Association between single nucleotide polymorphisms in DNA repair genes and the efficacy of radiotherapy in nasopharyngeal carcinoma patients.

Introduction: Single nucleotide polymorphisms (SNPs) in DNA repair genes are mainly correlated with the response to radiotherapy in nasopharyngeal cancer (NPC). In NPC patients, previous research has studied the association between X-ray repair cross-complementing group 1 and 3 (XRCC1 and XRCC3) polymorphisms and radio-therapeutic response. The objective of our study was to test the association between XRCC1 Arg399Gln and XRCC3 Thr241Met polymorphisms and the response to radiotherapy in the NPC Moroccan population. Material and methods: A total of 100 patients with NPC were genotyped for polymorphisms in XRCC1 and XRCC3 genes. Results: The results revealed that the genotypes and alleles of both SNPs did not show any significant association with clinical stages (for XRCC1 Arg399Gln: p [genotype] = 0.559; p [allele] = 0.440) and (for XRCC3 Thr241Met: p [genotype] = 0.638; p [allele] = 0.567). Moreover, in the study of the association between the polymorphisms and radiotherapy, the response to radiation therapy between genotypes and alleles was not statistically significant (for XRCC1 Arg399Gln p [genotype] = 0.583; p [allele] = 0.459) and (for XRCC3 Thr241Met p [genotype] = 0.660; p [allele] = 0.590). Conclusions: The present study suggests that XRCC1 Arg399Gln polymorphism does not have any impact on the radio-therapeutic response in Moroccan NPC patients whereas XRCC3 Thr241Met polymorphism may act as a prognostic indicator for NPC patients treated with radiotherapy. However, studies with a larger sample are needed to confirm our results.

The Evaluation of Vascular Endothelial Growth Factor A (VEGFA) and VEGFR2 Receptor as Prognostic Biomarkers in Bladder Cancer.

Vascular endothelial growth factor (VEGF) and its receptors (VEGFR1 and VEGFR2) are the most important tissue factors involved in tumor growth and angiogenesis. The aim of this study was to evaluate the promoter mutational status of VEGFA and the expression levels of VEGFA, VEGFR1, and VEGFR2 in bladder cancer (BC) tissues and to correlate the results with the clinical-pathological parameters of BC patients. A total of 70 BC patients were recruited at the Urology Department of the Mohammed V Military Training Hospital in Rabat, Morocco. Sanger sequencing was performed to investigate the mutational status of VEGFA, and RT-QPCR was used to evaluate the expression levels of VEGFA, VEGFR1, and VEGFR2. Sequencing of the VEGFA gene promoter revealed the presence of -460T/C, -2578C/A, and -2549I/D polymorphisms, and statistical analyses showed a significant correlation between -460T/C SNP and smoking (p = 0.02). VEGFA and VEGFR2 expressions were significantly up-regulated in patients with NMIBC (p = 0.003) and MIBC (p = 0.03), respectively. Kaplan-Meier analyses showed that patients with high VEGFA expression had significantly longer disease-free survival (p = 0.014) and overall survival (p = 0.009). This study was very informative, showing the implication of VEGF alterations in BC, suggesting that VEGFA and VEGFR2 expressions could be promising biomarkers for the better management of BC.

Genetic Polymorphisms in ERCC1 Gene and Their Association with Response to Radiotherapy in Moroccan Patients with Nasopharyngeal Carcinoma.

