Cancer is the major cause of morbidity and mortality in the world today. The third most common cancer and which is most diet related is colorectal cancer (CRC). Although there is complexity and limited understanding in the link between diet and CRC, the advancement in research methods have demonstrated the involvement of non-coding RNAs (ncRNAs) as key regulators of gene expression. MicroRNAs (miRNAs) which are a class of ncRNAs are key players in cancer related pathways in the context of dietary modulation. The involvement of ncRNA in cancer progression has recently been clarified throughout the last decade. ncRNAs are involved in biological processes relating to tumor onset and progression. The advances in research have given insights into cell to cell communication, by highlighting the pivotal involvement of extracellular vesicle (EV) associated-ncRNAs in tumorigenesis. The abundance and stability of EV associated ncRNAs act as a new diagnostic and therapeutic target for cancer. The understanding of the deranging of these molecules in cancer can give access to modulating the expression of the ncRNAs, thereby influencing the cancer phenotype. Food derived exosomes/vesicles (FDE) are gaining interest in the implication of exosomes in cell-cell communication with little or no understanding to date on the role FDE plays. There are resident microbiota in the colon; to which the imbalance in the normal intestinal occurrence leads to chronic inflammation and the production of carcinogenic metabolites that lead to neoplasm. Limited studies have shown the implication of various types of microbiome in CRC incidence, without particular emphasis on fungi and protozoa. This review discusses important dietary factors in relation to the expression of EV-associated ncRNAs in CRC, the impact of diet on the colon ecosystem with particular emphasis on molecular mechanisms of interactions in the ecosystem, the influence of homeostasis regulators such as glutathione, and its conjugating enzyme-glutathione S-transferase (GST) polymorphism on intestinal ecosystem, oxidative stress response, and its relationship to DNA adduct fighting enzyme-0-6-methylguanine-DNA methyltransferase. The understanding of the molecular mechanisms and interaction in the intestinal ecosystem will inform on the diagnostic, preventive and prognosis as well as treatment of CRC.
The circadian system temporally regulates physiology to maintain homeostasis. Co-opting and disrupting circadian signals appear to be distinct attributes that are functionally important for the development of a tumor and can enable or give rise to the hallmarks that tumors use to facilitate their initiation, growth and progression. Because circadian signals are also strong regulators of immune cell proliferation, trafficking and exhaustion states, they play a role in how tumors respond to immune-based cancer therapeutics. While immuno-oncology has heralded a paradigm shift in cancer therapeutics, greater accuracy is needed to increase our capability of predicting who will respond favorably to, or who is likely to experience the troubling adverse effects of, immunotherapy. Insights into circadian signals may further refine our understanding of biological determinants of response and help answer the fundamental question of whether certain perturbations in circadian signals interfere with the activity of immune checkpoint inhibitors. Here we review the body of literature highlighting circadian disruption as a cancer promoter and synthesize the burgeoning evidence suggesting circadian signals play a role in how tumors respond to immune-based anti-cancer therapeutics. The goal is to develop a framework to advance our understanding of the relationships between circadian markers, cancer biology, and immunotherapeutics. Bolstered by this new understanding, these relationships may then be pursued in future clinical studies to improve our ability to predict which patients will respond favorably to, and avoid the adverse effects of, traditional and immune-based cancer therapeutics.
The steady increase in global cancer burden has fuelled the development of several modes of treatment for the disease. In the presence of an actionable mutation, targeted therapies offer a method to selectively attack cancer cells, increasing overall efficacy and reducing harmful side effects. However, different drug molecules are in different stages of development, with new molecules obtaining approvals from regulatory agencies each year. To augment clinical impact, it is important that this information reaches clinicians, patients and researchers swiftly and in a structured, well-annotated manner. To this end, we have developed Mutation-Specific Therapies Resource and Database in Cancer (MUSTARD), a database that is designed to be a centralized resource with diverse information such as cancer subtype, associated mutations, therapy offered and its effect observed, along with links to external resources for a more comprehensive annotation. In its current version, MUSTARD comprises over 2105 unique entries, including associations between 418 unique drug therapies, 189 cancer subtypes and 167 genes curated and annotated from over 862 different publications. To the best of our knowledge, it is the only resource that offers comprehensive information on mutation-specific, gene fusions and overexpressed gene-targeted therapies for cancer. Database URL: http://clingen.igib.res.in/mustard/
Pancreatic ductal adenocarcinoma (PDAC) is the most common exocrine tumor of the pancreas characterized by late diagnosis, adverse overall 5-year survival, a higher propensity for metastatic disease, and lack of efficacy of systemic therapy options. These adverse outcomes can be partly attributed to complex tumor microenvironment (TME). Over the past decade, immunotherapy has revolutionized the management of certain cancers; thus far, the immunologically ‘non-inflamed’ tumor microenvironment in PDACs has proven to be challenging. Indolamine 2,3-dioxygenase 1 (IDO1) is the rate-limiting enzyme in the catabolic pathway of L-Tryptophan, an essential amino acid, that gives rise to the immunosuppressive metabolite Kynurenine. IDO1, Indolamine 2,3-dioxygenase 2 (IDO2), and Tryptophan 2,3-dioxygenase (TDO) are the key enzymes in the tryptophan catabolic pathway but we focus on the role of the predominant enzyme form IDO1 in this review. Nicotinamide phosphoribosyl transferase (iNAMPT) regulates the intracellular concentration of NAD and is upregulated in the tumor. In light of the potential role of IDO1 as a driver of hostile TME in PDAC and NAD+ as a key coenzyme in anti-tumor immune response, this review urges focus on extensive research and initiation of clinical trials using IDO1 and NAMPT inhibitors in pancreatic cancer in the future.
