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Article ; Online: Discovery of new therapeutic targets in ovarian cancer through identifying significantly non-mutated genes

Halema Al-Farsi / Iman Al-Azwani / Joel A. Malek / Lotfi Chouchane / Arash Rafii / Najeeb M. Halabi

Journal of Translational Medicine, Vol 20, Iss 1, Pp 1-

2022 Volume 15

Abstract: Abstract Background Mutated and non-mutated genes interact to drive cancer growth and metastasis. While research has focused on understanding the impact of mutated genes on cancer biology, understanding non-mutated genes that are essential to tumor ... ...

Abstract	Abstract Background Mutated and non-mutated genes interact to drive cancer growth and metastasis. While research has focused on understanding the impact of mutated genes on cancer biology, understanding non-mutated genes that are essential to tumor development could lead to new therapeutic strategies. The recent advent of high-throughput whole genome sequencing being applied to many different samples has made it possible to calculate if genes are significantly non-mutated in a specific cancer patient cohort. Methods We carried out random mutagenesis simulations of the human genome approximating the regions sequenced in the publicly available Cancer Growth Atlas Project for ovarian cancer (TCGA-OV). Simulated mutations were compared to the observed mutations in the TCGA-OV cohort and genes with the largest deviations from simulation were identified. Pathway analysis was performed on the non-mutated genes to better understand their biological function. We then compared gene expression, methylation and copy number distributions of non-mutated and mutated genes in cell lines and patient data from the TCGA-OV project. To directly test if non-mutated genes can affect cell proliferation, we carried out proof-of-concept RNAi silencing experiments of a panel of nine selected non-mutated genes in three ovarian cancer cell lines and one primary ovarian epithelial cell line. Results We identified a set of genes that were mutated less than expected (non-mutated genes) and mutated more than expected (mutated genes). Pathway analysis revealed that non-mutated genes interact in cancer associated pathways. We found that non-mutated genes are expressed significantly more than mutated genes while also having lower methylation and higher copy number states indicating that they could be functionally important. RNAi silencing of the panel of non-mutated genes resulted in a greater significant reduction of cell viability in the cancer cell lines than in the non-cancer cell line. Finally, as a test case, silencing ANKLE2, a ...
Keywords	RNAi ; Epithelial ovarian cancer ; RNA-Seq ; Non-mutated genes ; Unmutated genes ; Cancer somatic mutation ; Medicine ; R
Subject code	616
Language	English
Publishing date	2022-05-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Health influenced by genetics

Maroua Boujemaa / Najah Mighri / Lotfi Chouchane / Mohamed Samir Boubaker / Sonia Abdelhak / Hamouda Boussen / Yosr Hamdi

PLoS ONE, Vol 17, Iss 3, p e

A first comprehensive analysis of breast cancer high and moderate penetrance susceptibility genes in the Tunisian population.

2022 Volume 0265638

Abstract: Significant advances have been made to understand the genetic basis of breast cancer. High, moderate and low penetrance variants have been identified with inter-ethnic variability in mutation frequency and spectrum. Genome wide association studies (GWAS) ...

Abstract	Significant advances have been made to understand the genetic basis of breast cancer. High, moderate and low penetrance variants have been identified with inter-ethnic variability in mutation frequency and spectrum. Genome wide association studies (GWAS) are widely used to identify disease-associated SNPs. Understanding the functional impact of these risk-SNPs will help the translation of GWAS findings into clinical interventions. Here we aim to characterize the genetic patterns of high and moderate penetrance breast cancer susceptibility genes and to assess the functional impact of non-coding SNPs. We analyzed BRCA1/2, PTEN, STK11, TP53, ATM, BRIP1, CHEK2 and PALB2 genotype data obtained from 135 healthy participants genotyped using Affymetrix Genome-Wide Human SNP-Array 6.0. Haplotype analysis was performed using Haploview.V4.2 and PHASE.V2.1. Population structure and genetic differentiation were assessed using principal component analysis (PCA) and fixation index (FST). Functional annotation was performed using In Silico web-based tools including RegulomeDB and VARAdb. Haplotype analysis showed distinct LD patterns with high levels of recombination and haplotype blocks of moderate to small size. Our findings revealed also that the Tunisian population tends to have a mixed origin with European, South Asian and Mexican footprints. Functional annotation allowed the selection of 28 putative regulatory variants. Of special interest were BRCA1_ rs8176318 predicted to alter the binding sites of a tumor suppressor miRNA hsa-miR-149 and PALB2_ rs120963 located in tumorigenesis-associated enhancer and predicted to strongly affect the binding of P53. Significant differences in allele frequencies were observed with populations of African and European ancestries for rs8176318 and rs120963 respectively. Our findings will help to better understand the genetic basis of breast cancer by guiding upcoming genome wide studies in the Tunisian population. Putative functional SNPs may be used to develop an efficient polygenic risk ...
Keywords	Medicine ; R ; Science ; Q
Subject code	616
Language	English
Publishing date	2022-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: THE FUTURE OF MEDICINE, healthcare innovation through precision medicine

