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.

OBJECTIVE: 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.
METHODS: This summary was based on national and international guidelines on the monitoring and therapeutic management of genetic risk, and a recent review of the literature covering the last five years.
RESULTS: Despite successive technical developments, the probability of identifying a causal variant in a situation suggestive of a predisposition to breast and ovarian cancer remains around 10% in France. The risk of breast cancer in women with a causal variant of the BRCA1, BRCA2, PALB2, TP53, CDH1 and PTEN genes is estimated at between 35% and 85% at age 70. The presence of a causal variant in one of these genes is the subject of different recommendations for men and women, concerning both surveillance, the age of onset and imaging modalities of which vary according to the genes involved, and risk-reduction surgery, which is possible for women as soon as their risk level exceeds 30% and remains exceptionally indicated for men. In the case of breast cancer, PARP inhibitors are a promising new class of treatment for BRCA germline mutations.
CONCLUSIONS: A discipline resolutely focused on understanding molecular mechanisms, screening and preventive medicine/surgery, oncology genetics is currently also involved in new medical/surgical approaches, the long-term benefits/risks of which will need to be monitored.

Malignant mesothelioma is a rare tumour, usually the result of asbestos exposure. Several cases of familial aggregation have been reported and recently shown to be associated with constitutional mutations of the BAP1 gene. BAP1 is a deubiquitinating enzyme implicated in several different cellular mechanisms such as the repair or differentiation of DNA. About a half of malignant mesotheliomas present a somatic, bi-allelic inactivation of BAP1, demonstrated by nuclear extinction on histochemistry. Constitutional alterations of BAP1 are extremely rare. Present in the heterozygous state they are transmitted as an autosomal dominant. They are associated with a risk of developing other tumours such as uveal and cutaneous melanomas, benign melanocytic tumours (melanocytic BAP1-mutated atypical intradermal tumour or MBAITS) and clear cell renal carcinomas. The causal link between mesothelioma and germinal mutations of BAP1 has still not been clearly identified. At present there is, in France, no consensus on recommendations for the management of patients with these mutations. This article is a synthesis of the literature on the functions of the BAP1 gene, the tumour risks related to its alteration and the follow up of patients bearing a constitutional mutation.

Genetic predisposition to prostate cancer rarely corresponds to a high penetrance Mendelian pattern of inheritance. These hereditary forms are specific entities for which mutations in the BRCA2 gene, the HOXB13 gene (variant G84E) or, to a lesser extent BRCA1 gene, must be researched. In contrast, the genetic component of the majority of prostate cancer is polygenic, involving an unfavorable combination of common genetic variants, resulting from a mixture of the genetic inheritance of the father and the mother. One hundred of these genetic susceptibility variants have now been identified and validated. The main phenotypic trait associated with hereditary predisposition is the younger age at onset, which warrants special monitoring in order to stay in the window of curability at diagnosis. The psychological impact of a family history of prostate cancer or breast cancer favors the establishment of a dedicated monitoring and procedures for early diagnosis.

BACKGROUND: Multiple Endocrine Neoplasia Type 1 (MEN1) is an autosomal dominant inherited syndrome, related to mutations in the MEN1 gene. Controversial data suggest that the nonsynonymous p.Ala541Thr variant, usually considered as a non-pathogenic polymorphism, may be associated with an increased risk of MEN1-related lesions in carriers.
OBJECTIVE: The aim of this study was to evaluate the pathogenic influence of the p.Ala541Thr variant on clinical and functional outcomes.
METHODS: We analysed a series of 55 index patients carrying the p.Ala541Thr variant. Their clinical profile was compared to that of 117 MEN1 patients. The biological impact of the p.Ala541Thr variant on cell growth was additionally investigated on menin-deficient Leydig cell tumour (LCT)10 cells generated from Men1+/Men1- heterozygous knock-out mice, and compared with wild type (WT).
RESULTS: The mean age at first appearance of endocrine lesions was similar in both p.Ala541Thr carriers and MEN1 patients, but no p.Ala541Thr patient had more than one cardinal MEN1 lesion at initial diagnosis. A second MEN1 lesion was diagnosed in 13% of MEN1 patients and in 7% of p.Ala541Thr carriers in the year following preliminary diagnosis. Functional studies on LCT10 cells showed that overexpression of the p.Ala541Thr variant did not inhibit cell growth, which is in direct contrast to results obtained from investigation of WT menin protein.
CONCLUSIONS: Taken together, these data raise the question of a potential pathogenicity of the p.Ala541Thr missense variant of menin that commonly occurs within the general population. Additional studies are required to investigate whether it may be involved in a low-penetrance MEN1 phenotype.