Methionine

What determines whether we become overweight? Aside from lifestyle, predisposition plays a role, but genes cannot fully explain the inherited propensity to accumulate excess weight. A new study shows that a kind of formatting of the DNA code in one gene that is associated with satiety is implicated in a slightly elevated risk of excess body weight -- at least in women. This 'epigenetic marking' is established early on during the embryonic stage. What determines whether we become overweight? Aside from lifestyle, predisposition plays a role, but genes cannot fully explain the inherited propensity to accumulate excess weight. A new study by Charité -- Universitätsmedizin Berlin in Science Translational Medicine* shows that a kind of formatting of the DNA code in one gene that is associated with satiety is implicated in a slightly elevated risk of excess body weight -- at least in women. This "epigenetic marking" is established early on during the embryonic stage. People who are overweight, especially those who are severely overweight, are at increased risk of a number of serious diseases such as cardiovascular disease, diabetes, and cancer. It is a growing health issue. All over the world, the number of overweight people is increasing. In the European Region, two out of three adults (59 percent) are overweight or obese, according to the World Health Organization. But what determines whether people will become overweight? Genetic predisposition plays a major role, alongside lifestyle. The similarity of the body mass index (BMI) in identical twins ranges from 40 to 70 percent. Even identical twins raised in different families still show the same significant similarity. Scientists have identified several genetic variants that influence a person's body weight -- and with it, the risk of developing obesity. But even taken all together, they cannot explain the heritability that has been observed. Researchers began to suspect there must be additional non-genetic factors that affect a person's propensity to gain excess weight. Satiety gene is not altered, but formatted Researchers led by Prof. Peter Kühnen, Director of the Department of Pediatric Endocrinology at Charité, have now identified one such factor in their recent study. According to their findings, women's risk of being overweight increases by about 44 percent if there are an especially large number of methyl groups adhering to the POMC (pro-opiomelanocortin) gene, which is responsible for the feeling of satiety. Methyl groups are tiny chemical units the body uses to mark the letters in the DNA code to activate or deactivate genes without modifying the sequence of letters in the DNA. In other words, the effect is much like highlighting a section of a text without rewriting the text itself. This type of "DNA formatting" is known as epigenetic marking. For their study, the team of researchers analyzed the "formatting" of the POMC gene in more than 1,100 people. They found more methyl groups attached to the satiety gene in obese women with a BMI of over 35 than in women with normal body weight. "A 44 percent increase in the risk of obesity is about the same as the effect that has been observed for individual gene variants as well," says Kühnen. "By comparison, socioeconomic factors have a much stronger effect. They can increase the risk by a factor of two to three. As for why the methylation effect only shows up in women, we don't know yet." The POMC gene is "formatted" very early on during embryonic development, as the researchers showed by comparing methylation patterns in more than 15 sets each of identical and fraternal twins. While the "formatting" of the satiety gene was the same in most of the identical twins, there was hardly any correlation in the fraternal twins. "This indicates that the epigenetic marking of the POMC gene is established shortly after the egg and sperm cells merge, before the fertilized egg divides into two twin embryos," explains Lara Lechner, the study's first author, who works at the Department of Pediatric Endocrinology. This means the very early stage of pregnancy is crucial. What influences formatting? But what influences how much methylation the satiety gene undergoes -- and thus, the risk that a person will become overweight? Past studies indicated that the presence or absence of certain nutrients that supply methyl groups could have an effect on epigenetic processes. These nutrients include betaine, methionine, and folic acid, all of which are typically absorbed through a person's diet. A newly developed method involving individual human stem cells allowed the Charité researchers to simulate in the lab how the methylation pattern is determined during embryonic development and how nutrients affect it. "On the one hand, our studies and others as well show that folic acid, betaine, and other nutrients have a limited effect on the extent of methylation," Kühnen notes. "We've observed that the 'DNA formatting system' is very stable on the whole, with cells compensating for minor fluctuations in the nutrient supply. On the other hand, there are indications that the variability of this 'formatting' develops at random. That means that it is not possible -- not yet, at any rate -- to externally influence whether a person has more or less methylation in the POMC region." Medications may help At least in theory, women who are at elevated risk of developing obesity due to methylation of the POMC gene could receive medications to help them lose weight, as initial studies of four severely obese women and one man with this exact type of "formatting" of the satiety gene suggest. The subjects were given a specific drug that curbs the feeling of hunger and has already been approved to treat obese patients with a mutation of the POMC gene. Within three months after starting treatment, all five patients experienced less hunger. They lost an average of seven kilograms, or about five percent of their body weight. Some of them continued the treatment and continued to lose weight. "These findings show, for a start, that a POMC gene that has undergone epigenetic changes can in fact potentially be addressed through medication," Kühnen says. "Further large controlled studies will be needed to show whether treatment with this drug would also be effective over a longer period, and if so, how effective and how safe this type of treatment is. Overall, though, a medication like this would still need to be just one piece of a holistic treatment strategy."

