Tuberous sclerosis is an autosomal dominant genetic disorder that is characterized by epilepsy, mental retardation and facial angiofibromas. Usually, the disease is diagnosed in childhood but there are frustrates form of tuberous sclerosis with or without genetic mutation. This clinical case about a man who is diagnosed a colonic polyposis, a rectal adenocarcinoma and a tuberous sclerosis.

Gliomas are the most common primary brain tumors and include different diagnoses associated with a different prognosis. Histology remains the gold standard for the diagnosis of these tumors. However, pathologists may encounter diagnostic difficulties due to tumor heterogeneity or to the small size of the samples. Recently, major advances in discovery of molecular alterations of these cancers have led to the development of new molecular markers, some with a diagnostic role, others with a prognostic impact and / or predictive of therapeutic response. The testing of different molecular alterations such as 1p / 19q codeletion, mutations of IDH genes, p16 deletion, EGFR amplification or MGMT promoter methylation has been included in the daily practice in order to confirm the diagnosis, assess the patient prognosis and guide treatment choices.

Malignant melanoma is a highly aggressive cancer with a propensity for early metastasis. Melanocyte transformation results predominantly from oncogenic mutations in BRAF, NRAS or NF1 leading to constitutive activation of the MAP kinase pathway driving cell proliferation and second site mutations such as loss of CDKN1A, or PTEN or activating mutations in the beta-catenin pathway that allow escape from oncogene induced senescence. Nevertheless, irrespective of the nature of the driver mutations, melanoma cell physiology is strongly regulated by transcription factors and epigenetic mechanisms. MITF (Microphthalmia-associated Transcription Factor) and SOX10 are two major transcription factors that regulate both normal melanocyte and melanoma cell physiology. Using a combination of mouse genetics, biochemistry and high throughput genomics we have identified cofactors for MITF and addressed the mechanisms by which MITF, SOX10 and their cofactors regulate gene expression in melanocytes and melanoma.

Renal cell carcinoma is a rare pediatric malignant tumor of the kidney. Unlike Wilms tumor, the efficacy of chemotherapy and radiation therapy in pediatric renal cell carcinoma remains uncertain. Surgery is the best treatment and prognosis is favorable when the tumor is localized and completely eradicated. We report an exceptional observation in a 7-year-old girl with renal cell carcinoma who had been treated 20 months previously for Ewing sarcoma with chemotherapy and radiotherapy. The renal tumor was revealed by abdominal pain without hematuria. She underwent a radical nephrectomy, and histopathology concluded in renal carcinoma associated with translocation Xp 11.2 grade 3 of Furhrman pT3a N1. No adjuvant therapy was given. After 3 years of follow-up, there is no evidence of local or metastatic recurrence. This observation is significant given the very young age of this patient, the occurrence after Ewing sarcoma with a short disease-free interval. It seems that translocation renal cell carcinoma is associated with previous exposure to chemotherapy, particularly topoisomerase II inhibitors or alkylating agents.

Retinoblastoma is the most common intraocular malignancy of infancy with an incidence of 1/15,000 births. Sixty percent of retinoblastomas are unilateral, with a median age at diagnosis of 2 years, and in most cases they are not hereditary. Retinoblastoma is bilateral in 40% of cases, with an earlier median age at diagnosis of 1 year. All bilateral and multifocal unilateral forms are hereditary and are part of a genetic cancer predisposition syndrome. All children with a bilateral or familial form, and 10-15% of children with a unilateral form, constitutionally carry an RB1 gene mutation. The two most frequent symptoms at diagnosis are leukocoria and strabismus. Diagnosis is made by fundoscopy, with ultrasound and magnetic resonance imaging (MRI) contributing both to diagnosis and assessment of the extension of the disease. Treatment of patients with retinoblastoma must take into account the various aspects of the disease (unilateral/bilateral, size, location), the risks for vision, and the possible hereditary nature of the disease. The main prognostic aspects are still early detection and adapted coverage by a multidisciplinary, highly specialized team. Enucleation is still often necessary in unilateral disease; the decision for adjuvant treatment is made according to the histological risk factors. The most important recent therapeutic advances concern conservative treatment, which is proposed for at least one of the two eyes in most bilateral cases: laser alone or in combination with chemotherapy, cryotherapy, or brachytherapy. Recently, the development of new conservative techniques of treatment, such as intra-arterial selective chemotherapy perfusion and intravitreal injections, aims at preserving visual function in these children and decreasing the number of enucleations and the need for external beam radiotherapy. The vital prognosis related to retinoblastoma is now excellent in industrialized countries, but long-term survival is still related to the development of secondary tumors, mainly secondary sarcoma. Retinoblastoma requires multidisciplinary care as well as a long-term specialized follow-up. Early counseling of patients and their family concerning the risk of transmission of the disease and the risk of development of secondary tumors is necessary.

