Obesity and cancer: focus on leptin.

Over the past decades, obesity has grown to epidemic proportions worldwide. It has been associated with an increased risk for different types of cancer. In addition, obesity has been associated with a poor prognosis, an increased risk of metastasis and mortality, and resistance to anti-cancer therapies. The pathophysiological mechanisms underlying the obesity-cancer connection have not yet been fully elucidated. However, this connection could result, at least in part, from the action of adipokines, whose levels are increased in obesity. Among these adipokines, evidence suggests leptin's critical role in linking obesity to cancer. In this review, we first summarize the current state of the literature regarding the implication of leptin in tumorigenic processes. Next, we focus on the effects of leptin on the anti-tumor immune response. Then, we discuss the influence of leptin on the efficiency of antineoplastic treatments and the development of tumor resistance. Finally, we highlight the use of leptin as a potential target for the prevention and treatment of cancer.

Understanding COVID-19 vaccine hesitancy and resistance: another challenge in cancer patients.

INTRODUCTION: We aimed to measure the acceptability towards the COVID-19 vaccination in cancer patients and to investigate determinant factors associated with the patient's choice. METHODS: We conducted a cross-sectional survey with a self-administered questionnaire delivered to 329 cancer patients in 3 oncology cancer centers in Tunisia between February-May 2021. Logistic regression was used to evaluate odds ratio predicting patient's intentions toward the vaccine. RESULTS: Acceptance rate was 50.5%, 28.3% (n = 93) reported to definitely refuse the vaccine and 21.2% (n = 70) did not make their decision yet. High educational level, history of comorbidities, history of influenza vaccination in the current season, and patient's opinion about the severity of COVID-19 did not predict vaccine resistance. However, patients who think that the vaccine may interfere with treatment efficacy (OR = 7.28, 95%CI [2.5-12.32]), or may impact cancer outcome (OR = 6.14, 95%CI [2.27-16.7]), were significantly more likely to refuse the vaccine. Patients who disagree that the vaccine is a major weapon against the pandemic (OR = 6.07, 95%CI [2.34-9.52]) or that it could reduce the virus transmission (OR = 7.34, 95%CI [4.22-11.81]) were also significantly more likely to reject the vaccination. Safety concerns were also significant predictive factors (OR = 7.9, 95%CI [4.10-11.27]. Confidence level in the authorities played a significant role in patient's acceptance of the vaccine, indeed patients who are not registered (OR = 5.9, 95%CI [1.58-8.7]) or not informed about the Tunisian national vaccination platform EVAX (OR = 5.51, 95%CI [2.1-7.9]) were more likely to be against the vaccine. CONCLUSION: Cancer patient's education about the impact of the vaccine on their disease and on the COVID-19 is needed. Governments should build strategies to gain more population confidence.

Docetaxel monotherapy induces necrotic acute pancreatitis.

INTRODUCTION: Drug-induced acute pancreatitis (AP) is uncommon and represents 0.1 to 2% of all AP cases. Chemotherapy-induced AP is very rare. Docetaxel monotherapy-induced AP has been reported only once in the literature. Herein we report the second case of docetaxel-related AP and the first case of necrotic AP induced by this agent. CASE REPORT: We describe the case of a severe docetaxel-induced AP classified as stage E Balthazar in a 55-year-old female treated with adjuvant docetaxel for localized breast cancer. Symptoms occurred five hours following the first infusion of docetaxel. MANAGEMENT AND OUTCOME: The patient was hospitalized for 15 days for appropriate management. According to the CTCAE (Common Terminology Criteria for Adverse Events) version 5.0 this was a grade 4 toxicity and chemotherapy was withdrawn thereafter. Drug rechallenge was not possible because of the severity of the presentation. DISCUSSION: Medical oncologists should be aware that docetaxel may induce severe pancreatitis. Therefore, they should prompt testing of serum lipase when patients consult for unusual abdominal pain following chemotherapy infusion. Recognizing this entity is paramount to allow early and appropriate management.

Assessing the financial toxicity in Tunisian cancer patients using the Comprehensive Score for Financial Toxicity (COST).

