👤 Mohamed Samir Boubaker

Radioiodine-refractory thyroid cancers have poor outcomes and limited therapeutic options (tyrosine kinase inhibitors) due to transient efficacy and toxicity of treatments. Therefore, combinatorial treatments with new therapeutic approaches are needed. Many studies link G protein-coupled receptors (GPCRs) to cancer cell biology. To perform a specific atlas of GPCR expression in progressive and refractory thyroid cancer to identify potential targets among GPCRs aiming at drug repositioning. We analyzed samples from tumor and normal thyroid tissues from 17 patients with refractory thyroid cancer (12 papillary thyroid cancers [PTCs] and 5 follicular thyroid cancers [FTCs]). We assessed GPCR mRNA expression using NanoString technology with a custom panel of 371 GPCRs. The data were compared with public repositories and pharmacological databases to identify eligible drugs. The analysis of prognostic value of genes was also performed with TCGA datasets. With our transcriptomic analysis, 4 receptors were found to be downregulated in FTC (VIPR1, ADGRL2/LPHN2, ADGRA3, and ADGRV1). In PTC, 24 receptors were deregulated, 7 of which were also identified by bioinformatics analyses of publicly available datasets on primary thyroid cancers (VIPR1, ADORA1, GPRC5B, P2RY8, GABBR2, CYSLTR2, and LPAR5). Among all the differentially expressed genes, 22 GPCRs are the target of approved drugs and some GPCRs are also associated with prognostic factors. For the first time, we performed GPCR mRNA expression profiling in progressive and refractory thyroid cancers. These findings provide an opportunity to identify potential therapeutic targets for drug repositioning and precision medicine in radioiodine-refractory thyroid cancer. Show less

Hereditary breast cancer accounts for 5-10% of all breast cancer cases. So far, known genetic risk factors account for only 50% of the breast cancer genetic component and almost a quarter of hereditary cases are carriers of pathogenic mutations in BRCA1/2 genes. Hence, the genetic basis for a significant fraction of familial cases remains unsolved. This missing heritability may be explained in part by Copy Number Variations (CNVs). We herein aimed to evaluate the contribution of CNVs to hereditary breast cancer in Tunisia. Whole exome sequencing was performed for 9 BRCA negative cases with a strong family history of breast cancer and 10 matched controls. CNVs were called using the ExomeDepth R-package and investigated by pathway analysis and web-based bioinformatic tools. Overall, 483 CNVs have been identified in breast cancer patients. Rare CNVs affecting cancer genes were detected, of special interest were those disrupting APC2, POU5F1, DOCK8, KANSL1, TMTC3 and the mismatch repair gene PMS2. In addition, common CNVs known to be associated with breast cancer risk have also been identified including CNVs on APOBECA/B, UGT2B17 and GSTT1 genes. Whereas those disrupting SULT1A1 and UGT2B15 seem to correlate with good clinical response to tamoxifen. Our study revealed new insights regarding CNVs and breast cancer risk in the Tunisian population. These findings suggest that rare and common CNVs may contribute to disease susceptibility. Those affecting mismatch repair genes are of interest and require additional attention since it may help to select candidates for immunotherapy leading to better outcomes. Show less

Nucleotide excision repair is a multistep process that recognizes and eliminates a spectrum of DNA damages. Five proteins, namely XPC, RAD23, Centrin 2, DDB1 and DDB2 act as a heterodimeric complex at the early steps of the NER pathway and play a crucial role in the removal of DNA lesions. Several exonic mutations on genes coding for these proteins have been identified as associated with Xeroderma-pigmentosum (XP), a rare monogenic disorder. However, the role of regulatory polymorphisms in disease development and inter-ethnic diversity is still not well documented. Due to the high incidence rate of XP in Tunisia, we performed a genotyping analysis of 140 SNPs found on these 5 genes in a set of 135-subjects representing the general Tunisian-population. An inter-ethnic comparison based on the genotype frequency of these SNPs have been also conducted. For the most relevant variants, we performed a comprehensive assessment of their functional effects. Linkage disequilibrium and principal component analysis showed that the Tunisian-population is an admixed and intermediate population between Sub-Saharan Africans and Europeans. Using variable factor maps, we identified a list of 20 polymorphisms that contribute considerably to the inter-ethnic diversity of the NER complex. In-silico functional analysis showed that SNPs on XPC, DDB1 and DDB2 are associated with eQTLs mainly DDB2-rs10838681 that seems to decrease significantly the expression level of ACP2 (p = 6.1 × 10 Show less