One to 3% of gastric cancers are secondary to genetic predisposition, notably hereditary diffuse gastric cancers (HDGC) caused by CDH1 gene mutations. According to French recommendations, in case of CDH1 gene mutation, a prophylactic total gastrectomy should be performed between 20 and 30 years old. This gastrectomy should remove all the gastric mucosa at both extremities (duodenal and esophageal sides). Histopathological examinations of prophylactic total gastrectomies in asymptomatic CDH1-mutated patients reveal microscopic foci of diffuse-type cancer in 90 to 100% of cases. Lymph node involvement and lympho-vascular invasion are extremely rare, justifying the use of a D1-only lymphadenectomy. In the context of prophylaxis, limited lymphadenectomy and the development of minimally invasive oesogastric surgery, the minimally invasive approach might be the preferred approach, in expert centers. Surgical outcomes seem to be similar to those after gastrectomy for cancer. Prophylactic total gastrectomy is the cornerstone of CGDH management, associated with multidisciplinary follow-up and mammary surveillance in women.

Renal cell carcinomas (RCC) represent a group of heterogeneous tumors whose classification has greatly evolved since 1981. The latest update in 2022 classifies all renal cell carcinomas into six categories according to their morphology or the detection of specific molecular alterations. Molecular disassembly of renal cell carcinomas with papillary features has enabled the identification of new entities characterized by a specific molecular alteration, such as Fumarate Hydratase (FH) deficient RCC, TFE3-rearranged RCC or TFEB-altered RCC. This new classification allows for a more accurate diagnosis but requires a thorough knowledge of the genomic alterations to search for with immunohistochemical or molecular biology techniques. According to the new WHO 2022 classification, papillary renal cell carcinoma (PRC) type 1 or type 2 classification is no longer recommended. A classification based on nucleolar ISUP grade must be preferred: low-grade PRC (ISUP 1-2) or high-grade PRC (ISUP 3-4). The other prognostic factors remain the same: the pTNM stage, lymphovascular invasion, and the presence or absence of dedifferentiated areas referring to sarcomatoid or rhabdoid features. Of note, the presence of necrosis is not currently recognized as a poor prognostic element for this type of carcinoma. The diagnosis of high-grade PRC is from now on a diagnosis of exclusion. It can only be sustained after having ruled out TFE3-rearranged RCC, TFEB-altered RCC, and FH-deficient RCC. For clinicians, the diagnosis of PRC implies suggesting an oncogenetic consultation to screen for an associated genetic tumor syndrome regardless of the patient's age.

Cancer is an inevitable collateral problem inherent in the evolution of multicellular organisms, which appeared at the end of the Precambrian. Faced to this constraint, a range of diverse anticancer defenses has evolved across the animal kingdom. Today, investigating how animal organisms, especially those of large size and long lifespan, manage cancer-related issues has both fundamental and applied outcomes, as it could inspire strategies for preventing or treating human cancers. In this article, we begin by presenting the conceptual framework for understanding evolutionary theories regarding the development of anti-cancer defenses. We then present a number of examples that have been extensively studied in recent years, including naked mole rats, elephants, whales, placozoa, xenarthras (such as sloths, armadillos and anteaters) and bats. The contributions of comparative genomics to understanding evolutionary convergences are also discussed. Finally, we emphasize that natural selection has also favored anti-cancer adaptations aimed at avoiding mutagenic environments, for example by maximizing immediate reproductive efforts in the event of cancer. Exploring these adaptive solutions holds promise for identifying novel approaches to improve human health.

Lung cancer is the first cancer-related cause of death worldwide. This is in partially due to therapeutic resistance, which occurs in around 70% of patients, especially those receiving platinum salts, the gold-standard chemotherapy. The massive deregulation of alternative transcript splicing processes observed in many cancers has led to the development of a new class of pharmacological agents aimed at inhibiting the activity of the splicing machinery (spliceosome). The molecular mechanisms by which these inhibitors act remain largely unknown, as do the benefits of using them in combination with other therapies. In this context, our work is focused on an inhibitor of the SRPK1 kinase, a major regulator of the spliceosome.

Polycythemia is suspected when hemoglobin and/or hematocrit levels exceed established norms based on gender and age. This biological anomaly can arise from a myeloproliferative neoplasm known as polycythemia vera, or be secondary to excess erythropoietin (EPO) or decreased in plasma volume. Faced with polycythemia, the search for JAK2 mutations and measurement of serum EPO levels can guide toward the etiology. In polycythemia vera, thromboembolic events are the most lethal complications and unfortunately often the initial manifestation of the disease. The condition can also progress to myelofibrosis or acute leukemia. Management aims at reducing the hematocrit below 45 %, in order to limit, but not completely prevent, thrombo-embolic complications. This article elaborates on the clinical considerations around this biological anomaly, relevant complementary examinations, and briefly the therapeutic management.

In recent years, several nasal cavity and sinus entities have been described with fusion genes. Salivary gland tumors with fusion genes will not be discussed in this article, but it should be kept in mind that accessory salivary glands are present in the nasal cavity and sinuses and can therefore lead to tumoral lesions. Entities with specific or more frequently described rearrangements in the nasal cavities and sinuses are DEK::AFF2 squamous cell carcinomas,;non-intestinal and non-salivary nasosinusal adenocarcinomas, some of which displaying ETV6 gene rearrangements; biphenotypic nasosinusal sarcomas, most of which displaying PAX3 gene rearrangements; and Ewing's adamantinoma-like sarcomas, which display the same rearrangements as conventional Ewing's sarcomas, mainly the EWSR1::FLI1 rearrangement. Each entity will be described morphologically, immunohistochemically, and prognostically.