BACKGROUND: Cancer care-related out-of-pocket expenses and financial toxicity (FT) are a rising burden for patients. We aimed to evaluate patient-reported FT and to identify relevant correlates within a Tunisian population. METHODS: We conducted a survey using the 11-item Comprehensive Score for Financial Toxicity (COST) that could range from 0 = high to 44 = low. FT was grade 0 if ≥ 26, grade 1 = (14-25), grade 2 = (1-13), and grade 3 = 0. Scores were collected along with data regarding patient medical/social features and out-of-pocket expenses. Univariate and multivariate analyses were performed to identify factors associated with higher financial burden. RESULTS: Among the 179 participants, median COST score was 20.8 (Q1 17-Q3 24), with 80.4% of patients experiencing financial toxicity: grade 0 = 20%, grade 1 = 68.4%, grade 2 = 11.7%, grade 3 = 0%. Most patients (66.5%) used to work before cancer and 44.7% reported ceasing work because of cancer. The time to go to the hospital was > 30 min in 66.5% of cases. Unemployment, time to hospital > 30 min, ceasing work because of cancer, and expenses on non-chemotherapy drugs exceeding 70 dinars (25 US dollars) were mostly associated with higher FT on univariate analysis. Distance to hospital and ceasing work because of cancer were the single most significant factors in multivariate analysis. CONCLUSIONS: Losing work due to cancer and unequal distribution of health care particularly in cities with long travel times to the nearest hospital are the main sources of financial distress.

Family specific genetic predisposition to breast cancer: results from Tunisian whole exome sequenced breast cancer cases.

BACKGROUND: A family history of breast cancer has long been thought to indicate the presence of inherited genetic events that predispose to this disease. In North Africa, many specific epidemio-genetic characteristics have been observed in breast cancer families when compared to Western populations. Despite these specificities, the majority of breast cancer genetics studies performed in North Africa remain restricted to the investigation of the BRCA1 and BRCA2 genes. Thus, comprehensive data at a whole exome or whole genome level from local patients are lacking. METHODS: A whole exome sequencing (WES) of seven breast cancer Tunisian families have been performed using a family-based approach. We focused our analysis on BC-TN-F001 family that included two affected members that have been sequenced using WES. Relevant variants identified in BC-TN-F001 have been confirmed using Sanger sequencing. Then, we conducted an integrative analysis by combining our results with those from other WES studies in order to figure out the genetic transmission model of the newly identified genes. Biological network construction and protein-protein interactions analyses have been performed to decipher the molecular mechanisms likely accounting for the role of these genes in breast cancer risk. RESULTS: Sequencing, filtering strategies, and validation analysis have been achieved. For BC-TN-F001, no deleterious mutations have been identified on known breast cancer genes. However, 373 heterozygous, exonic and rare variants have been identified on other candidate genes. After applying several filters, 12 relevant high-risk variants have been selected. Our results showed that these variants seem to be inherited in a family specific model. This hypothesis has been confirmed following a thorough analysis of the reported WES studies. Enriched biological process and protein-protein interaction networks resulted in the identification of four novel breast cancer candidate genes namely MMS19, DNAH3, POLK and KATB6. CONCLUSIONS: In this first WES application on Tunisian breast cancer patients, we highlighted the impact of next generation sequencing technologies in the identification of novel breast cancer candidate genes which may bring new insights into the biological mechanisms of breast carcinogenesis. Our findings showed that the breast cancer predisposition in non-BRCA families may be ethnic and/or family specific.

A genome wide SNP genotyping study in the Tunisian population: specific reporting on a subset of common breast cancer risk loci.

BACKGROUND: Breast cancer is the most common cancer in women worldwide. Around 50% of breast cancer familial risk has been so far explained by known susceptibility alleles with variable levels of risk and prevalence. The vast majority of these breast cancer associated variations reported to date are from populations of European ancestry. In spite of its heterogeneity and genetic wealth, North-African populations have not been studied by the HapMap and the 1000Genomes projects. Thus, very little is known about the genetic architecture of these populations. METHODS: This study aimed to investigate a subset of common breast cancer loci in the general Tunisian population and to compare their genetic composition to those of other ethnic groups. We undertook a genome-wide haplotype study by genotyping 135 Tunisian subjects using the Affymetrix 6.0-Array. We compared Tunisian allele frequencies and linkage disequilibrium patterns to those of HapMap populations and we performed a comprehensive assessment of the functional effects of several selected variants. RESULTS: Haplotype analyses showed that at risk haplotypes on 2p24, 4q21, 6q25, 9q31, 10q26, 11p15, 11q13 and 14q32 loci are considerably frequent in the Tunisian population (> 20%). Allele frequency comparison showed that the frequency of rs13329835 is significantly different between Tunisian and all other HapMap populations. LD-blocks and Principle Component Analysis revealed that the genetic characteristics of breast cancer variants in the Tunisian, and so probably the North-African populations, are more similar to those of Europeans than Africans. Using eQTl analysis, we characterized rs9911630 as the most strongly expression-associated SNP that seems to affect the expression levels of BRCA1 and two long non coding RNAs (NBR2 and LINC008854). Additional in-silico analysis also suggested a potential functional significance of this variant. CONCLUSIONS: We illustrated the utility of combining haplotype analysis in diverse ethnic groups with functional analysis to explore breast cancer genetic architecture in Tunisia. Results presented in this study provide the first report on a large number of common breast cancer genetic polymorphisms in the Tunisian population which may establish a baseline database to guide future association studies in North Africa.

