In a compatible clinico-radiological setting, the diagnosis of Erdheim-Chester disease (ECD) involves the analysis of histiocytes in tissue biopsies: they are typically foamy and CD68+ CD1a, whereas in Langerhans cell histiocytosis (LCH) they are CD68+ CD1a+. Overlap forms of histiocytoses are frequent. Technetium bone scintigraphy showing nearly constant tracer uptake by the long bones is highly suggestive of ECD and a 'hairy kidney' appearance on abdominal CT scan is observed in more than half ECD cases. CNS involvement is a strong prognostic factor and an independent predictor of death in cases of ECD. Optimal initial therapy for ECD appears to be administration of IFN-α (and/or pegylated IFN-α) and prolonged treatment significantly improves survival; however, tolerance may be poor. Best alternative therapies are anakinra, mainly effective for mild forms of the disease, infliximab, and sirolimus. Cases of ECD present with strong systemic immune activation, involving IFN-α, IL-1/IL1-RA, IL-6, IL-12, and MCP-1, consistent with the systemic immune Th-1-oriented disturbance associated with the disease. Between 57 and 75 % of ECD patients carry the BRAFV600E mutation, an activating mutation of the proto-oncogene BRAF. More than 50 cases harboring BRAF mutation and with severe multisystemic and refractory ECD (sometimes associated with LCH) have been treated worldwide with vemurafenib, a BRAF inhibitor that proved to be very beneficial. Other recurrent mutations of the MAPK (NRAS, MAP2K1) and PIK3 pathways (PIK3CA) have been found among ECD patients. As recurrent mutations in the MAPK pathway are found in ECD and LCH on a background of chronic inflammation, we believe that both conditions should be redefined as an inflammatory myeloid neoplasia.

Usher syndrome is defined by the association of a progressive or non-progressive congenital sensorineural hearing loss with variable severity and a gradually blinding pigmentary retinopathy. Von Recklinghausen neurofibromatosis or Neurofibromatosis type 1 is the major clinically form of neurofibromatosis which occurs in approximately 90% of cases. Both types of disease are genetic in origin with very low prevalence. The probability of co-occurrence of these diseases in a single individual is exceptional. Inbreeding, as well as all genetic diseases, increases quite significantly the probability of their occurrence. Consanguineous marriages are still widespread in Maghreb and in some regions of the western African. This observation reports an exceptional case of this association in a 40-year-old man of Mauritanian origin born from a consanguineous union.

In France, 126 centers for cancer genetics coordinate genetic testing and high-risk cancer surveillance for individuals and their families with hereditary cancer syndromes. Since 2012, the French National Cancer Institute (INCa) supports 17 projects to promote and manage the monitoring of individuals genetically predisposed to cancer. They were assigned 4 missions by INCa including expertise for difficult cases.

The identification of RAS status (KRAS and NRAS) has changed the management of metastatic colorectal cancer (mCRC). The impact of the RAS mutation on cytotoxic chemotherapy efficacy has not yet been determined. Nevertheless, several retrospective studies suggest a greater efficacy of oxaliplatin in mCRC with KRAS mutation.

Breast cancer involves various types of tumors. The objective of this review was to provide a summary of the main methods currently available in clinical practice to characterize breast cancers at a molecular level and to discuss their prognostic and predictive values. Hormonal receptors expression and the HER2 status are prognostic markers and can also predict the response to targeted therapies. Their analysis through immunohistochemistry is systematical. Ki67 is an effective prognostic marker, but its reliability is debated because of its low reproducibility between laboratories and between pathologists. Commercial genomic signatures are all considered valid prognostic tools and may guide physicians to make therapeutic choices. These signatures are costly and should therefore be restricted to situations in which the use of chemotherapy remains equivocal.

A newly established company called Grail and spun out from Illumina promises to develop a "liquid biopsy" test suitable for asymptomatic cancer detection and general screening. While the necessary sensitivity may be attainable through ultra-deep sequencing of plasma DNA, it seems unlikely that the extremely high specificity needed to avoid false positives can be reached. This would defeat the purpose of the test, as it has been realized recently that insufficiently specific tests (prostate specific antigen levels for prostate cancer, and possibly frequent mammography for breast cancer) cause harms that outweigh their benefits.

The identification of an activating mutation of the gene encoding the epidermal growth factor receptor (EGFR) is a predictive factor of effectiveness of tyrosine kinase EGFR inhibitors (TKIs). In advanced stages of the disease, however, this identification is difficult due to the invasiveness of the biopsy and the small size of tumor samples. In that context, liquid biopsies could be useful.

How genomics upsets understanding of adrenal tumors ? Adrenal tumors include pheochromocytomas adenomas, hyperplasia and adrenocortical carcinomas. Recently these tumors have been analyzed by genomic approaches, measuring the molecular variability at a large scale, in the DNA sequence, the gene expression, and in the genome structure. From these works came out : new genes responsible for these tumors, which will enable a more accurate diagnosis, family screening, and liquid biopsies (detection of these mutations in the blood) ; the discovery of two main forms of adrenocortical carcinomas, associated with very different prognoses, that will stratify the treatment of patients; and new mechanisms of tumorigenesis, opening the way to new therapeutic perspectives.

Trisomy 21 (T21) is the most common chromosomal abnormality and one of the main causes of intellectual disability. The tumor profile of T21 patients is characterized by the low frequency of solid tumors including breast cancer.