OBJECTIVE: Nasopharyngeal carcinoma (NPC) is a severe malignant disease. Despite its low frequency, NPC is very common in North African population. Radiotherapy is the standard therapeutic treatment of NPC. However, radioresistance hampers the success of treatment. At the molecular scale, radioresistance is due to genetic variations involved in DNA repair pathways in NPC patients. Several studies reported that single nucleotide polymorphisms (SNPs) in excision repair cross complementing group 1 (ERCC1) could be associated with radioresistance. In this optic, the present study aimed to evaluate the association between DNA repair gene polymorphisms ERCC1 C8092A and ERCC1 C118T and radiotherapy response of patients with NPC. METHODS: A total of 95 patients with confirmed NPC were recruited at the Mohammed VI Center for Cancer Treatment, Casablanca - Morocco between 2016 and 2018. Two single nucleotide polymorphisms in ERCC1 gene were genotyped. Multiple analysis software was used to assess the correlation between these SNPs and radio-therapeutic response. RESULTS: Sequencing of ERCC1 C8092A polymorphism revealed that CC and CA genotypes were found in 51.6% and 45.3% of cases, respectively, whereas the homozygote AA genotype was reported in only 3.1% of cases. For ERCC1 C118T polymorphism, the heterozygote CT genotype was identified in 49.5% of cases. Homozygotes genotypes CC and TT were detected in 17.9% and 32.6% respectively of NPC cases. Of note, no significant association was found between the ERCC1 C8092A polymorphism and response to radiation therapy (p=0.81). Similarly, there was no significant association between the response to radiotherapy and allelic distribution (p=0.56). Likewise, no correlation was observed neither with genotypes (p=0.07) nor with alleles (p=0.09) of ERCC1 C118T polymorphism and response to radiation therapy. CONCLUSION: Our results clearly showed that ERCC1 C8092A and ERCC1 C118T polymorphisms were not associated with response to radiotherapy in Moroccan NPC patients. Large studies are warranted to confirm the role of these SNPs in therapeutic response of NPC patients.

AKT1 and PIK3CA activating mutations in Moroccan bladder cancer patients´ biopsies and matched urine.

Introduction: in cancer cells, activating mutations in PIK3CA and AKT1 genes, major players of PI3K-AKT-mTOR signalling pathway, are widely reported in many cancers and present attractive targets for the identification of new therapeutics and better cancer management. The present study was planned to evaluate the mutational status of PIK3CA and AKT1 genes in bladder cancer patients and to assess the association between these mutations and patients´ clinico-pathological features. Methods: in this prospective study, bladder cancer biopsies and matched urine sediments samples were collected form 70 patients. Mutations were assessed by deoxyribonucleic acid (DNA) sequencing and correlation with clinico-pathological data was performed using SPSS software. Results: AKT1 alterations were poorly detected. Only one patient with pT1 stage and high-grade tumour carried the E17K mutation. In PIK3CA exon 9, 2 point mutations, E545K and Q546E, and a SNP (E547E) were reported, whereas in exon 20, 2 point mutations (L989V and H1047R) and 2 SNPs (I1022I and T1025T) were detected. PIK3CA mutations were mainly observed in early stages and high-grade tumours. Statistical analysis showed no significant association between the studied AKT1 and PIK3CA mutations and patients´ clinico-pathological parameters (p > 0.05). Detection of these mutations in voided urine samples showed a high specificity (100%) for both genes and a moderate sensitivity: 100% for AKT1 and 66.7% for PIK3CA genes. Conclusion: this study shows clearly that mutations in AKT1 and PIK3CA are rare events and could not be considered as valuable biomarkers for bladder cancer management.

Evaluation of DNA methylation in promoter regions of hTERT, TWIST1, VIM and NID2 genes in Moroccan bladder cancer patients.

Promoter hypermethylation have been reported to play a key role in bladder cancer development and progression. The aim of this study is to evaluate the methylation status of hTERT, TWIST1, VIM and NID2 genes in bladder cancer. The methylation status was evaluated using the Methylation-Specific PCR (MSP) approach on 70 tumour biopsies from Moroccan bladder cancer patients. Overall, methylation frequencies of hTERT, TWIST1, VIM and NID2 genes, were 90%, 85.71%, 67.14% and 67.14%, respectively. Hypermethylation of all studied genes was found in all pathological grades and stages of bladder cancer. Nevertheless, statistical analysis showed no significant association between promoter methylation of hTERT, TWIST1, VIM and NID2 genes and tumours stage/grade (p value >0.05). Moreover, we have investigated the association between the methylation pattern of selected genes and the treatment outcome in a sub-group of non-muscle-invasive bladder cancer cases (52/70). Hypermethylation of hTERT, TWIST1, VIM and NID2 was detected in 83.34%; 66.67%; 83.34% and 58.34% of recurrent cases, respectively, and in 80%; 80%; 80% and 60% of progressive cases, respectively. Statistical analysis highlighted a significant association between TWIST1 hypermethylation and tumour recurrence (p = 0.041<0.05). Our results indicate that hypermethylation of hTERT, TWIST1, VIM and NID2 genes is a frequent epigenetic event in bladder cancer and could be a promising therapeutic target to prevent bladder cancer progression and metastasis.