About molecular profile of lung cancer in Tunisian patients.

BACKGROUND: Molecular profile of lung cancer is well known in developed countries. These countries reached the era of liquid biopsies, immunotherapy, and urine circulating tumor DNA. The discrepancies between developed countries and developing ones are becoming deeper. Because of a lack of data in Tunisia, we tried to analyze the molecular profile of non-small-cell carcinomas and to assess the morphologic subtype of adenocarcinomas according to their mutational profile. METHODS: We performed molecular analyses in Tunisia and in France of 84 patients who were able to afford the cost of the diagnostic techniques carcinomas diagnosed between 2012 and 2015. The diagnosis was established in our Department of Pathology and the percentage of the tumor cells was estimated by the pathologists. The paraffin-embedded blocks were sent to France, in 41 cases and were analyzed in Tunisia in 43 cases. A next-generation sequencing was performed in France and a real-time polymerase chain reaction (PCR) was performed in our country. RESULTS: During the period of study, 1122 lung cancers were diagnosed and 87 patients were able to afford the molecular analyses cost. The mean age of these patients was 53 years. The sex ratio reached 1.9. The molecular analyses were not performed in three cases because of a low tumor cell rate. EGFR mutations were present in 16 cases: 3 men and 13 women. The adenocarcinomas were classified as acinar in 11 cases and solid in 5 cases. ALK-EML4 translocation was present in six cases. Mutations of BRAF, KRAS, P53, and ERBB4 genes were, respectively, detected in two cases, five cases (3 codon 12), three cases, and one case. CONCLUSION: This study made us wonder about the possibility of implementing molecular techniques in low-income countries and about the necessity of optimizing the financial resources.

Early onset breast cancer: differences in risk factors, tumor phenotype, and genotype between North African and South European women.

PURPOSE: This report compares the risk factors, the tumor phenotypes, and the BRCA1/BRCA2 genotype of early onset breast cancer (EOBC) patients between Southern Europe and North Africa. METHODS: Four hundred and fifty six women with invasive EOBC (≤40 years) were prospectively included from four centers in France (n = 270) and four centers in North Africa (Algeria, Egypt, Morocco, Tunisia; n = 186). Life style, tumor phenotype, familial history, BRCA1/BRCA2 genotype were compared between the two populations. RESULTS: We found an older age at menarche, a higher number of childbearing, a more frequent breastfeeding, a higher body mass index, a lower use of oral contraceptives in North African women compared to French women. TNM stage at diagnosis was higher in North African women than in French women. North African women had a lower incidence of triple negative and proliferative (Ki 67 index > 20%) tumors. There was a lower rate of BRCA1 mutation in North Africa (7 vs. 15%, P = 0.02). Three putative BRCA1/2 founder mutations were identified in North Africa. CONCLUSIONS: In EOBC, we found significant differences in risk factors, phenotype and a higher incidence of BRCA1 mutations in Southern Europe as compared to North Africa. The worst prognosis previously reported for EOBC in North Africa is more likely due to a higher stage at diagnosis than to a more aggressive phenotype, since triple negative tumors are more common in Southern Europe and advanced tumors in North Africa.

Prognostic implications of the intrinsic molecular subtypes in male breast cancer.