M. Walid Qoronfleh / Lotfi Chouchane / Borbala Mifsud / Maryam Al Emadi / Said Ismail

Life Sciences, Society and Policy, Vol 16, Iss 1, Pp 1-

policy case study of Qatar

2020 Volume 20

Abstract: Abstract In 2016, the World Innovation Summit for Health (WISH) published its Forum Report on precision medicine “PRECISION MEDICINE - A GLOBAL ACTION PLAN FOR IMPACT”. Healthcare is undergoing a transformation, and it is imperative to leverage new ... ...

Abstract	Abstract In 2016, the World Innovation Summit for Health (WISH) published its Forum Report on precision medicine “PRECISION MEDICINE - A GLOBAL ACTION PLAN FOR IMPACT”. Healthcare is undergoing a transformation, and it is imperative to leverage new technologies to generate new data and support the advent of precision medicine (PM). Recent scientific breakthroughs and technological advancements have improved our disease knowledge and altered diagnosis and treatment approaches resulting in a more precise, predictive, preventative and personalized health care that is customized for the individual patient. Consequently, the big data revolution has provided an opportunity to apply artificial intelligence and machine learning algorithms to mine such a vast data set. Additionally, personalized medicine promises to revolutionize healthcare, with its key goal of providing the right treatment to the right patient at the right time and dose, and thus the potential of improving quality of life and helping to bring down healthcare costs. This policy briefing will look in detail at the issues surrounding continued development, sustained investment, risk factors, testing and approval of innovations for better strategy and faster process. The paper will serve as a policy bridge that is required to enhance a conscious decision among the powers-that-be in Qatar in order to find a way to harmonize multiple strands of activity and responsibility in the health arena. The end goal will be for Qatar to enhance public awareness and engagement and to integrate effectively the incredible advances in research into healthcare systems, for the benefit of all patients. The PM policy briefing provides concrete recommendations on moving forward with PM initiatives in Qatar and internationally. Equally important, integration of PM within a primary care setting, building a coalition of community champions through awareness and advocacy, finally, communicating PM value, patient engagement/empowerment and education/continued professional development programs of the healthcare workforce. Key recommendations for implementation of precision medicine inside and outside Qatar: 1. Create Community Awareness and PM Education Programs 2. Engage and Empower Patients 3. Communicate PM Value 4. Develop appropriate Infrastructure and Information Management Systems 5. Integrate PM into standard Healthcare System and Ensure Access to Care PM is no longer futuristic. It is here. Implementing PM in routine clinical care does require some investment and infrastructure development. Invariably, cost and lack of expertise are cited as barriers to PM implementation. Equally consequential, are the curriculum and professional development of medical care experts. Policymakers need to lead and coordinate effort among stakeholders and consider cultural and faith perspectives to ensure success. It is essential that policymakers integrate PM approaches into national strategies to improve health and health care for all, and to drive towards the future of medicine precision health.
Keywords	Precision medicine ; Population genomics ; Cancer ; Primary care ; Healthcare research ; Evidence-based research ; Medical philosophy. Medical ethics ; R723-726
Subject code	360
Language	English
Publishing date	2020-11-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A Report on a Family with TMTC3-Related Syndrome and Review

Sayeeda Hana / Deepak karthik / Jingxuan Shan / Stephany El Hayek / Lotfi Chouchane / André Megarbane

Case Reports in Medicine, Vol

2020 Volume 2020

Abstract: Recessive mutations in the TMTC3 gene have been reported in thirteen patients to date exhibiting development delay, intellectual disability (ID), seizures, and muscular hypotonia, accompanied occasionally by neuronal migration defects expressed as either ...