Degradation of p53 by HPV16-E6 variants isolated from cervical cancer specimens of Moroccan women.

Cervical cancer is the second most diagnosed cancer in Moroccan women. The main etiological factor for developing cervical cancer is the persistent infection with HPV16. Genetic studies have reported the occurrence of amino acid variations within the E6 oncoprotein that promotes host cell transformation by targeting p53 for degradation. To verify the biological effects of E6 polymorphisms towards p53 degradation, HPV16-E6 prototype and 7 variants isolated from cervical cancer biopsies of Moroccan women were evaluated for their activities by transient expression assays using pcDNA3.1-E6 constructs in C33A cell line. Expression of E6 genes in transfected cells was detected with reverse transcription PCR (RT-PCR), then, p53 levels were evaluated by western blot analysis. Significant dissimilarities in p53 degradation activities of HPV16-E6 prototype and intratypic variants were noticed. As compared to the prototype, the highest p53 degradation were exhibited by the African variants Af2-a/r, Af1-d/G295 and Af2-a/G285 (p < 0.001), followed by the European variants E- C442/G350 and E-G350/r (p < 0.01), then, the North American variant NA1-b/r (p < 0.05). The inter-variant differences were statistically significant between Af2-a/r variant and the North American variants NA1-b/r and NA1 (p < 0.05). Thus, the Af2-a/r variant was significantly more active in degrading p53 in our in vitro experiments (p < 0.0001). Our findings support the fact that HPV16-E6 variations have a biological impact on degrading p53, and so, represent a significant carcinogenic potential for developing cervical cancer.

Association between Gene Promoter Methylation and Cervical Cancer Development: Global Distribution and A Meta-analysis.

DNA methylation is the main epigenetic event for gene silencing and is associated with carcinogenesis. In this meta-analysis, we evaluated the association between the methylation of the promoter regions of APC, CADM1, CCNA1, CDH1, DAPK, FHIT, HIC1, MAL, MGMT, hMLH1, P16, PAX1, RAR-ß, and RASSF1 genes and the risk of cervical cancer development and progression. Overall, 194 eligible studies were identified assessing the associations of promoter methylation status of aforementioned genes with low- and high-grade squamous intraepithelial lesions (LSIL and HSIL) and cervical cancer development. The majority of studies were conducted on Caucasian and Asian populations, whereas rare studies were available on the African population. Promoter methylation frequencies were shown to be significantly higher in LSIL and HSIL cervical cancer cases as compared to control specimens for CADM1, CCNA1, CDH1, DAPK1, FHIT, MAL, P16, PAX1, RAR-ß, and RASSF1 genes. A moderate association was found between HIC promoter methylation, whereas APC, MGMT, and hMLH1 promoter methylation was not correlated with cervical cancer development. Promoter methylation could be considered as a noninvasive biomarker for early cervical lesions, making them highly promising targets for a personalized therapeutic approach.

Immune Checkpoint and Telomerase Crosstalk Is Mediated by miRNA-138 in Bladder Cancer.

BACKGROUND: Tumor recurrence and progression in non-muscle invasive bladder cancer (NMIBC), therapy failure, and severe side effects in muscle invasive bladder cancer (MIBC) are the major challenges in the clinical management of bladder cancer (BC). Here, we identify new molecular targetable signatures to improve BC patients' stratification and the outcome of current immunotherapies. MATERIAL AND METHODS: In a prospective cohort of 70 BC patients, we assessed the genetic and molecular regulation of TERT in maintaining telomere length in parallel to immune checkpoint and microRNA expression. RESULTS: TERT was undetectable in healthy bladder tissues but upregulated in invasive BC stages and high tumor grade. Its expression was linked with the combined effect of the C250T mutation and THOR hypermethylation, associated with progressing tumors and maintaining of telomere length. In the same cohort, PD-L1 scored highest in NMIBC, while PD-L2 was upregulated in MIBC. We also show that miR-100-5p and 138-5p were highly expressed in healthy bladder specimens and cell line, while expression decreased in the BC tissues and BC cell lines. In line with the binding prediction for these miRNAs on target genes, miRs 100-5p and 138-5p expression strongly inverse correlated with TERT, PD-L1, and PD-L2 expression, but not PD1. CONCLUSION: We identify a loop involving TERT, PD1-ligands, and miR-138-5p in BC, that might represent not only a useful biomarker for improved diagnosis and patients' stratification but also as a promising axis that might be therapeutically targeted in situ.

