Fumarate hydratase deficient renal cell carcinoma (FH-RCC) is a rare malignant neoplasia caused by constitutive or somatic mutations in the FH gene whose diagnosis is primordial, requiring genetic counselling. Because of histological heterogeneity, such tumors have been in the past misclassified as "type 2 papillary carcinoma", "tubulo-cystic renal cell carcinoma" or "high grade papillary carcinoma". We report here a case of FH deficient renal cell carcinoma (FH-RCC) in a 69years old patient. Through this observation, we precise the epidemiological and histological aspects and diagnosis criteria of this rare tumor.

The cytoplasmic histone deacetylase 6 (HDAC6) is defined today as a new key player in the treatment of many diseases. Overexpression of HDAC6 was observed in a variety of diseases. Over the past ten years, plenty of new selective inhibitors of HDAC6 activity have been synthesized and characterized. Many studies have shown the high efficiency and beneficial effects of HDAC6 inhibitors in many diseases such as cancers, neurodegenerative, inflammatory, or neuromuscular diseases. The mechanisms of HDAC6 action that explain the benefit of its inhibition in various pathologies are still unknown. We have recently shown that HDAC6, via the regulation of the microtubule network, plays a role at the level of neuromuscular junctions by controlling acetylcholine receptor delivery.

Following the CodeBreak 100 study, since 2021 sotorasib has been available in France, with authorization for early access in treatment of non-small cell lung cancer with a KRAS G12C mutation. Our retrospective observational study was designed to determine the efficacy and safety of sotorasib under real-life conditions in patients treated at the Tours CHRU. Our study of 15 patients showed sotorasib to be effective in 47% of cases, with overall survival of 4 months and median progression-free survival of 5.5 months for responders. Tumor control was achieved in 7/8 (87%) of patients with PS of 0 or 1 and in 1/7 (14%) of patients with a PS of 2 or greater. Grade 3 acute hepatitis occurred in 3/15 patients (20%). While sotorasib is an interesting therapeutic option, with efficacy that seems better in patients in good general condition, it entails a possible risk of drug-induced hepatitis, which remains to be specified in dedicated studies.

Advanced cholangiocarcinoma and gene fusions Cholangiocarcinomas (CCAs) are rare digestive tumors classified as intrahepatic (iCCA), perihilar (pCCA), and distal (dCCA) CCAs. These tumors are most often diagnosed at an advanced stage, unresectable or metastatic, and associated with a poor prognosis. The identification in recent years of multiple molecular alterations of interest, particularly in iCCA, has nevertheless allowed the development of new targeted therapeutic options for a significant proportion of patients. Gene fusions are among the most frequent alterations, involving FGFR2 in 10-15% of iCCAs in particular, and NTRK genes at a lower frequency (<1%). A dedicated analysis, most often based on RNA sequencing, is required to identify such alterations. Three FGFR inhibitors, pemigatinib, infigratinib and futinatinib, have recently received FDA approval for use in pre-treated patients. These compounds are currently being evaluated as first-line therapy in several phase III trials. Promising results have also been reported with new-generation inhibitors such as RLY-4008, which may soon constitute new therapeutic options. In the case of NTRK fusion, larotrectinib and entrectinib have also demonstrated their efficacy. The objectives of this review are to clarify the specific diagnostic modalities for gene fusions and to summarize the results of the main trials and developments underway for the management of advanced CCA with gene fusions.

RISK AND PROTECTIVE FACTORS FOR COLORECTAL CANCER Behaviour and environment play a more important role than heredity in colorectal carcinogenesis. The proportion of colorectal cancers (CRCs) attributable to occupational exposure, pollution or poor socio- economic status is low. The risk levels on which the French CRC screening recommendations are based are obsolete and need to be updated. An individual with one or two non-advanced adenomas resected at colonoscopy is at low risk of CRC. Only a first-degree family history of CRC in one parent before age 50 or in two parents at any age confers a significant increased risk. Certain diseases or situations that are sources of an increased risk of CRC were not previously considered: cystic fibrosis, radiotherapy and paediatric cancer survivors. New inherited predisposition syndromes associated with a very high risk of CRC have been described in addition to Lynch syndrome and familial adenomatous polyposis: MUTYH-associated polyposis, constitutional MMR deficiency, Lynch-like, PPAP and X syndromes. Half of all CRCs are related to modifiable risk factors associated with westernized lifestyle such as physical inactivity, junk food and obesity. There is nothing specific about dietary recommendations for the primary prevention of CRC: physical activity, limitation of red and processed meat, increase in dietary fibre and dairy products, limitation of alcohol and avoidance of tobacco. Finally, it is premature to use aspirin in primary prevention of CRC outside of Lynch syndrome and associated significant cardiovascular risk.

