Aberrant expression of immune checkpoints (ICs) in cancer creates an immunosuppressive microenvironment, which supports immune evasion of tumor cells. We have recently reported that epigenetic modifications are critical for ICs expression in the tumor microenvironment (TME) of primary breast cancer (PBC) and colorectal cancer (CRC). Herein, we investigated transcriptomic expression of ICs (PD-1, CTLA-4, LAG-3, TIM-3, TIGIT) and PD-L1 in peripheral blood of PBC and CRC patients, compared to healthy donors (HD). We found that expressions of TIM-3, TIGIT, PD-L1 were significantly upregulated, while LAG-3 expression was downregulated in peripheral blood of PBC and CRC patients. Demethylation enzymes TET2 and TET3 were also upregulated. In addition, promoter DNA methylation status of PD-1 was significantly hypermethylated, while PD-L1 was hypomethylated in PBC and CRC patients. Furthermore, TIGIT was significantly hypomethylated only in CRC patients. Remarkably, promoter methylation status of LAG-3, TIGIT and PD-L1 was in concordance with transcriptomic expression in CRC: the more the hypomethylation, the higher the expression. In comparison, we found that CTLA-4, TIM-3, TIGIT and PD-L1 in PBC, and CTLA-4 in CRC patients were significantly upregulated in peripheral blood, compared with tumor tissues of the same patients. However, demethylation status of all ICs was higher in TT, except for TIGIT in PBC, and CTLA-4 in CRC patients. These data indicate that the underlying mechanisms behind peripheral upregulation of PD-L1 and TIGIT in cancer patients could be due to aberrant promoter methylation profile. Moreover, demethylation inhibitors together with anti-PD-L1/ anti-TIGIT could be a more efficient therapeutic strategy in cancer patients. ARTICLE HISTORY

Maturity-onset diabetes of the young (MODY) is a rare monogenic form of diabetes mellitus. In this study, we estimated the prevalence and genetic spectrum of MODY in the Middle Eastern population of Qatar using whole-genome sequencing (WGS) of 14,364 subjects from the population-based Qatar biobank (QBB) cohort. We focused our investigations on 14 previously identified genes ascribed to the cause of MODY and two potentially novel MODY-causing genes, RFX6 and NKX6-1. Genetic variations within the 16 MODY-related genes were assessed for their pathogenicity to identify disease-causing mutations. Analysis of QBB phenotype data revealed 72 subjects (0.5%) with type 1 diabetes, 2915 subjects (20.3%) with type 2 diabetes and 11,377 (79.2%) without diabetes. We identified 22 mutations in 67 subjects that were previously reported in the Human Genetic Mutation Database (HGMD) as disease-causing (DM) or likely disease causing (DM?) for MODY. We also identified 28 potentially novel MODY-causing mutations, predicted to be among the top 1% most deleterious mutations in the human genome, which showed complete (100%) disease penetrance in 34 subjects. Overall, we estimated that MODY accounts for around 2.2–3.4% of diabetes patients in Qatar. This is the first population-based study to determine the genetic spectrum and estimate the prevalence of MODY in the Middle East. Further research to characterize the newly identified mutations is warranted.

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