Background: Colorectal cancer is a heterogeneous disease of tumors from distinct anatomical and embryological sources. According to GLOBOCAN2020, it is the second leading cause of cancer-related mortality1. Methodology: Utilising NIH-GDC2 datasets, we applied Bioinformatic algorithms to categorize LCRC and RCRC based on multi-omic variables. Mutational analysis was done using STRING v11.53. Kaplan-Meier were plotted. Transcriptome data was accessed using Bioconductor4 package TCGABiolinks5 and annotated as ‘Left’ or ‘Right’ based on tissue of origin. DE analysis was performed using DESeq6. DEGs were analyzed using Enrichr7 for signaling pathways. Further, differential methylation analysis was performed. Results: Tumors from left and right sides represent early Stage IIA non-metastatic cancers largely. Mutational analysis showed dissimilar genes in left vs right-sided tumors. CSMD1, CDH23, PCDH15, DSCAM, CDH9, and NRXN1 formed unique hubs within LCRC network while FLNC, CACNA1H, KMT2B, KMT2D, FAT4 and BRAF formed hubs in RCRC network. LCRC-specific genes were cadherins and EMT based, while RCRC-specific genes were related to lymphocytic invasion and epigenetic markers. TTN (p-value=4.61e-2) and ABCA13 (p-value=4.78e-2) significantly influenced OS in LCRC while SOX11 (p-value=4.12e-2) influenced OS in RCRC. For transcriptomic analysis, we obtained 766 DE genes at p-adjusted value <= 0.01, |log2 FC| > 1. Enrichr KEGG pathway analysis highlighted neuroactive ligand-receptor interaction (OR=3.11) and complement-coagulation cascade (OR=6.07) activity in LCRC. Platelet interaction with cancer cells have been demonstrated8 to have therapeutic potential in CRCs. NK cell mediated cytotoxicity (OR=4.33) and antigen processing-presentation (OR=6.95) were enriched in RCRC. Mean methylation analysis showed higher values in RCRC than LCRC (p-value=1.5e-05). Differential methylation gave 998 hypo- and 45 hyper-methylated genes in RCRC and LCRC respectively. RCRC evidently has an underlying hypermethylated biology when compared to LCRC. RCRCs are dependent on immune-regulated biology explaining rationale of immunotherapy. Right colon develops from midgut and is supplied by SMA. It can be hypothesized that a vast lymphatic drainage system carrying increased T-cells may play a role in creating dissimilarity. On the other hand, angiogenic factors and coagulation cascade rule left colon. This could be the reason for early metastatic potential in LCRCs. Our study unambiguously differentiates LCRC from RCRC by correlating anatomical, physiological, and multi-omic variables. Citation Format: Anu R I, Aastha Vatsyayan, Ambily Sivadas, Dileep Damodaran, Kurt van der Speeten. Multi-omic analysis classifies colorectal cancer into distinct angiogenic and immunogenic subtypes based on anatomical laterality [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1154.
Introduction: Next-generation sequencing (NGS) has paved the way for precision oncology in oncology clinics today. With rapidly advancing therapeutics, it is becoming increasingly important to obtain information about the molecular milieu of a patient's tumor. However, reporting and interpreting of NGS is fraught with complexity and variability. To understand the questions surrounding NGS reporting in India, we conducted a survey. Objectives: The aim of this study was to assess the gaps in NGS reporting and interpretation in Indian medical oncology clinics. Materials and Methods: An anonymized 10-question survey-based study among Indian medical oncologists through Google forms was conducted between October 4 and 8, 2022. Results: The sample size was n = 58. Seventy-one percent felt there was heterogeneity in NGS reporting, 72% were unaware of NGS reporting guidelines, and 62% did not feel the need for a molecular scientist assist in NGS interpretation. Almost all (98%) felt there was a need for uniform NGS reporting as well as an Indian NGS repository and data-sharing system (93%). Conclusion: Our survey highlights the need for a uniform national guideline concerning NGS reporting.
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