Abstract	Recessive mutations in the TMTC3 gene have been reported in thirteen patients to date exhibiting development delay, intellectual disability (ID), seizures, and muscular hypotonia, accompanied occasionally by neuronal migration defects expressed as either cobblestone lissencephaly or periventricular hypertopia. Here, we report a new case of a TMTC3-related syndrome in a Lebanese family with two affected siblings showing severe psychomotor retardation, intellectual disability, microcephaly, absence of speech, muscular hypotonia, and seizures. Whole exome sequencing revealed a homozygous pathogenic variant c.211 C > T (p.R71C) in the TMTC3 gene in both siblings. A review of the literature on TMTC3-related syndrome and its causal mutations is provided.
Keywords	Medicine ; R
Language	English
Publishing date	2020-01-01T00:00:00Z
Publisher	Hindawi Limited
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Angiocrine endothelium

Jennifer Pasquier / Pegah Ghiabi / Lotfi Chouchane / Kais Razzouk / Shahin Rafii / Arash Rafii

Journal of Translational Medicine, Vol 18, Iss 1, Pp 1-

from physiology to cancer

2020 Volume 17

Abstract: Abstract The concept of cancer as a cell-autonomous disease has been challenged by the wealth of knowledge gathered in the past decades on the importance of tumor microenvironment (TM) in cancer progression and metastasis. The significance of endothelial ...

Abstract	Abstract The concept of cancer as a cell-autonomous disease has been challenged by the wealth of knowledge gathered in the past decades on the importance of tumor microenvironment (TM) in cancer progression and metastasis. The significance of endothelial cells (ECs) in this scenario was initially attributed to their role in vasculogenesis and angiogenesis that is critical for tumor initiation and growth. Nevertheless, the identification of endothelial-derived angiocrine factors illustrated an alternative non-angiogenic function of ECs contributing to both physiological and pathological tissue development. Gene expression profiling studies have demonstrated distinctive expression patterns in tumor-associated endothelial cells that imply a bilateral crosstalk between tumor and its endothelium. Recently, some of the molecular determinants of this reciprocal interaction have been identified which are considered as potential targets for developing novel anti-angiocrine therapeutic strategies.
Keywords	Angiocrine ; Endothelium ; Cancer ; Cancer microenvironment ; Angiogenesis ; Medicine ; R
Subject code	610
Language	English
Publishing date	2020-02-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A map of copy number variations in the Tunisian population

Lilia Romdhane / Nessrine Mezzi / Hamza Dallali / Olfa Messaoud / Jingxuan Shan / Khalid A. Fakhro / Rym Kefi / Lotfi Chouchane / Sonia Abdelhak

npj Genomic Medicine, Vol 6, Iss 1, Pp 1-

a valuable tool for medical genomics in North Africa

2021 Volume 18

Abstract: Abstract Copy number variation (CNV) is considered as the most frequent type of structural variation in the human genome. Some CNVs can act on human phenotype diversity, encompassing rare Mendelian diseases and genomic disorders. The North African ... ...

Abstract	Abstract Copy number variation (CNV) is considered as the most frequent type of structural variation in the human genome. Some CNVs can act on human phenotype diversity, encompassing rare Mendelian diseases and genomic disorders. The North African populations remain underrepresented in public genetic databases in terms of single-nucleotide variants as well as for larger genomic mutations. In this study, we present the first CNV map for a North African population using the Affymetrix Genome-Wide SNP (single-nucleotide polymorphism) array 6.0 array genotyping intensity data to call CNVs in 102 Tunisian healthy individuals. Two softwares, PennCNV and Birdsuite, were used to call CNVs in order to provide reliable data. Subsequent bioinformatic analyses were performed to explore their features and patterns. The CNV map of the Tunisian population includes 1083 CNVs spanning 61.443 Mb of the genome. The CNV length ranged from 1.017 kb to 2.074 Mb with an average of 56.734 kb. Deletions represent 57.43% of the identified CNVs, while duplications and the mixed loci are less represented. One hundred and three genes disrupted by CNVs are reported to cause 155 Mendelian diseases/phenotypes. Drug response genes were also reported to be affected by CNVs. Data on genes overlapped by deletions and duplications segments and the sequence properties in and around them also provided insights into the functional and health impacts of CNVs. These findings represent valuable clues to genetic diversity and personalized medicine in the Tunisian population as well as in the ethnically similar populations from North Africa.
Keywords	Medicine ; R ; Genetics ; QH426-470
Language	English
Publishing date	2021-01-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Precision medicine in the era of artificial intelligence

Murugan Subramanian / Anne Wojtusciszyn / Lucie Favre / Sabri Boughorbel / Jingxuan Shan / Khaled B. Letaief / Nelly Pitteloud / Lotfi Chouchane

Journal of Translational Medicine, Vol 18, Iss 1, Pp 1-

implications in chronic disease management

2020 Volume 12

Abstract: Abstract Aberrant metabolism is the root cause of several serious health issues, creating a huge burden to health and leading to diminished life expectancy. A dysregulated metabolism induces the secretion of several molecules which in turn trigger the ... ...