HPV16 L1 diversity and its potential impact on the vaccination-induced immunity.

Human Papillomavirus 16 (HPV16) is the most oncogenic HPV and the most associated genotype with cervical cancer development and progression. Currently, all developed vaccines are targeting HPV16 and were designed based on the major L1 capsid protein. Thus, evaluation of the diversity of HPV16 L1 sequence, mainly in the antigenic regions, will be of a great interest to assess the efficacy of the prophylactic vaccines and to predict the impact of genetic variations in these regions on the vaccination-induced immunity. A total of 377 HPV16 L1 sequences, published in public domain GenBank database, from the Americas, Africa, Asia, and Europe were collected and assembled. A total of 626 mutation events affecting 83 distinct nucleotides into the five antigenic regions of L1 gene of HPV16 were reported, and most SNPs were located in DE (27.38%, 23/83) and FG (31%, 26/83) loops. Overall, 4 mutations were frequently found in HPV16 sequences: T176N and N181T in EF loop; A266T in the FG loop and T353P/I/N HI loop. Of particular interest, some SNPs are ubiquitous and were found in all populations whereas others were population specific and their presence was limited to one or 2 at the maximum. Association between mutations in the antigenic regions and ethnicity was also investigated and showed that mutations in BC and DE loops were present with no significant difference in sequences from Europe, Asia, America and Africa. However, most mutations in FG loop are reported in sequences from European cases and are less pronounced in cases from America and Asia, whereas mutations EF and HI loops prevail in Asian cases. These data highlight a high number of variant amino acid residues that could affect the vaccination-induced immunity and impact the effectiveness of the prophylactic vaccination to fight against HPV, warranting the need of further investigation for vaccines and natural history studies of HPV16.

BRCA1 c.68_69delAG (exon2), c.181T>G (exon5), c.798_799delTT and 943ins10 (exon11) mutations in Burkina Faso.

The worldwide variation of BRCA mutations is well known. The c.68_69delAG, c.181T>G, c.798_799delTT mutations in BRCA1 were observed in Moroccan, Algerian and Tunisian Breast Cancer families and were described founder mutation in Northern Africa. The 943ins10 is also recognized a founder mutation in West Africa. To our knowledge no study has been published on BRCA1/2 germline mutations and hereditary breast cancer (HBC) in population of Burkina Faso. The aim of the present study (first in Burkina Faso) was to screen for these four mutations in 15 unrelated patients with HBC. Mutation analysis was performed by Sanger sequencing of coding exon2, Exon5 and exon11A sequences of the BRCA1 gene. Blood specimens of 15 patients from Burkina Faso, with HBC were collected at the University Hospital Yalgado OUEDRAOGO (CHU-YO) of Ouagadougou in Burkina Faso. c.68_69delAG (exon2), c.181T>G (exon5), c.798_799delTT and 943ins10 (exon11) mutations were not detected in any of the 15 women diagnosed with family breast cancer history. Genetic analysis in this study, we show that targeting relevant exons in BRCA1 genes did not allow detection of mutations in the population of Burkina Faso. Therefore, such an approach may be of interest to perfom a complete sequencing of BRCA1 and BRCA2 genes in families at a high risk of developing breast cancer in Burkina Faso.

Evaluation of glutathione S-transferase pi 1 expression and gene promoter methylation in Moroccan patients with urothelial bladder cancer.

BACKGROUND: Glutathione S-transferase pi 1 (GSTP1) is a cytosolic detoxifying enzyme that protects cells against deleterious effects of oxidative stress. Deregulated expression of GSTP1 protein and aberrant promoter methylation of GSTP1 gene were reported in various human tumors and were shown to be involved in the molecular pathway for cancer development. AIMS AND METHODS: In this study, we aimed to determine the expression status of GSTP1 in relation to its gene promoter methylation in Moroccan population of 30 bladder cancer (BC) patients and in two noncancerous bladder tissues used as controls. GSTP1 expression was assessed by immunohistochemistry and GSTP1 gene promoter methylation status was studied by methylation-specific PCR (MS-PCR). RESULTS: Glutathione S-transferase pi 1 was expressed in the two normal tissues. In BC cases, GSTP1 expression was strong in 23.33% (7/30), moderate in 60% (18/30), and weak in 13.33% (4/30) of cases, while GSTP1 was not expressed in one cancer case (3.33%). Variability of GSTP1 expression does not correlate with high-grade cancer or invasive-stage (p > 0.05). No GSTP1 gene promoter methylation was detected in all control and cancer cases. CONCLUSION: Our data suggest that GSTP1 expression is not associated with BC development, limiting its use as a biomarker for BC management in Morocco. Moreover, difference in GSTP1 expression among BC cases is not due to GSTP1 promoter methylation.