The "liquid biopsy" approach shows promise for characterization and monitoring of cancer during treatment; however a blood-based detection test for "high-risk" but asymptomatic individuals, recently introduced by Pathway Genomics, lacks supporting data and has no proven clinical utility.

Adult medulloblastoma is a rare disease. Characteristics which are different from those of the pediatric population have been reported in recent years: a more frequent localization in the cerebellar hemispheres, higher proportion of the desmoplastic subtype, lower incidence of metastatic spread and delayed recurrences. It is probable that these differences are a consequence of specific cytogenetic and molecular characteristics distinguishing the two populations. A number of prognostic factors have been described in the adult population such as age, gender, histopathology, residual disease after surgery, M stage. However, the increased presence of activating mutations in the Sonic Hedgehog cell pathway, and to a lesser degree in the Wingless pathway, may explain the clinical discrepancies. Also, differences in the cytogenetic profile such as the loss of 10q and gain of 17q seem to play a critical role in the prognosis of these patients. It is obvious that knowledge of oncogene amplifications and cytogenetic markers is the key to the future management of medulloblastomas. Molecular inhibitors targeting cell signaling pathways that are activated in medulloblastoma will play an increasing role in future trials.

Promoter methylation of the MGMT gene, encoding the enzyme O6-methylguanine-ubiquitous methyltransferase, is a theranostic good prognosis marker of glioblastomas treated with alkylating chemotherapy (temozolomide, Temodal(®)). Among the methylation analysis techniques, pyrosequencing is a reproducible and sensitive quantitative method. As part of the accreditation of the hospital platform of molecular genetics of cancer, Besançon, our objective was to verify the performance of the pyrosequencing commercial kit therascreen(®) MGMT Pyro(®) (Qiagen) in terms of repeatability, reproducibility, limit of blank (LOB), limit of detection (LOD), linearity and contamination by the guide SH GTA 04 delivered by the Cofrac. The repeatability tests show an average methylation of 3.22% [standard deviation (SD) = 0.41, coefficient of variation (CV) = 12.75%] for the unmethylated control and 70.16% (SD = 2.20, CV = 3.14%) for the methylated control. Reproducibility demontrates an average methylation of 1.39% (SD = 0.25, CV = 18.25%) for the unmethylated control and of 94.03% (SD = 2.56, CV = 2.73%) for the methylated control. The percentages of LOB and LOD are respectively 3.43% and 6.22% methylation. The regression coefficient of 0,983 confirms the linearity of the assay from 0% to 100% methylation. No contamination has been observed. Over 40% of glioblastomas studied in 2013 in our laboratory have shown a methylated MGMT gene. Our results confirms that the theraScreen(®) MGMT Pyro(®) kit (Qiagen) is performant in compliance with the quality requirements of the NF EN ISO 15189 for the routine analysis of methylation status of MGMT in glioblastomas.

Bladder cancer is the sixth cause of cancer mortality in France and prognosis of muscle-invasive tumors remains poor due to lack of effective treatments. Recent advances in molecular biology applied to tumors and results of recent genome-wide studies have brought a important impact on the understanding of bladder carcinogenesis. Main molecular alterations concern FGFR3, TP53 and HER2, and it is now possible to distinguish three subgroups of tumors according to molecular profile. This paper proposes a review of different genetic and epigenetic alterations in bladder cancer, their potential role as theranostic markers in clinical oncology and new targeted therapies according to the concept of personalized medicine.

Around 4% of advanced non-small cell lung cancers (NSCLC) harbor a ALK rearrangement, with high sensitivity to ALK inhibitor as crizotinib. However, the vast majority of these tumors end with a tumor progression after several months of treatment with crizotinib. Ceritinib is a 2nd generation ALK inhibitor, which showed high efficiency in NSCLC with ALK rearrangement. Results from phase I trial showed a response rate at 58% in these tumors, with a similar rate for previously crizotinib-treated patients or crizotinib-naïve patients. Moreover, cerebral responses were observed with ceritinib. Preliminary date from a phase 2 trial confirmed these results. These promising results allowed a European marketing authorization (autorisation de mise sur le marché [AMM]) since May 2015 for the treatment of advanced NSCLC with ALK rearrangement and resistance or intolerance to crizotinib.