Abstract	Abstract Aberrant metabolism is the root cause of several serious health issues, creating a huge burden to health and leading to diminished life expectancy. A dysregulated metabolism induces the secretion of several molecules which in turn trigger the inflammatory pathway. Inflammation is the natural reaction of the immune system to a variety of stimuli, such as pathogens, damaged cells, and harmful substances. Metabolically triggered inflammation, also called metaflammation or low-grade chronic inflammation, is the consequence of a synergic interaction between the host and the exposome—a combination of environmental drivers, including diet, lifestyle, pollutants and other factors throughout the life span of an individual. Various levels of chronic inflammation are associated with several lifestyle-related diseases such as diabetes, obesity, metabolic associated fatty liver disease (MAFLD), cancers, cardiovascular disorders (CVDs), autoimmune diseases, and chronic lung diseases. Chronic diseases are a growing concern worldwide, placing a heavy burden on individuals, families, governments, and health-care systems. New strategies are needed to empower communities worldwide to prevent and treat these diseases. Precision medicine provides a model for the next generation of lifestyle modification. This will capitalize on the dynamic interaction between an individual’s biology, lifestyle, behavior, and environment. The aim of precision medicine is to design and improve diagnosis, therapeutics and prognostication through the use of large complex datasets that incorporate individual gene, function, and environmental variations. The implementation of high-performance computing (HPC) and artificial intelligence (AI) can predict risks with greater accuracy based on available multidimensional clinical and biological datasets. AI-powered precision medicine provides clinicians with an opportunity to specifically tailor early interventions to each individual. In this article, we discuss the strengths and limitations of ...
Keywords	Exposome ; Chronic inflammation ; Chronic diseases ; Precision medicine ; Personalized treatment ; Deep phenotyping ; Medicine ; R
Subject code	610
Language	English
Publishing date	2020-12-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Precision medicine in breast cancer

Ali Bettaieb / Catherine Paul / Stéphanie Plenchette / Jingxuan Shan / Lotfi Chouchane / François Ghiringhelli

Journal of Translational Medicine, Vol 15, Iss 1, Pp 1-

reality or utopia?

2017 Volume 13

Abstract: Abstract Many cancers, including breast cancer, have demonstrated prognosis and support advantages thanks to the discovery of targeted therapies. The advent of these new approaches marked the rise of precision medicine, which leads to improve the ... ...

Abstract	Abstract Many cancers, including breast cancer, have demonstrated prognosis and support advantages thanks to the discovery of targeted therapies. The advent of these new approaches marked the rise of precision medicine, which leads to improve the diagnosis, prognosis and treatment of cancer. Precision medicine takes into account the molecular and biological specificities of the patient and their tumors that will influence the treatment determined by physicians. This new era of medicine is accessible through molecular genetics platforms, the development of high-speed sequencers and means of analysis of these data. Despite the spectacular results in the treatment of cancers including breast cancer, described in this review, not all patients however can benefit from this new strategy. This seems to be related to the many genetic mutations, which may be different from one patient to another or within the same patient. It comes to give new impetus to the research—both from a technological and biological point of view—to make the hope of precision medicine accessible to all.
Keywords	Breast cancer ; Molecular subtypes ; Triple-negative ; HER2+ ; Tumor heterogeneity ; Precision medicine ; Medicine ; R
Subject code	616
Language	English
Publishing date	2017-06-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Prevalence of antibodies against a cyclic peptide mimicking the FG loop of the human papillomavirus type 16 capsid among Tunisian women

Elham Hassen / Devendra Bansal / Randa Ghdira / Anouar Chaieb / Hedi Khairi / Abdelfattah Zakhama / Sami Remadi / Johan Hoebeke / Ali A. Sultan / Lotfi Chouchane

Journal of Translational Medicine, Vol 18, Iss 1, Pp 1-

2020 Volume 11

Abstract: Abstract Background In the past decade, cervical cancer has gone from being the second to the fourth most common cancer in women worldwide, but remains the second most common in developing countries. This cancer is most commonly caused by high-risk types ...

