Deciphering the Role of Melatonin-Related Signatures in Tumor Immunity and the Prognosis of Clear Cell Renal Cell Carcinoma

Published on Monday, 26 June 2023

Abstract

Methods: Adopting multiomics data from TCGA and other public datasets, we analysed the expression, mutation, and prognostic evaluation in multiple cancers. ccRCC patients were categorized into two subgroups by an unsupervised cluster algorithm: melatonin-pattern cancer subtype 1 (MPCS1) and subtype 2 (MPCS2). We then explored the immune microenvironment, immune therapy response, and tumor metabolic pathways between the two subtypes. The clinical characteristics, genomic mutation landscape, and molecular inhibitor response were further investigated. Finally, a melatonin regulator-related prognostic model was constructed to predict patient prognosis in ccRCC.

Results: We found that melatonin regulators were dysregulated depending on distinct cancer types, which were associated with genomic variation. The two subtypes indicated different clinical characteristics and biological processes in ccRCC. MPCS2, an aggressive subtype, led an advanced clinical stage and poorer survival of ccRCC patients. The activated oncogenic signaling pathway and metabolic signatures were responsible for cancer progression in the MPCS2 subtype. The MPCS2 subgroup suggested a higher tumor mutational burden and immune dysfunction state, resulting in a lower response to immunotherapy. The copy number variations of MPCS2 were significantly more frequent than those of MPCS1. In addition, the two subgroups exhibited distinct drug responsiveness, with MPCS2 being less responsive to multiple drugs. Finally, we established a subtype biomarker-based prognostic risk model that exhibited satisfactory performance in ccRCC patients.

Conclusion: Melatonin regulator-related features could remodel functional pathways and the tumor immune microenvironment through genomic mutations and pathway regulation. Melatonin regulator-associated molecular subtypes enhance the understanding of the molecular characteristics of renal cancer and can guide clinical treatment. Activating the melatonergic system axis may improve the effect of immunotherapy for ccRCC.

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- The Di Bella Method (A Fixed Part - Melatonin tablets. From 30-40mg/day up to 200mg/day orally in patients with advanced stage of cancer disease and/or patients without respond to traditional treatments);

- Melatonin use in cancer patients have started in 1974, when melatonin prepared according to Prof. Di Bella’s formulation [...]. For 11 days was administered to the patient, admitted to the general medical ward at the Maggiore-Pizzardi Hospital in Bologna, very slowly (over approx. 8 hours) and intravenously administered 1000 mg of melatonin for 11 days. During the course of each day, the patient was intravenously administered 4 saline drips of 500 ml, each containing ten 25 mg bottles of freeze-dried melatonin, lasting 2 hours, totaling 1000 mg per day. No other drug of any kind was administered in order to ascertain the effect of the MLT without interference [...]. From Melatonin with adenosine solubilized in water and stabilized with glycine for oncological treatment - technical preparation, effectivity and clinical findings;

- About Melatonin - In vitro, review and in vivo publications;

- Publication: Melatonin anticancer effects: Review (from Di Bella's Foundation);

- Publication: Key aspects of melatonin physiology: 30 years of research (from Di Bella's Foundation);

- The Di Bella Method (A Fixed Part - All-Trans Retinoic Acid, Analogues and/or Derivatives - Approximately 60mg per day orally: 40mg per day Beta-Carotene/β-Carotene, 10mg per day ATRA and 10mg per day Axerophthol palmitate);

- All-Trans-Retinoic Acid (ATRA - analogues and/or derivatives) - In vitro, review and in vivo publications;

- Solution of retinoids in vitamin E in the Di Bella Method biological multitherapy;

- The Di Bella Method (A Fixed Part - Alpha tocopheryl acetate/Vitamin E, approximately 20 grams per day orally);

- Cancer and Vitamin E (analogues and/or derivatives) and cancer - In vitro, review and in vivo publications;

- The Di Bella Method (A Fixed Part - Cyclophosphamide 50mg tablets and/or Hydroxyurea 500mg tablets, one or two per day);

- The Di Bella Method (A Fixed Part - Calcium, 2 grams per day, orally);

- The Di Bella Method (A Fixed Part - Somatostatin, Octreotide, Sandostatin LAR, analogues and/or derivatives);

- Somatostatin in oncology, the overlooked evidences - In vitro, review and in vivo publications;