNfvrNvNxIWqWK8SutMXsHfQBYLtWKQ_tOtK2bToGE Literature Cited Baylin Stephen B and Peter A Jones. Epigenetic Determinants of Cancer. Cold Spring Harb Perspect Biol. 2016 Sep; 8(9): a019505 Ben Boursi, Kevin Haynes, Ronac Mamtani, Yu‐Xiao Yang Eur J Cancer. 2015 Nov; 51(17): 2655–2664 (Published online 2015 Aug 3). Antibiotics increased risk of cancer. Chen T, Tan J, Wan Z, Zou Y, Afewerky HK, Zhang Z, Zhang. Pesticides induced mitochondrial fragmentation at low levels. Int J Mol Sci Nov 23;18(12). W.P.CochraneJ, SinghW, MilesB.Wakeford. 1981. Determination of chlorinated dibenzo-p-dioxin contaminants in 2,4-D products by gas chromatography-mass spectrometric techniques. J. Of Chromatography. Volume 217, 6 November 1981, Pages 289-299. Cole Joe, Chairman of the IAOC. Phenoxy herbicide contaminants from the House Oversight Committee. http://pr-rp.hc-sc.gc.ca/pi-ip/result-eng.php… IARC Carcinogenic Infectious Agents. https://gco.iarc.fr/causes/infections/help Kaalghatigi, S. Antibiotic harms mammalian mitochondria. Sci Transl Med. 2013 Jul 3;5(192):192ra85. Llinàs-Arias and Manuel Esteller. Published: 20 September 2017 https://doi.org/10.1098/rsob.170152 Newman Tim. Medical News Today, Antibiotics may increase the risk of bowel cancer. April 5, 2017 University of Illinois at Urbana-Champaign. "Microbes in the human body swap genes, even across tissue boundaries, study indicates. (ScienceDaily, 11 April 2019 Wang H1, Wu J, Meng X, Ying X, Zuo Y, Liu R, Pan Z, Kang T, Huang W. MicroRNA-342 inhibits colorectal cancer cell proliferation and invasion by directly targeting DNA methyltransferase 1. Carcinogenesis. 2011 Jul;32(7):1033-42. doi: 10.1093/carcin/bgr081. Epub 2011 May 11. Yong Ed. The Scientist, June 20 2013; Crisp et al. Genome Biology 2015 Tags: all diseases, cancers, discussion paper, epigenetics, regulatory reform