Abstract	Abstract Background In the past decade, cervical cancer has gone from being the second to the fourth most common cancer in women worldwide, but remains the second most common in developing countries. This cancer is most commonly caused by high-risk types of human papillomavirus (HPV), mainly type 16 (HPV16), which are sexually transmitted. This study aimed to investigate the usefulness of a cyclic synthetic peptide designed from the major L1 capsid protein of HPV16 for detecting anti-HPV16 antibodies. Methods We designed and synthetized a peptide that corresponds to the full sequence of the surface-exposed FG loop. We tested the antigenicity of the linear and the cyclic peptides against HPV16 L1 monoclonal antibodies. We used ELISA to detect anti-peptide antibodies in sera and cervical secretions of 179 Tunisian women, and we applied polymerase chain reaction and direct sequencing methods to detect and genotype HPV DNA. Results Both the linear and the cyclic peptides were recognized by the same neutralizing monoclonal antibodies, but the cyclic peptide was more reactive with human sera. The prevalence of the anti-peptide antibodies in sera was higher in women with low-grade squamous intraepithelial lesions (LGSIL) than in women with high-grade squamous intraepithelial lesions (HGSIL) (44% and 15%, respectively). This contrasts with HPV16 DNA prevalence. Compared to women from the general population, systemic IgG prevalence was significantly higher among sex workers (25%; P = 0.002) and women with LGSIL (44%; P = 0.001). In addition, systemic IgA and cervical IgG prevalence was higher among sex workers only (P = 0.002 and P = 0.001, respectively). We did not observe anti-peptide IgG antibodies in women with a current HPV16 infection. Conclusion Anti-peptide IgG in sera or in cervical secretions could be markers of an effective natural immunization against HPV16. This may open novel perspectives for monitoring vaccinated women and for the design of synthetic peptide-based vaccines.
Keywords	HPV16 ; Antibodies ; Cyclic peptide ; Major capsid protein L1 ; Tunisia ; Medicine ; R
Subject code	540 ; 610
Language	English
Publishing date	2020-07-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Prostate cancer small non-coding RNA transcriptome in Arabs

Jingxuan Shan / Khalid Al-Rumaihi / Karim Chouchane / Issam Al-Bozom / Danny Rabah / Karim Farhat / Lotfi Chouchane

Journal of Translational Medicine, Vol 15, Iss 1, Pp 1-

2017 Volume 11

Abstract: Abstract Background Prostate cancer (PCa) is a complex disorder resulting from the combined effects of multiple environmental and genetic factors. Small non-coding RNAs (sRNAs), particularly microRNAs (miRNAs), regulate several cellular processes and ... ...

Abstract	Abstract Background Prostate cancer (PCa) is a complex disorder resulting from the combined effects of multiple environmental and genetic factors. Small non-coding RNAs (sRNAs), particularly microRNAs (miRNAs), regulate several cellular processes and have an important role in many human malignancies including PCa. We assessed the sRNA profiles associated with PCa in Arabs, a population that has rarely been studied. Methods We used next generation sequencing technology to obtain the entire sRNA transcriptome of primary prostate tumor formalin-fixed paraffin-embedded tissues, and their paired non-tumor tissues, collected from Bedouin patients (Qatari and Saudi). The miRNA and the target gene expression were evaluated by real-time quantitative PCR. miRNA KEGG pathway and miRNA target genes were subsequently analyzed by starBase and TargetScan software. Results Different expression patterns of several sRNA and miRNA editing were revealed between PCa tumor and their paired non-tumor tissues. Our study identified four miRNAs that are strongly associated with prostate cancer, which have not been reported previously. Differentially expressed miRNAs significantly affect various biological pathways, such as cell cycle, endocytosis, adherence junction and pathways involved in cancer. Prediction of potential targets for the identified miRNAs indicates the overexpression of KRAS, BCL2 and down-regulation of PTEN in PCa tumor tissues. Conclusion These miRNAs, newly associated with prostate cancer, may represent not only markers for the increased risk of PCa in Arabs, but may also reflect the clinical and pathological diversity as well as the ethno-specific heterogeneity of prostate cancer.
Keywords	Prostate cancer ; Small RNA transcriptome ; miRNA ; miRNA editing ; Arabs ; Medicine ; R
Subject code	610 ; 570
Language	English
Publishing date	2017-12-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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