PURPOSE: Intrinsic molecular subtyping has been widely used in female breast cancer, and it has proven its significance. In this article, we aimed to study the intrinsic subtypes of male breast cancer (MBC) in correlation with clinicopathological features. METHODS: We retrospectively identified 130 MBC cases from 2004 to 2013. Intrinsic molecular subtypes were determined by immunohistochemistry (IHC). RESULTS: From a total of 130 MBC cases, 45.4% of tumors were luminal A subtype, 44.6% were luminal B, 5% were HER2 positive and 5% were triple negative tumors. There were statistically significant differences between different IHC intrinsic subtypes regarding tumor size (p=0.001), estrogen receptor (ER) status (p=0.001), progesterone receptor (PR) status (p=0.001), HER2 status (p=0.001) and Ki67 proliferation index (p=0.001). CONCLUSION: The distribution of breast cancer intrinsic subtypes in males is different compared to its female counterpart; however, they don't seem to give the same prognostic value.

Prognostic impact of polymorphism of matrix metalloproteinase-2 and metalloproteinase tissue inhibitor-2 promoters in breast cancer in Tunisia: case-control study.

Matrix metalloproteinases (MMPs) are proteolytic enzymes that play important roles in tumor invasion and metastasis by degrading extracellular matrix components. Genetic variations in promoter regions of MMP genes, affecting their expression, have been associated with susceptibility to cancers. The aim of this study was to investigate the susceptibility and prognostic implications of the matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinase-2 (TIMP-2) polymorphism in Tunisian breast cancer patients. MMP-2 genotypes were determined by real-time polymerase chain reaction (RT-PCR), and TIMP-2 genotypes were identified using a PCR-restriction fragment length polymorphism (RFLP) method in 210 breast cancer patients and 250 frequency-matched control women. Association of the clinicopathological parameters and the genetic markers with risk of breast cancer was assessed using univariate analyses. We found that the variant MMP-2 genotype (-1306CT or TT) was associated with substantially reduced risk of breast cancer [odds ratio (OR), 0.49; 95 % confidence interval (95 % CI), 0.033-0.73], compared with the CC genotype. For TIMP-2, a moderately reduced risk of the cancer (OR, 0.57; 95 % CI, 0.37-0.87) was also associated with the variant allele (-418GC or CC), compared with the GG common allele. Furthermore, polymorphisms in both genes seem to have additive effects and the highest risk for breast cancer has been observed in those with MMP-2 CC genotype and TIMP-2 GC or CC genotype (p = 0.006). A significant association was also found between the CC genotype and the aggressive forms of breast cancer as defined by advanced stages at the time of diagnosis and metastasis. This is the first report on the association of MMP-2 and TIMP-2 gene polymorphisms in breast cancer in Tunisian population. Our results suggest that the presence of the variant allele in the promoter of MMP-2 or TIMP-2 may be a protective factor for the development of breast cancer.

Genomic classification of lung cancer: toward a personalized treatment.

Lung cancer is the first cause of death by cancer worldwide. In Tunisia, its incidence has increased from 17.6 cases per 100.000 persons in 1997 to 27.6 cases per 100.000 persons in 2003. Its prognosis has been improving thanks to the emergence of molecular targets. The first one is represented by EGFR (Epidermal growth factor receptor), which marks this (2014) its tenth anniversary. many other targets have been identified. the most famous and useful of them the fusion gene ALK-EML4 but other oncogenic pathways have been implicated and under investigations including HER2, BRAF, MET, RET... The relevant challenges encountered are represented by the difficulty to achieve a consensual decisional and therapeutic algorithm, the absence of standardized diagnostic techniques and unavoidable occurrence of secondary resistance due to the activation of other oncogenic pathways that must be explored and targeted. In this update, we tried to present the major pathways implicated and the most relevant practice routine strategies.

Exocrine Pancreatic carcinoma in Tunisia: A retrospective study about 158 cases.