MICROSATELLITE INSTABILITY IN ENDOMETRIAL CANCERS The microsatellite instability reflects genetic instability that can be sought in tumors, using two methods, immunohistochemistry and molecular biology. Currently in France, a systematic evaluation of microsatellites is recommended in any endometrial cancer from diagnosis. The interest of this evaluation is threefold: diagnostic, prognostic and therapeutic. The presence of microsatellite instability in endometrial cancer allows to detect Lynch syndrome, a hereditary cancer predisposition syndrome, in some patients. The microsatellite status is essential for establishing the molecular classification of endometrial cancers, a classification which has a well-established prognostic value, and finally it determines the eligibility for immunotherapy.

Review of literature shows that it is possible to establish tumor-derived organoids, or tumoroids, from almost any type of tumor, and that these "micro-tumors" could be used to develop functional assays allowing the prediction of the patient response to treatments and/or the identification of predictive molecular signatures associated with the development of these therapies. Although it is still essential to optimize culture conditions to promote and accelerate the establishment of tumoroids, or to recapitulate tumor microenvironment, many applications are now possible in the field of prediction of response to treatments and in guiding therapeutic decision-making. Using tumoroids as standard tools in clinical oncology could make precision oncology enter a new era in the coming decade. Numerous ongoing research and clinical trials conducted throughout the world aim to validate the interest of this approach.

HR+ breast cancers are defined by the prominence of signaling pathways dependent on the estrogen receptor. Endocrine therapy is the standard treatment for these advanced diseases. Resistance to these treatments, called hormone resistance, appears invariably with biological mechanisms that have led to the development of therapeutic opportunities. An exhaustive literature review was carried out concerning the biology of the hormone resistance pathways, the therapeutic options before the era of CDK4/6 inhibitors, the rise of CDK4/6 inhibitors and the therapeutic prospects in a situation of hormone resistance. Various biological abnormalities have been identified in the mechanisms of hormone resistance such as changes in the estrogen receptor, mutations in the ESR1 gene, aberrant activation of the PI3K pathway or cell cycle deregulations. Historical strategies for circumventing this hormone resistance have been based on hormonal manipulation, on the development of new endocrine therapy such as fulvestrant (selective estrogen receptor inhibitor, SERD), on combinations of treatments such as everolimus, a mTOR inhibitor. This strategy combining endocrine therapy and targeted therapy has led to the development of combinations with CDK4/6 inhibitors which have now become a standard treatment in the hormone resistance phase. The future of this therapeutic era remains to be written with new combinations of hormone therapy and targeted therapy such as PI3K inhibitors or even with the positioning of new SERDs in clinical development.

The advent of new technologies has made it possible to identify genetic predispositions to myelodysplastic syndromes (MDS) and acute leukemias (AL) more frequently. The most frequent and best characterized at present are mutations in CEBPA, RUNX1, GATA2, ETV6 and DDX41 and, either in the presence of one of these mutations with a high allelic frequency, or in the case of a personal or family history suggestive of blood abnormalities such as non-immune thrombocytopenia, it is recommended to look for the possibility of a hereditary hematological malignancy (HHM). Indeed, early recognition of these HHMs allows better adaptation of the management of patients and their relatives, as allogeneic hematopoietic stem cell transplantation (HSCT) is very often proposed for these pathologies. According to current data, with the exception of the GATA2 mutation, the constitutional or somatic nature of the mutations does not seem to influence the prognosis of hematological diseases. Therefore, the indication for an allograft will be determined according to the usual criteria. However, when searching for a family donor, it is important to ensure that there is no hereditary disease in the donor. In order to guarantee the possibility of performing the HSC allograft within a short period of time, it may be necessary to initiate a parallel procedure to find an unrelated donor. Given the limited information on the modalities of HSC transplantation in this setting, it is important to assess the benefit/risk of the disease and the procedure to decide on the type of conditioning (myeloablative or reduced intensity). In view of the limited experience with the risk of secondary cancers in the medium and long-term, it may be appropriate to recommend reduced intensity conditioning, as in the case of better characterized syndromic hematological diseases such as Fanconi anemia or telomere diseases. In summary, it seems important to evoke HHM more frequently, particularly in the presence of a family history, certain mutations or persistent blood abnormalities, in order to discuss the specific modalities of HSC allografting, particularly with regard to the search for a donor and the evaluation of certain modalities of the procedure, such as conditioning. It should be noted that the discovery of HHM, especially if the indication of an allogeneic HSC transplant is retained, will raise ethical and psychological considerations not only for the patient, but also for his family. A multidisciplinary approach involving molecular biologists, geneticists, hematologists and psychologists is essential.

