BackgroundMutations in KRAS and NRAS often result in constitutive activation of RAS in the epidermal growth factor receptor (EGFR) signaling pathway. Mutations in KRAS exon 2 (codon 12–13) predict resistance to anti-EGFR targeted therapy in patients with metastatic colorectal carcinoma (mCRC). However, it's currently known that a significant proportion of mCRC have RAS mutations outside KRAS exon 2, particularly in exons 3 and 4 of KRAS and exons 2, 3 and 4 of NRAS. No data about RAS mutations outside KRAS exon 2 are available for Tunisian mCRC. The aim of this study was to analyze RAS, using pyrosequencing, in nine hotspots mutations in Tunisian patients with mCRC.MethodsA series of 131 mCRC was enrolled. Nine hotspots sites mutations of KRAS and NRAS were analyzed (KRAS: codons 12–13, codons 59–61, codon 117 and codon 146, NRAS: codons 12–13, codon 59, codon 61, codon 117 and codon 146) using Therascreen KRAS and RAS extension pyrosequencing kits.ResultsAnalysis was successful in 129 cases (98.5%). Mutations were observed in 97 cases (75.2%) dominated by those in KRAS exon 2 (86.6%). KRAS G12V was the most dominated mutation, observed in 25 cases (25.8%), and followed by KRAS G12S and KRAS G12D, each in 17 cases (17.5%). Mutations outside of KRAS exon 2 presented 13.4% of mutated cases and almost a third (28.8%) of KRAS exon 2 wild type mCRC. Among those, 9 cases (69.3%) carried mutations in NRAS exons 2, 3 and 4 and 4 cases (30.7%) in KRAS exons 3 and 4.ConclusionsRAS mutations outside exon 2 of KRAS should be included in routine practice, since they predict also response to anti-EGFR. That would make certain these patients benefit from appropriate testing and treatment. In addition unjustified expenses of anti-EGFR targeted therapy could be avoided.

IL23/IL17 pathway plays an important role in the development of inflammatory bowel diseases (IBD). In general, the genes encoding the cytokines are genetically polymorphic and polymorphisms in genes IL23R and IL17 have been proved to be associated with its susceptibility to inflammatory diseases as well as cancer including colorectal cancer. Moreover, it has been shown that these interleukins are involved in anti-tumor or pro-tumor effects of various cancers. Previously, we showed that there is a significant association between IL17A, IL17F and IL23R polymorphisms as well as the occurrence of colorectal cancer and the clinical features of the disease. The purpose of the present work is to investigate an association between IL17A, IL17F and IL23R polymorphisms in 102 Tunisian patients with colorectal cancer treatment. The association was analyzed by statistical tools. We found that patients with mutated genotypes of IL17A G197A SNP could be a risk factor for the inefficiency of chemotherapy and radiotherapy. Unlike IL17F variant, patients with wild type genotypes require surgery and adjuvant chemotherapy. On the one hand, we found no evidence that supports a significant association between IL23R polymorphism and the combined genotypes of these three genes and the colorectal cancer treatment. On the other hand, we showed that there is an important interaction between IL17A/IL17F polymorphisms and the stage of the disease as well as its treatment. Finally, patients with IL17F wild type genotype highlighted that there is a valid longer OS without all treatments and with radiotherapy and a neoadjuvant chemotherapy. In contrast, we observed that there are no relationships between IL17A, IL23R and the survival of these patients neither with nor without the treatment. Our results suggest that polymorphisms in IL17A and IL17F genes may be a predictive source of colorectal cancer therapy type. Therefore, IL17F may serve as an independent prognostic factor for overall survival in patients with colorectal cancer.