BACKGROUND: Exocrine pancreatic carcinoma (EPC) occurs in the majority of cases with early locoregional spread and distant metastasis at diagnosis, leading to dismal prognosis and limited treatment options. Traditional cytotoxic chemotherapy provide only modest benefit to patients with EPC. Identification of different molecular pathways, overexpressed in pancreatic cancer cells, has provided the opportunity to develop targeted therapies with a crucial therapeutic role in this cancer setting. OBJECTIVE: Our aim is to study the epidemiological, clinicopathological characteristics, treatment modality and clinical outcome of pancreatic adenocarcinoma in Tunisian patients treated in the department of medical oncology Abderrahmane Mami Ariana. METHODS: This retrospective study concerned patients with exocrine pancreatic carcinoma treated between 2009 and 2012. We analysed the following data: Anamnesis, age, sex, delay to diagnosis(DD), symptoms, clinical exam, performance status, stage, therapeutic protocol and results. RESULTS: We collected 158 patients (113 males/45 females, SR 2.5) with a median age of 64 years (20-93). The median DD was 2 months (1-12). Abdominal pain, jaundice and weight loss were the most frequent symptoms, 88.6%, 43% and 55.1% of cases respectively. Performance status was < 2 in 56.9% (90 pts). Seric CA19-9 was increased in 86.6% of cases. Tumor was at stage III in 24.7% and stage IV in 58.2%. Surgery was done in 24.7% of cases (39pts), curative in 21 patients. Neoadjuvant chemotherapy(NACT) was administrated to 10.8% of patients, adjuvant to 13.9% (22 pts) and palliative chemotherapy(PCT) concerned 58.8% of patients. We used weekly Gemcitabine, Gemcitabine-CDDP, Gemcitabine-Oxaliplatine and LV5-FU2-CDDP in palliative setting respectively in 20%, 31.1%, 2.2 and 36.7% of cases. Median survival was 6 months (2-60) and the 1year overall survival at 38.8%. CONCLUSION: EPC remains a rare cancer in Tunisia. The prognosis is still grim worldwide and so does in our country. In this retrospective serie, we noted the predominance of locally advanced and metastatic cases with a long delay to diagnosis. Awareness campaigns have to be programmed to improve early diagnosis in EPC and improve outcomes.

Glioblastoma in Tunisia: A retrospective study about 41 cases.

BACKGROUND: Glioblastoma (GB) is the most common and lethal primary brain tumor in adults representing 25% of primary brain tumors in adults. The objective of our study was to report the epidemiologic, clinical and therapeutic features of GB in Tunisia. METHODS: Our retrospective study included 41 patients with histologically confirmed GB treated between 2006 and 2012 at the medical oncology departments of Abderrahmane Mami hospital in Ariana and the military hospital in Tunis. RESULTS: Median age was 54 years (13 to 72 years) and sex-ratio was 2.3. Karnofsky performance status (KPS) was <70% in 31.7% of cases, while Recursive partitioning analysis radiation therapy oncology group (RTOG-RPA) classification was III in 11 (26.8%), IV in 19 (46.3%), V in 10 (24.3%) and VI in 1 (2.4%) cases. Complete resection (CR) was achieved in 29 patients (70.7%), partial resection (PR) or tumor debulking in 5 patients (12.2%) and biopsy alone (BA) in 7 patients (17.1%). All patients received brain radiotherapy (RT) at a dose of 60 Gy combined with concurrent temozolomide (TMZ). Nineteen patients (46.3%) received adjuvant TMZ, 8 of them completed 6 cycles. Median overall survival (OS) was 12 months (2 to 56 months). Six, 12, 18 and 24-months OS rates were 84.6%, 57.6%, 35.4% and 20.7%, OS being correlated to age, KPS, RPA and quality of resection. CONCLUSION: Our retrospective study is the first African GB series. Despite it included predominantly poor prognosis patients with impaired neurocognitive function and adjuvant treatment discontinuation, our median OS was comparable to Stupp.

[Carcinogenesis of non small cell lung cancer and therapeutic implications]. / Carcinogénèse des carcinomes bronchiques non a petites cellules et implications thérapeutiques.

The occurrence of a lung cancer is a consequence of a long-lasting process dealing with a transformation of a normal cell to a malignant one. The four steps of transformation reflect the genetic modifications of the cells. The molecular studies of pre-invasive lesions have already established a correlation between the lesion continuum and the multi-step carcinogenesis. Gradual genetic alterations are correlated with the increase of the cell's malignant potential. We tried to present the carcinogenesis of the lung non microcellular carcinomas and to highlight the main therapeutic targets.

Navigating the Cancer Journey: Experiences and Perspectives of Young Adult Patients in Tunisia.