Salivary gland tumors represent a diagnostic challenge for pathologists due to their rarity, their very wide histopathological and immuno-phenotypic spectrum, and the recent identification of new entities. This article presents the main molecular characteristics of these tumors in order to allow any pathologist to perceive the diagnostic tracks of these ENT tumors and to better guide the molecular approach to establish the diagnosis and guide therapy.

The neuroepithelial tumor with PATZ1 fusion is a recently described tumor type, at the border between central nervous system and mesenchymal tumors. The histopathological diagnosis of this neoplasm, not recognized by the 2021 WHO classification, is challenging due to its varied and non-specific morphologic features. Most cases are densely cellular with monomorphous nuclei. Perivascular pseudo-rosettes of the ependymal type and astroblastic features are frequent. Blood vessels may be hyalinized. The tumor may display low- or high-grade features. OLIG2 and GFAP are variably expressed. Guided by DNA methylation profiling, a pathologist aware of this tumor type will search for a fusion involving PATZ1 and EWSR1 or MN1. The physiopathology of neuroepithelial tumor with PATZ1 fusion is not fully understood. The prognosis appears to align with that of intermediate-grade tumors but follow-up data are scarce. The therapeutic management is often similar to that of high-grade neoplasms. Nonetheless, PATZ1 fusion is a potential therapeutic avenue that may lead to personalized and less aggressive treatments.

In some tumoral subtypes chromosomal translocations lead to an oncogenic chimeric protein acting as a tumorigenesis driver event. The main fusion model combines the promoter swapping of an inactivated tumor suppressor gene and a functional kinase that evades its regulatory system. The range of described fusions keeps growing in the 2023 WHO classification of melanocytic tumours. It is not limited to the group of Spitz tumours as previously but now extends to blue tumours and dermal tumours with a melanocytic phenotype. Molecular pathology helps detect these anomalies using clinical and morphological features. This analysis is essential as this strongly conditions the adapted local treatment of such tumours who are often overtreated.

Oral Squamous cell carcinoma represent the 17th most frequent cancer in the world. The main risk factors are alcohol and tobacco consumption but dietary, familial, genetic, or oral diseases may be involved in oral carcinogenesis. Diagnosis is made on biopsy, but detection remains late, leading to a poor prognosis. New technologies could reduce these delays, notably Artificial Intelligence and the quantitative evaluation of salivary biological markers. Currently, management of oral cancer consists in surgery, which can be mutilating despite possible reconstructions. In the future, immunotherapies could become a therapeutic alternative and the immune microenvironment could constitute a source of prognostic markers.

The spectrum of childhood leukemia predisposition syndromes has grown significantly over last decades. These predisposition syndromes mainly involve CEBPA, ETV6, GATA2, IKZF1, PAX5, RUNX1, SAMD9/SAMD9L, TP53, RAS-MAPK pathway, DNA mismatch repair system genes, genes associated with Fanconi anemia, and trisomy 21. The clinico-biological features leading to the suspicion of a leukemia predisposition are highly heterogeneous and require varied exploration strategies. The study of the initial characteristics of childhood leukemias includes high-throughput sequencing techniques, which have increased the frequency of situations where a leukemia predisposing syndrome is suspected. Identification of a leukemia predisposition syndrome can have a major impact on the choice of chemotherapy, the indication for hematopoietic stem cell transplantation, and screening for associated malformations and pathologies. The diagnosis of a predisposition syndrome can also lead to the exploration of family members and genetic counseling. Diagnosis and management should be based on dedicated and multidisciplinary care networks.

Breast oncology genetics emerged almost 30 years ago with the discovery of the BRCA1 and BRCA2 genes. The evolution of analytical practices has progressively allowed access to tests whose results now have a considerable impact on the management of both female and male breast cancers. The Sénologie commission of the Collège national des gynécologues et obstétriciens français (CNGOF) asked five specialists in breast surgery, oncology and oncological genetics to draw up a summary of the oncogenetic testing criteria used and the clinical implications for the female and male population of the test results, with or without an identified causal variant. In the case of proven genetic risk, surveillance, risk-reduction strategies, and the specificities of surgical and medical management (with PARP inhibitors in particular) were updated.

Systematic screening for pancreatic cancer in high risk individuals is justified by the poor prognosis of the majority of cases diagnosed at a symptomatic stage that are mostly advanced and unresectable Individual risk assessment is based on both genetic data and family history. The screening of a panel of susceptibiility genes should be offered to any affected individual when a genetic predisposition is suspected. An international consortium has proposed a definition of the at risk population, candidate for screening, and there is a consensus on the target lesions of this screening: early adenocarcinoma and benign lesions with a high potential for malignant transformation: Intraductal Papillary Mucinous Neopasm (IPMN) and Pancreatic Intraepithelial Neoplasia (PanIN) with high-grade dysplasia. Its modalities currently consist of an annual pancreatic MRI and/or endoscopic ultrasound (EUS), associated with screening for diabetes mellitus. The main limitation of screening, the effectiveness of which has not yet been demonstrated, is its lack of sensitivity, which results in a non-negligible rate of interval cancers and sometimes advanced diagnoses. Insufficient specificity is also imperfect, in particular with regard to benign lesions with a low potential for degeneration, and can lead to the proposal of unjustified surgeries. This situation makes the future integration of new imaging techniques and promising new biological approaches that are being explored highly desirable.