The gastro-intestinal neuroectodermal tumor (GNET) is a rare sarcoma of the digestive tract, which was recently recognised. The knowledge of the morphological, immunohistochemical and molecular diagnostic criteria is necessary to not mistake it for the metastasis of a melanoma or for another sarcoma of the digestive tract as the gastro-intestinal clear cells sarcoma or the malignant peripheral nervous system tumor (MPNST). We report the case of a 41-year-old patient with a GNET of the small intestine with hepatic metastasis. The histological examination showed a diffuse proliferation of epithelioid cells, which only express PS100. The presence EWSR1-ATF1 gene fusions with any melanocytic differentiation leads to the diagnosis of GNET.

The 21-gene assay (Oncotype DX(®)) test is used to estimate the risk of recurrence and to predict the benefit of adjuvant chemotherapy at an early stage of endocrine responsive breast cancers, without HER2 overexpression or amplification. This test corresponds to a recurrence score (RS), classifying patients into three groups (low, intermediate or high risk). The objective of this two-center prospective study is to define the impact of Oncotype DX(®) in clinical practice.

Cytochrome P450 2E1 (CYP2E1) is a detoxifying enzyme that belongs to the phase I metabolism of xenobiotics. This enzyme is encoded by a highly polymorphic gene whose common polymorphism corresponds to the substitution of cytosine (C) and thymine (T) at position -1019 (rs2031920). This polymorphism has been identified in several cancers including nasopharyngeal cancer (NPC). The study involved 124 patients with nasopharyngeal carcinoma, compared with 166 healthy controls. The presence or absence of the polymorphism is determined by PCR-RFLP. The frequency comparison between the two groups is determined by the χ(2) test. The analysis of our results showed a significant difference between the two groups regarding the mutant genotype (C2/C2) (5% vs. 0.5%, P=0.04) and has a risk factor for NPC in Tunisia (OR=8.39; CI 95% [0.99-388.1]). Also, the C2 allele was significantly associated with the group of patients than the control group (6% vs. 2%, P=0.016) and increased three times the risk of NPC in Tunisia (OR=2.99, CI 95% [1.12-8.79]). Our results confirm the results reported in other populations and emphasize the importance of the involvement of this gene in the development of detoxification of the NPC, which seems more and more strongly associated with environmental factors.

Peripheral T-cell lymphomas (PTCL) belong to the group of non-Hodgkin lymphoma and particularly that of mature T /NK cells lymphoproliferative neoplasms. The 2008 WHO classification describes different PTCL entities with varying prevalence. With the exception of histologic subtype "ALK positive anaplastic large cell lymphoma", PTCL are characterized by a poor prognosis. The mechanisms underlying the pathogenesis of these lymphomas are not yet fully understood, but development of genomic high-throughput analysis techniques now allows to extensively identify the molecular abnormalities present in tumor cells. This review aims to summarize the current knowledge and recent advances about the molecular events occurring at the origin or during the natural history of main entities of PTCL. The first part published in the October issue was focused on the three more frequent entities, i.e. angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma, not otherwise specified, and anaplastic large cell lymphoma. The second part presented herein will describe other subtypes less frequent and of poor prognosis : extranodal NK/T-cell lymphoma, nasal type, adult T-cell leukemia/lymphoma, and enteropathy-associated T-cell lymphoma.

Within the glycerophospholipid family, phosphoinositides, which are minor components of eukaryotic cell membranes, play a critical role as spatiotemporal organizers of cell dynamics. By specifically interacting with proteins, they coordinate the formation and the organization of multiprotein complexes involved in cell signaling, intracellular trafficking and cytoskeleton rearrangement. The highly precise spatiotemporal dynamics of phosphoinositides-regulated mechanisms is ensured by kinases and phosphatases that specifically produce, hydrolyze and control the interconversion of these lipids. The direct implication of these enzymes in human pathologies such as genetic diseases, cancer or infectious pathologies, and the recent arrival of inhibitors targeting some phosphoinositide kinases in clinic, illustrate the mandatory functions of these fascinating lipids.