Treatment with adjuvant TAGRISSO reduced the risk of death by more than half WILMINGTON, DE, USA I June 04, 2023 I Positive results from the ADAURA Phase III trial showed AstraZeneca’s TAGRISSO ® (osimertinib) demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS), compared to placebo in the adjuvant treatment of patients with early-stage (IB, II and IIIA) epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) after complete tumor resection with curative intent. These results will be presented today in an oral presentation during the Plenary Session at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting (abstract #LBA3). TAGRISSO reduced the risk of death by 51% compared to placebo in both the primary analysis population (Stages II-IIIA) (21% data maturity, OS hazard ratio [HR] of 0.49; 95.03% confidence interval [CI] 0.33-0.73; p=0.0004), and in the overall trial population (Stages IB-IIIA) (18% data maturity, OS HR of 0.49; 95.03% CI 0.34-0.70; p<0.0001). In the primary analysis population, an estimated 85% of patients treated with TAGRISSO were alive at five years compared to 73% on placebo. In the overall trial population, an estimated 88% of patients treated with TAGRISSO were alive at five years compared to 78% on placebo. Median OS was not yet reached in either population or treatment group. Patients on placebo that recurred with metastatic disease had the opportunity to receive TAGRISSO as a subsequent treatment. Roy S. Herbst, MD, PhD, Deputy Director and Chief of Medical Oncology at Yale Cancer Center and Smilow Cancer Hospital, New Haven, Connecticut, US, and principal investigator in the trial, said: “These highly anticipated overall survival results, with 88 per cent of patients alive at five years, are a momentous achievement in the treatment of early-stage EGFR-mutated lung cancer. These data underscore that adjuvant treatment with osimertinib provides patients with the best chance of long-term survival.” Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: “TAGRISSO cut the risk of death by more than half in the adjuvant setting, further establishing this transformative medicine as the backbone treatment for EGFR-mutated lung cancer. These results emphasize the importance of diagnosing patients with lung cancer early, testing for EGFR mutations and treating all those with an EGFR mutation with TAGRISSO.” Summary of OS results: ADAURA i At the previously reported disease-free survival analysis, all patients had completed or discontinued treatment. The safety and tolerability of TAGRISSO with extended follow-up were consistent with its established profile and previous analyses with no new safety concerns reported. Adverse events at Grade 3 or higher from all causes occurred in 23% of patients in the TAGRISSO arm versus 14% in the placebo arm. INDICATIONS Please see complete Prescribing Information , including Patient Information for TAGRISSO. You may report side effects related to AstraZeneca products by clicking here . Notes Lung cancer Lung cancer is the leading cause of cancer death among both men and women, accounting for about one-fifth of all cancer deaths. 1 Lung cancer is broadly split into NSCLC and small cell lung cancer. 2 The majority of all NSCLC patients are diagnosed with advanced disease while approximately 25-30% present with resectable disease at diagnosis. 4‑5 Early-stage lung cancer diagnoses are often only made when the cancer is found on imaging for an unrelated condition. 7‑8 For patients with resectable tumors, the majority eventually develop recurrence despite complete tumor resection and adjuvant chemotherapy. 9 ADAURA ADAURA was a randomized, double-blind, placebo-controlled, global Phase III trial in the adjuvant treatment of 682 patients with Stage IB, II, IIIA EGFRm NSCLC following complete tumor resection and, at physicians’ and patients’ discretion, adjuvant chemotherapy. Patients were treated with TAGRISSO 80mg once-daily oral tablets or placebo for three years or until disease recurrence. The trial was enrolled in more than 200 centers across more than 20 countries, including the US, Europe, South America, Asia and the Middle East. The primary endpoint was DFS in Stage II and IIIA patients and key secondary endpoints included DFS in Stage IB, II and IIIA patients, and OS in both the primary and overall populations. Though the primary data readout was originally anticipated in 2022, data from the trial were reported early following a recommendation from an Independent Data Monitoring Committee (IDMC) based on its determination of overwhelming efficacy. TAGRISSO ® TAGRISSO ® (osimertinib) is a third-generation, irreversible EGFR-TKI with proven clinical activity in NSCLC, including against central nervous system metastases. TAGRISSO (40mg and 80mg once-daily oral tablets) has been used to treat nearly 700,000 patients across its indications worldwide and AstraZeneca continues to explore TAGRISSO as a treatment for patients across multiple stages of EGFRm NSCLC. In addition to investigating TAGRISSO in early-stage disease, AstraZeneca is also studying the medicine in combination with chemotherapy in locally advanced and metastatic EGFRm NSCLC (FLAURA2). The Company is also researching ways to address tumor mechanisms of resistance through the SAVANNAH and ORCHARD Phase II trials, and the SAFFRON Phase III trial, which test TAGRISSO given concomitantly with savolitinib, an oral, potent and highly selective MET TKI, as well as other potential new medicines. AstraZeneca in lung cancer AstraZeneca is working to bring patients with lung cancer closer to cure through the detection and treatment of early-stage disease, while also pushing the boundaries of science to improve outcomes in the resistant and advanced settings. By defining new therapeutic targets and investigating innovative approaches, the Company aims to match medicines to the patients who can benefit most. The Company's comprehensive portfolio includes leading lung cancer medicines and the next wave of innovations, including tremelimumab-actl and gefitinib; durvalumab and tremelimumab-actl; fam-trastuzumab deruxtecan-nxki and datopotamab deruxtecan in collaboration with Daiichi Sankyo; savolitinib in collaboration with HUTCHMED; as well as a pipeline of potential new medicines and combinations across diverse mechanisms of action. AstraZeneca is a founding member of the Lung Ambition Alliance, a global coalition working to accelerate innovation and deliver meaningful improvements for people with lung cancer, including and beyond treatment. AstraZeneca in oncology AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients. The Company's focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyze changes in the practice of medicine and transform the patient experience. AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death. About AstraZeneca AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines in Oncology, Rare Diseases and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries, and its innovative medicines are used by millions of patients worldwide. For more information, please visit www.astrazeneca-us.com and follow us on Twitter @AstraZenecaUS . References SOURCE: AstraZeneca