Purpose: This study aimed to explore the experiences of young adult cancer patients within the Tunisian context. Methods: A total of 104 patients between the ages of 20 and 40, undergoing treatment for various types and stages of cancer, participated in a questionnaire-based survey. The survey encompassed topics related to the socioeconomic and psychological impacts of cancer, coping mechanisms, relationships, sexuality, and future aspirations. Results: Of the participants, 78 were women (75%) and 26 were men (25%), with an average age of 33 years. Financial difficulties were reported by 60 patients (57.7%). The most common emotional responses to the diagnosis were sadness (54.8%), followed by denial (18.3%) and anger (5.8%). Thirteen patients (12.5%) choose not to receive information about the stage of their disease. In addition, 42 patients (40.4%) experienced a decrease in perceived physical attractiveness, while negative effects on sexuality were observed in 44.2% of cases. The primary concerns reported by patients were the fear of recurrence or progression (48%) and infertility (48%). Furthermore, 43 patients (41.3%) expressed a decrease in self-confidence, notably influenced by financial difficulties (OR: 2.77 [95% CI: 1.12-6.87]), physical alterations (OR: 0.18 [95% CI: 0.07-0.45]), and sexual issues (OR: 0.17 [95% CI: 0.06-0.48]). Notably, 78 patients (75%) continued to make future plans, particularly those under 30 years of age (OR: 0.2 [95% CI: 0.04-0.96]). Moreover, 47.1% of patients expressed an inclination toward immigration to developed countries, primarily due to perceived superior health care systems (61.5%). Conclusions: Young cancer patients face a range of social and psychological challenges, suggesting the necessity for a specialized care approach.

Inflammatory breast cancer: Epidemiologic data and therapeutic results.

Since the early description more than a century ago, inflammatory breast cancer (IBC) remains an aggressive disease, with a different geographic repartition, with the highest ones incidence reported in the North of Africa (Tunisia, Algeria, Morocco, and Egypt), and the lowest incidence in Western countries (USA, Europe…). In this study, we reviewed the literature using the Surveillance, Epidemiology, and End Results (SEER) database compared to other published series. We observed that in the high incidence areas (North of Africa) when compared to "classical" breast cancer, IBC was associated to younger age (less than 50 years) with rapid evolution of signs and symptoms (in less than 3 up to 6 months), and more aggressive clinical and histopathological-molecular parameters, due to the predominance of triple-negative and HER2+ subtypes in around 60% of cases. An epidemiologic trend was observed in both high and low incidence areas since the eighties are towards reduction of IBC prevalence. Concerning Tunisia, in comparison with the historical series of the 1980s, the incidence decreased in part by applying more stringent diagnostic criteria but also probably due to a slight improvement of the socio-economic level (SEL). This trend was also observed in the US, due to the efforts of collaborative IBC groups from MD Anderson Cancer Center (MDACC), Duke and IBC patient advocacy groups. Therapeutic results are slightly better due to the standardization of a multidisciplinary approach and the use of combined primary chemotherapy and/or targeted therapies (especially in HER2 positive patients), followed by mastectomy plus radiotherapy. The 5-year overall and disease-free survival is at more than 60%, related to an IBC mortality decrease observed in the cohorts of patients treated in the last decade.

Uncovering the clinical relevance of unclassified variants in DNA repair genes: a focus on BRCA negative Tunisian cancer families.

Introduction: Recent advances in sequencing technologies have significantly increased our capability to acquire large amounts of genetic data. However, the clinical relevance of the generated data continues to be challenging particularly with the identification of Variants of Uncertain Significance (VUSs) whose pathogenicity remains unclear. In the current report, we aim to evaluate the clinical relevance and the pathogenicity of VUSs in DNA repair genes among Tunisian breast cancer families. Methods: A total of 67 unsolved breast cancer cases have been investigated. The pathogenicity of VUSs identified within 26 DNA repair genes was assessed using different in silico prediction tools including SIFT, PolyPhen2, Align-GVGD and VarSEAK. Effects on the 3D structure were evaluated using the stability predictor DynaMut and molecular dynamics simulation with NAMD. Family segregation analysis was also performed. Results: Among a total of 37 VUSs identified, 11 variants are likely deleterious affecting ATM, BLM, CHEK2, ERCC3, FANCC, FANCG, MSH2, PMS2 and RAD50 genes. The BLM variant, c.3254dupT, is novel and seems to be associated with increased risk of breast, endometrial and colon cancer. Moreover, c.6115G>A in ATM and c.592+3A>T in CHEK2 were of keen interest identified in families with multiple breast cancer cases and their familial cosegregation with disease has been also confirmed. In addition, functional in silico analyses revealed that the ATM variant may lead to protein immobilization and rigidification thus decreasing its activity. We have also shown that FANCC and FANCG variants may lead to protein destabilization and alteration of the structure compactness which may affect FANCC and FANCG protein activity. Conclusion: Our findings revealed that VUSs in DNA repair genes might be associated with increased cancer risk and highlight the need for variant reclassification for better disease management. This will help to improve the genetic diagnosis and therapeutic strategies of cancer patients not only in Tunisia but also in neighboring countries.