Prevalence of mucosal and cutaneous human papillomavirus in Moroccan breast cancer.

BACKGROUND: Due to recent technical improvements and some encouraging new results, there has been a resurgence of interest in the possibility that a substantial proportion of breast cancers (BCs) may be caused by viral infections, including Human papillomavirus (HPV). The aim of this study was to determine the prevalence of mucosal and cutaneous HPV in tumours from Moroccan BC patients. MATERIALS AND METHODS: Frozen tumours from 76 BC cases and 12 controls were evaluated for the presence of 62 HPV-types using highly sensitive assays that combine multiplex polymerase chain reaction and bead-based Luminex technology. RESULTS: HPV DNA was found in 25.0% of BC tumours and only 8.3% of controls. Beta and gamma HPV types were found in 10.5% and 6.6% of BC tumours, respectively. High-risk mucosal types HPV16 and 18 were not detected in the subjects, but other probable/possible high-risk or high-risk -HPV types (HPV51, 52, 58, 59, and 66) were found in 5.3% of BC tumours. Statistical analysis showed no significant difference between, controls, BC cases and the inflammatory status (p > 0.05). CONCLUSION: HPV DNA was found 3 times as frequently in the BC tumours as in the controls. However, this difference requires confirmation in a larger sample.

Association between glutathione peroxidase 1 codon 198 variant and the occurrence of breast cancer in Rwanda.

BACKGROUND: Glutathione peroxidase 1 gene (GPX1) is one of the antioxidant enzyme that remove the reactive oxygen species in a continuous process. Since the identification of a well-characterized functional polymorphism named p.Pro198Leu (rs1050450 C>T) in GPX1 gene, abundant studies have evaluated the association between p.Pro198Leu polymorphism and tumor risk in diverse population. But, the available results related to breast cancer are conflicting and absent in Africa. The present case-control study was planned to assess the presence of GPX1 Pro198Leu polymorphism in Rwanda population to determine whether it is associated with the risk of developing breast cancer. METHODS: Genomic DNA from peripheral blood leukocytes of 41 patients with breast cancer and 42 healthy controls were enrolled and genotyped GPX1 Pro198Leu polymorphism by PCR amplification and DNA sequencing. RESULTS: No significant difference in the frequencies of Pro/Pro (49%) and Pro/Leu (51%) genotypes in cancer cases and in controls (50% each) were found. The allelic frequencies of Pro and Leu were 74% versus 26% and 75% versus 25% in breast cancer cases and controls respectively. No association was observed in allele frequencies of Pro and Leu, and familial history. Only an overall association of GPX1 Pro198Leu with grade of cancer (Pro/Leu vs. Pro/Pro: p = .0200) was detected. CONCLUSION: The result of this study suggested that GPX1 Pro198Leu polymorphism could not be a risk factor for breast cancer in Rwanda. However, large-scale studies on the effect of this polymorphism on the factors disturbing the redox homeostasis are needed for conclusive understanding.

CHEK2 Germ Line Mutations are Lacking among Familial and Sporadic Breast Cancer Patients in Rwanda

Worldwide, breast cancer is the most frequent neoplasm and the second leading cause of cancer death among females. It dominates in both developed and developing countries and represents a major public health problem. The etiology is multifactorial and involves exogenous agents as well as endogenous factors. Although they account for only a small fraction of the breast cancer burden, mutations in the BRCA1 and BRCA2 genes are known to confer a high risk predisposition. Mutations in moderate/low-penetrance genes may also contribute to breast cancer risk. Previous studies have shown that mutations in the CHEK2 gene are involved in breast cancer susceptibility due to its impact on DNA repair processes and replication checkpoints. This study was conducted to evaluate the frequencies of three germline mutations in CHEK2 gene (c.1100delC, R145W and I157T) in breast cancers in Rwanda. Using direct DNA sequencing, we analyzed 41 breast cancer patients and 42 normal breast controls but could not detect any positives. CHEK2 mutations may be a rare event in Rwandan population and may only play a minor if an role in breast cancer predisposition among familial and sporadic cases.