Since January 16(th) 2010, the French legislation requires that the medical laboratories must be accredited according to ISO 15189 standards. This concerned all the biological medical technics, including molecular biology technics. In this work, we described the validation steps by real time quantitative PCR of L858R mutation in EGFR gene, frequently detected in non-small lung cancers (NSCLC). Epidermal growth factor - tyrosine kinase inhibitors (EGFR-TKIs) are authorized in Europe for the treatment of metastatic NSCLC after failure of, at least one, prior chemotherapy. Thus, in view of accreditation of this analysis, we have used the recommendation of the COFRAC (Comité français d'accréditation) and INCa (Institut national du cancer). Several parameters have been tested, such as the primers, the limit of detection, and the sensitivity and specificity of the method. In addition, a risk study has been evaluated. Although long and fastidious, the method of validation is required to perform analysis in optimal conditions to guaranty optimal results for the patients.

EGFR tyrosine kinase inhibitors and crizotinib are nowadays the optimal treatment for metastatic lung cancer with activation of EGFR mutations and ALK rearrangement. In addition, several targeted agents are in development for lung cancer with other oncodrivers. In France, since 2011, six oncodrivers are routinely tested in patients with stage IV. The aim of this study was to assess whether systematic detection of oncodrivers and matched targeted therapy improve overall survival in patients with advanced lung adenocarcinoma.

Tetraspanins are transmembrane proteins that interact laterally with each other and with different partners such as integrins, immunoglobulin (Ig)-domain-containing proteins, growth factors and cytokine receptors. Such tetraspanin-partner complexes help to organize dynamic membrane networks called "tetraspanin web", which trigger different signalling pathways. Despite the fact that tetraspanins seem abundantly and widely expressed, their function remained unclear. However, it is well established that they control fundamental cellular processes including cell survival, adhesion, migration, invasion or viral infection, but the underlying molecular mechanisms are not well elucidated. This review focuses on tetraspanins that are expressed in epidermis and the roles they play in normal and pathological conditions, specifically in skin cancer.

Diffuse malignant mesothelioma (MMD) is a rare disease. The diagnosis is difficult and needs an antibody panel. The tumor suppressor gene BRCA1 associated protein 1 (BAP1) is involved in several cancers, including MMD. Loss of BAP1 expression is correlated with BAP1 somatic or constitutional genetic defects. Our work assesses the value of integrating BAP1 in the panel of antibodies used for the diagnosis of MMD.

Pharmacokinetics is the link between genetic data and the use of treatments. It can be use on several relevant aspects in the clinic, including the treatment selection, efficacy or toxicity prediction and the choice of the dose. Pharmacogenetics has been applied in clinical nephrology since a long time by the genetic prediction of azathiorpine associated myelotoxicity. However, despite an extensive literature describing the links between genetics and metabolism and transport of drugs, genetic tests are little used in clinical practice. One reason for this poor implementation is the current lack of evidence of improved clinical outcomes with pharmacogenetic tests. In addition, with an effective therapeutic drug monitoring, it is possible to correct the effect of genotype on the pharmacokinetic differences, thus reducing the usefulness of the assay based on the genotype. The future of pharmacogenetics will be treatment models in which patient characteristics are combined with data on polymorphisms in multiple genes including pharmacodynamic parameters, drug transporter proteins, and predictors of toxicity.

Cholangiocarcinoma is a rare malignancy carrying a poor prognosis. Most patients are diagnosed with advanced-stage disease and are then ineligible for surgical resection, which is the only potentially curative therapeutic modality. The aim of this article is to provide an up-to-date review of medical management of patients with cholangiocarcinoma. The benefit of adjuvant therapy in patients undergoing curative-intent surgery is under evaluation. Combination chemotherapy with gemcitabine and platinum is the standard first-line treatment for patients with advanced cholangiocarcinoma. Targeted agents are not currently recommended due to limited data on use in this setting. The role of second-line chemotherapy is not established in advanced cholangiocarcinoma. Identification of predictive and prognostic markers to select patients who could benefit from second-line therapy is a major issue. A better understanding of the biological and molecular mechanisms underlying the carcinogenesis and the phenotypic heterogeneity of cholangiocarcinoma may path the way of new therapeutic strategies.

The ability of cancer cells to recognize damage and initiate DNA repair is an important mechanism for therapeutic resistance. The use of inhibitors of DNA damage repair or signaling pathways appears to provide a unique opportunity for targeting genetic differences between tumor and normal cells. In this review, we firstly describe the main DNA lesions induced by the different treatments and the pathways involved in their repair. Then we review the mechanism of action and applications of an innovative DNA repair inhibitor: Dbait (and its clinical form DT01). Dbait/DT01 consists of 32 bp deoxyribonucleotides forming an intramolecular DNA double helix that mimics DNA lesions. They act as a bait for DNA damage signaling enzymes, the polyadenyl-ribose polymerase (PARP), and the DNA-dependent kinase (DNA-PK), inducing a "false" DNA damage signal and ultimately inhibiting recruitment at the damage site of many proteins involved in double-strand break and single-strand break repair pathways. Preclinical studies have demonstrated the capacity of Dbait/DT01 to improve the efficiency of (i) chemotherapy in colorectal cancer or hepatocellular carcinoma models, (ii) radiofrequency ablative in colorectal cancer liver metastases models, and (iii) radiotherapy in xenografted mice with head & neck squamous cell carcinoma, glioblastoma and melanoma. Following this good preclinical results, we performed a first-in-human phase 1-2a study evaluating the safety and efficacy of the combination of DT01 with radiotherapy for the treatment of skin metastases of melanoma. Twenty-three patients were included. No dose-limiting toxicity was observed. An objective response was observed in 59% lesions, including 30% complete responses. This first promising clinical efficacy provides future potential interesting clinical development of Dbait/DT01 with various anticancer treatments.