Background: Pancreatic ductal adenocarcinoma (PDAC) and ampullary adenocarcinoma (AAC) are 2 gastrointestinal cancers that share overlapping symptoms. Although some studies have proposed the hypothesis of differences in pathogenesis and prognosis in these 2 cancers; they remain treated similarly. The classification of AAC into three subtypes [pancreatobiliary (PB), intestinal (IT) and mixed (M)] is especially crucial for the 3 axes of patients management (diagnosis, prognosis and therapy). Some studies suggest that PB subtype pathogenesis is comparable to PDAC. The objective of this study was to conduct a comparative analysis between PDAC and AAC; notably PB subtype; via mutational status analysis of 3 oncogenes (KRAS, NRAS and BRAF) hoping to consolidate AAC biology understanding. Methods: Nine hot spot mutation sites of KRAS, NRAS and BRAF were analysed using pyrosequencing in 39 PDAC and 21 AAC from Tunisian patients. Comparative study was performed using SPSS software. Results: Mutations in oncogenes were detected in almost 43% of AAC, especially in PB (47%) and 95% of PDAC. KRAS was the most mutated oncogene. There were statistical significant differences between PDAC and AAC in tumor differentiation (P<0.001), perineural invasion (P<0.001), vascular emboli (P=0.001), T stage (P=0.007), N stage (P=0.001) and mutational status (P<0.001). When comparing PDAC and PB subtype, there were also significant differences in tumor size (P=0.001), tumor differentiation (P<0.001), perineural invasion (P<0.001), vascular emboli (P=0.001), T stage (P=0.033), N stage (P<0.001) and mutational status (P<0.001). Conclusions: AAC even PB subtype is different from PDAC. We think that these different tumor types require highly individualized therapy guided by their histomolecular characteristics and that we should stop diagnosing and treating them as a unique entity.

Autism has been reported in untreated patients with phenylketonuria. The authors aimed to explore autism in 15 Tunisian and 4 Algerian phenylketonuria patients, and report their clinical, biochemical and molecular peculiarities. The Childhood Autism Rating Scale and the Autism Diagnostic Interview-Revised were used for the diagnosis of autism. Five exons of phenylalanine hydroxylase gene (7, 6, 10, 11, and 5) were amplified by polymerase chain reaction and directly sequenced. Among these patients, 15 were suffering from autism at the time of evaluation. Six mutations were identified: p.E280K, p.G352Vfs, IVS10nt11, p.I224T, p.R261Q, and p.R252W. There was no correlation between autism and mutations affecting the phenylalanine hydroxylase gene, but the age of diet onset was the determining factor in autistic symptoms' evolution.

Background: Ampullary carcinomas are rare and dominated by adenocarcinomas. They account for only 0.5% of all gastrointestinal malignancies. Ampullary adenocarcinoma (AAC) with pancreaticobiliary (PB) histology has a worse outcome than that with intestinal (IT) histology. The mixed subtype contains the two epitheliums. This subclassification remains a challenge for pathologists and induces a reasonable level of disagreement. Genetic features of these subtypes are unclear. In this study, we aimed to reclassify AAC cases then to evaluate differences in prognostic, pathological and molecular parameters including mutational status of three oncogenes between these subtypes. Methods: AACs from 21 Tunisian patients were used in this study. Reclassification was made based on histology and immunohistochemistry (IHC) using CK7, CK20, MUC1 and MUC2. Mutational analysis included the pyrosequencing of KRAS, NRAS and BRAF. Results: Fifteen cases were PB subtype, 2 cases were IT subtype and 4 cases were mixed subtype. CK20 and MUC2 were associated with N stage, MUC1 and histomolecular subtype with T stage. Nine cases were mutated and 12 were wild-type. Eight cases were KRAS mutated (5 G12D and 3 G12V). Only 1 case was NRAS mutated (G12D). No BRAF mutation was found. Genetic alterations didn't influence prognostic factors. Conclusions:We validate the prognostic utility of AAC histomolecular classification.

No abstract

AbstractObjectivesWe investigated the quality of life (QOL) in parents of children with late treated phenylketonuria (PKU) and its associated factors.MethodsWe conducted a cross sectional study in the reference center of inherited metabolic disease in Tunisia. We used the Tunisian version of the 36-item short-form health survey questionnaire (SF-36). We compared variables in the groups with and without impaired QOL and the SF-36 scores between subgroups of parents and children and between our sample and the Tunisian general population based on published data. We looked for associations between SF-36 scores and quantitative variables. Linear regression and logistic binary regression were used for multivariate analysis.ResultsSixty-five parents from 42 families participated. QOL was impaired in 61% of them. The mean SF-36 score was 55.3 ± 25.07. The physical component sub-score was higher than that reported in the Tunisian general population (63.66 ± 27.77 vs. 50.11 ± 8.53; p<0.001). The mental component sub-score was comparable to that reported in the Tunisian general population (46.99 ± 25.94 vs. 47.96 ± 9.82; p=0.830). Gender (mothers) (p=0.008), low monthly income (p = 0.027), low education (p=0.011), and autism in PKU children (p = 0.001) were associated with impaired QOL.ConclusionsWe identified at risk parents for altered quality of life among parents of PKU children. Our findings were used to develop a psychological and social support strategy for at-risk parents and to promote the implementation of newborn screening of this treatable disease in our low-income country.

No abstract