Detection of human papillomavirus DNA in tumors from Rwandese breast cancer patients.

BACKGROUND: During the last decades, a great interest was given to viral etiology of breast cancer. Indeed, due to recent technical improvements and some encouraging new results, it has been a resurgence of interest in the possibility that a substantial proportion of human breast cancers may be caused by viral infections. High-risk genotypes of human papillomavirus (HPV) have been found in breast cancer cases. In the present study, we aimed to assess the presence of HPV DNA in breast cancer cases from Rwanda and to evaluate the association between HPV infection and clinico-pathological features. METHODS: Therefore, a total of 47 archived formalin-fixed paraffin-embedded biopsies were collected and complete information was recorded. HPV detection and genotyping were done by PCR amplification and DNA sequencing. RESULTS: Overall, HPV DNA was found in 46.81% of cases, HPV16 being the most prevalent subtype (77.27%) followed by HPV33 (13.64%) and HPV31 (9.09%). Comparison of HPV with clinico-pathological features showed no significant difference between HPV infection and breast localization, histological subtype, clinical stage, tumor grade, and intrinsic molecular subtypes. CONCLUSIONS: These findings provide evidence of high prevalence of high-risk HPV in Rwandese patients with breast cancer and suggest that high-risk HPV infections could be a risk factor associated with human breast cancer development.

Association of p53 Codon 72 Polymorphism with Breast Cancer in a Rwandese Population.

BACKGROUND AND AIMS: A common polymorphism in the tumor suppressor gene p53 at codon 72 has been suggested to play a role in the development of a number of cancers. This polymorphism has been studied in many populations worldwide, with conflicting results. The present study was planned to assess the association of p53 codon 72 polymorphism with breast cancer development in a Rwandese population. METHODS: In this study, the polymorphism was examined by allele-specific PCR analysis in 40 patients with breast cancer and 39 healthy controls. RESULTS: The heterozygous genotype Pro/Arg prevailed in both breast cancer patients and controls, and was present in 80% (32/40) and 92.3% (36/39) of cases, respectively. No statistically significant association was observed between p53 codon 72 polymorphism and breast cancer risk. Distribution of p53 genotypes was also studied according to familial history, tumor grade, and clinical stage, and results clearly showed no statistically significant difference. CONCLUSION: These results suggest that p53 codon 72 polymorphism could not be assessed as a risk factor marker for predisposition to breast cancer in Rwanda. However, further studies using larger sample sizes are needed to provide more conclusive results and to investigate other genetic mutations affecting the activity of p53.

Naturally occurring capsid protein variants L1 of human papillomavirus genotype 16 in Morocco.

HPV L1 protein is a corner stone in HPV structure, it's involved in the formation of the viral capsid; widely used as a systematic material and considered as the main component in vaccines development and production. The present study aims to characterize genetic variation of L1 gene of HPV 16 specimens and to evaluate in silico the impact of major variants on the epitope change affecting its conformational structure. A fragment of L1 gene from 35 HPV 16 confirmed specimens were amplified by PCR and sequenced. Overall, five amino acids residues changes were reported: T390P in 16 specimens, M425I and M431I in 2 cases, insertion of Serine at 460 and aspartic acid deletion at position 477 in all analyzed cases. The 3D generated model showed that T389P amino acid substitution is located in the H-I loop; the two substitutions M424I and M430I are both located in the H2 helice. The Serine insertion and aspartic acid deletion are located in the H4 helice and B-C loop, respectively. Superimposition of sequences' structures showed that they share a very similar conformation highlighting that the reported amino acids variations don't affect the structure of the L1 protein. However T389P, located in the H-I loop identified as an immunogenetic region of L1 capsid, was reported in 51.4% of cases could interact with vaccines induced monoclonal antibodies suggesting a potential impact on the efficacy of available anti-HPV vaccines.

HPV and cofactors for invasive cervical cancer in Morocco: a multicentre case-control study.