Multiple endocrine neoplasia (MEN) are genetic predisposition syndromes to endocrine tumors including MEN1, MEN2 and exceptionally MEN4. MEN are transmitted in an autosomal dominant fashion with a high penetrance. Classically, there is no genotype/phenotype correlation for NEM1 whereas this is the case for NEM2. Patients with NEM1, linked to an inactivating mutation of the menin gene, may present with: primary hyperparathyroidism, pituitary adenoma, duodeno-pancreatic neuroendocrine tumors (NETs), bronchial tumors with an increased risk of thymoma, adrenal cortical tumors, an increased risk of breast cancer and characteristic skin involvement such as collagenomas, lentiginomas and an increased risk of skin cancer. These patients require at least annual follow-up. Screening of children is proposed from the age of 5 years. Patients with NEM2, linked to an activating mutation of the RET proto-oncogene, all present with medullary thyroid carcinoma (MTC) at a variable age depending on the genotype. Some patients present a pheochromocytoma (50 %) and hyperparathyroidism (20 %). Pediatric forms with aggressive CMT, ganglioneuromatosis and marfanoid syndrome exist (rare NEM2B). Some mutations are associated with a risk of aggressive CMT, justifying prophylactic thyroidectomy before 6 months of age. The age of genetic testing depends on the mutation subtype in the NEM2 parent. NEM4, related to a mutation in the CDKN1B gene, are rare, with a less well-known pathogenesis and their follow-up is not well codified.

Mutations in the epidermal growth factor receptor (EGFR) gene are commonly observed in non-small-cell lung cancer (NSCLC). Over the past decade, the management of NSCLC-carrying EGFR mutation has evolved considerably with the use of tyrosine kinase inhibitors (TKIs). The main objective of this retrospective study was to analyze the evolution of therapeutic strategies in a cohort of patients with metastatic or locally advanced EGFR- mutated NSCLC.

Waldenström's disease is a B-cell neoplasm characterized by the accumulation of lymphoplasmacytic cells (LPCs) in the bone marrow, and more rarely in the lymph nodes and the spleen, which produce a monoclonal immunoglobulin M (IgM) protein. The diagnosis requires the identification of LPCs in the bone marrow, using specific markers in flow cytometry. The MYD88L265P mutation is found in 95% of cases and the CXCR4 mutation in 30-40% of cases. These markers must be sought because they have a diagnostic and prognostic role, and they might become predictive in the future. The clinical presentation is very variable, and includes anomalies related to the bone marrow infiltration of the LPCs (such as anemia), but also anomalies of the physico-chemical and/or immunological activity of the overproduced IgM (hyperviscosity, AL amyloidosis, cryoglobulinemia, anti-MAG neuropathies, etc.). Prognostic scores (IPSSWM) now make it possible to understand the prognosis of symptomatic WM requiring appropriate treatment. The therapeutic management depends on many parameters, such as the specific clinical presentation, the speed of evolution and of course the age and comorbidities. Immuno-chemotherapy is often the 1st line treatment (rituximab-cyclophosphamide-dexamethasone (RCD) or bendamustine-rituximab (BR)) but the role of targeted therapies is becoming preponderant. Bruton tyrosine kinase inhibitors (BTKi) are used today in first relapse. Other therapeutic perspectives will certainly allow us tomorrow to better understand this incurable chronic disease, such as new generations of BTKi, BCL2 inhibitors, anti-CXCR4, bi-specific antibodies, and CAR-T cells.