Genetic testing for hereditary cancer syndromes in Tunisian patients: Impact on health system.

INTRODUCTION: Cancer management in Africa faces diverse challenges due to limited resources, health system challenges, and other matters. Identifying hereditary cancer syndromic cases is crucial to improve clinical management and preventive care in these settings. This study aims to explore the clinicopathological features and genetic factors associated with hereditary cancer in Tunisia, a North African country with a rising cancer burden MATERIALS AND METHODS: Clinicopathological features and personal/family history of cancer were explored in 521 patients. Genetic analysis using Sanger and next-generation sequencing was performed for a set of patients RESULTS: Hereditary breast and ovarian cancer syndrome was the most frequent cluster in which 36 BRCA mutations were identified. We described a subgroup of patients with likely ''breast cancer-only syndrome'' among this cluster. Two cases of Li-Fraumeni syndrome with distinct TP53 mutations namely c.638G>A and c.733G>A have been identified. Genetic investigation also allowed the identification of a new BLM homozygous mutation (c.3254dupT) in one patient with multiple primary cancers. Phenotype-genotype correlation suggests the diagnosis of Bloom syndrome. A recurrent MUTYH mutation (c.1143_1144dup) was identified in three patients with different phenotypes CONCLUSION: Our study calls for comprehensive genetic education and the implementation of genetic screening in Tunisia and other African countries health systems, to reduce the burden of hereditary diseases and improve cancer outcomes in resource-stratified settings.

[Aromatases inhibitors for breast cancer in menopausal patients]. / Les inhibiteurs de l'aromatase dans le traitement adjuvant du cancer du sein de la femme ménopausée.

AIMS: To analyze the litterature data concerning the results of the main international randomized trials of adjuvant Aromarase Inhibitors (AI) in adjuvant setting for early breast cancer and the impact on daily practice in the management of breast cancer. METHODS: We selected through a litterature review 30 publications concerned the topic of AI RESULTS: They concerned the large ATAC, BIG, MA17 and IES concerning anastrozole, letrozole and exemestane . AI have been compared to tamoxifen in upfront of swich intents and showed a superiority to reduce, mortality rate, controlateral breast cancer risk, a better tolerance profile compared to tamoxifen and a sigificant benefit in term of disease-free survival. These results made a revolution in the adjuvant BC treatment, leading to the systematic use of upfront AI in menopaused patients. CONCLUSION: Adjuvant hormonotherapy in menopaused patients is now based on AI and proved its superiority to tamoxifen in term of distant, controlateral risks reduction and disease-free survival, less for overall survival.

[Phenotypic and molecular changes of hemoglobinopathies in cancer]. / Variation phénotypique et moléculaire des hémoglobinopathies en milieu carcinologique.

BACKGROUND: The abnormalities of the haemoglobin divide into qualitative abnormalities and quantitative abnormalities. This variant contains polymorphisms often useful as markers of population. At present more than 693 types of abnormal haemoglobin are listed. This hemoglobinopathies can arise at reached subjects of cancerous pathologies. AIM: To bring to report association hémoglobinopathies-cancers. METHODS: Our study was realized to the Institute Salah azaiz (ISA) concerning hémoglobinopathies in carcinologic environment over a period spreading out of May 2004 in February 2008. The phenotypic and biochemical study of haemoglobin revealed the presence of 328 carriers of abnormalities of the haemoglobin on a total of 10550 patients followed to ISA. 7 types of abnormalities of the haemoglobin were identified (HbS, Hb C, Hb O arab, Hb D, Hb G, fast mutant and ß thalassemia. RESULTS: The sickle cell line represents the most wide-spread hémoglobinopathie (51.3 %). 48.2 % of the carrier subjects of abnormalities of the haemoglobin are followed for malignant pathologies. Among these hemoglobinopathies, we revealed the presence of two fast mutants of the haemoglobin corresponding to the haemoglobin Bangkok. This type of rare mutant is described for the first time in Tunisia. According to the genotypic study by these two cases, the haemoglobin Bangkok results from the replacement at the level of the chain ß some aspartic acid by the wisteria, further to a transfer at the level of the codon 56. A phenotypic study family revealed the presence of similar transfers at certain members of the family. CONCLUSION: Our work allowed us to notice a relatively important frequency of rare abnormalities of the haemoglobin at patients presenting varied tumoral processes.