BACKGROUND: Limited national information is available in Morocco on the prevalence and distribution of HPV-sub-types of cervical cancer and the role of other risk factors. The aim was to determine the frequency of HPV-sub-types of cervical cancer in Morocco and investigate risk factors for this disease. METHODS: Between November 2009 and April 2012 a multicentre case-control study was carried out. A total of 144 cases of cervical cancer and 288 age-matched controls were included. Odds-ratios and corresponding confidence-intervals were computed by conditional logistic regression models. RESULTS: Current HPV infection was detected in 92.5% of cases and 13.9% of controls. HPV16 was the most common type for both cases and controls. Very strong associations between HPV-sub-types and cervical cancer were observed: total-HPV (OR = 39), HPV16 (OR = 49), HPV18 (OR = 31), and multiple infections (OR = 13). Education, high parity, sexual intercourse during menstruation, history of sexually transmitted infections, and husband's multiple sexual partners were also significantly associated with cervical cancer in the multivariate analysis. CONCLUSIONS: Our results could be used to establish a primary prevention program and to prioritize limited screening to women who have specific characteristics that may put them at an increased risk of cervical cancer.

Tomentosin Induces Telomere Shortening and Caspase-Dependant Apoptosis in Cervical Cancer Cells.

Tomentosin, a natural sesquiterpene lactone purified from of Inula viscosa L., was investigated for its anti-proliferative, telomere shortening, and apoptotic effects on human cervical cancer HeLa and SiHa cell lines. Tomentosin was found to inhibit the growth of SiHa and HeLa cell lines in dose and time-dependent manner (IC50 values of 7.10 ± 0.78 µM and 5.87 ± 0.36 µM, respectively after 96 h of treatment). As evidenced by TTAGGG telomere length assay, tomentosin target specifically the telomeric overhang lengthening. This was confirmed by the evaluation of the cytotoxic effects of tomentosin in the foetal fibroblast Wi38 and JW10 cells which were derived from Wi38 and express hTERT, the telomerase catalytic subunit. We found that JW10 cells are 4.7-fold more sensitive to tomentosin which argues for telomere as its specific target. Furthermore, we found that tomentosin mediate this cytotoxic effect by inducing apoptosis and cell cycle arrest at G2/M phase. Morphological features of treated cells, as evidenced by Hoechst 33324 staining, revealed that the cytotoxic effect was due to induction of apoptosis. This was accompanied by pro-caspase-3 cleavage, an increase in caspase-3 activity and a cleavage of poly (ADP-ribose) polymerase (PARP). Moreover, tomentosin induced a decrease in mitochondrial membrane potential (ΔΨm) and an increase in reactive oxygen species (ROS), accompanied by a decrease in Bcl-2 expression. This indicates that tomentosin-induced apoptosis may involve a mitochondria-mediated signaling pathway. This study provides the first evidence that tomentosin targets telomere machinery and induces apoptosis in cervical cancer cells. The molecular mechanism underlying tomentosin-induced apoptosis may involve a mitochondria-mediated signaling pathway. J. Cell. Biochem. 118: 1689-1698, 2017. © 2016 Wiley Periodicals, Inc.

A review of the infection-associated cancers in North African countries.

Cancer is typically classified as a leading non-communicable disease; however, infectious agents, such as Helicobacter pylori (H. pylori), hepatitis B virus (HBV), hepatitis C virus (HCV) and human papilloma virus (HPV), contribute significantly to the pathogenesis of various cancers. Less developed countries, including countries of the North African (NA) region, endure the highest burden of infection-related cancers. The five most common infection-associated cancers in NA in order of incidence are bladder cancer, cervical cancer, liver cancer, stomach cancer, and nasopharyngeal carcinoma. This review aims to outline the epidemiologic pattern of infection-associated cancers in five NA countries (namely: Morocco, Algeria, Tunisia, Libya and Egypt) highlighting the similarities and differences across the region. The present study employed an initial literature review of peer-reviewed articles selected from PubMed, ScienceDirect and World Health Organization (WHO) databases based on key word searches without restriction on publication dates. Original research articles and reports written in French, as well as data from institutional reports and regional meeting abstracts were also included in this extensive review. Egypt, Libya, Tunisia, Algeria and Morocco were selected to be the focus of this review.