Links between gender norms and the intergenerational transmission of health information in parents carrying BRCA1/2 pathogenic variants.

Understanding how gender norms affect parents' communication of genetic and cancer risk information to their children can enable healthcare professionals to better facilitate cascade genetic testing. We conducted a qualitative study with semi-structured interviews to determine social factors associated with parents carrying the BRCA1/2 pathogenic variants who communicated cancer prevention practices to their children. Thirty adult carriers (23 women, 7 men) participated in the interviews. All had at least one child aged over 8 years old. Interview topics included their discovery of the variants, their relationship to their body and to the risk of cancer, as well as disclosure to and subsequent communication with their children after testing positive for BRCA1/2. The interviews were analyzed qualitatively, and the major themes identified were identified and compared. We described the roles played by the BRCA1/2 carriers and their partners in communicating cancer prevention practices to their children, from how they managed their own risk of cancer after testing positive, to how they disclosed the risks linked to these pathogenic variants to their children. We also described their involvement in the process of their children going for professional genetic consultation. Gender norms lead women to be more attentive than men to their own health and that of their loved ones. In the context of the transmission of genetic information to children, gender differences in behavior are reinforced by perceptions of the risks of BRCA1/2 variants and women's related health management practices. Cancer prevention is shaped by complex links between gender norms and health management practices.

[Infant rhabdoid tumors: a diagnostic emergency]. / Tumeurs rhabdoïdes du nourrisson : une urgence diagnostique.

Rhabdoid tumors are a heterogeneous family of aggressive tumors affecting young children. Their grouping within a single entity is recent, following the discovery of a bi-allelic inactivation of the hSNF5/INI1 tumor suppressor gene in tumoral cells. This bi-allelic inactivation of the hSNF5/INI1 gene found at the constitutional level in up to one-third of cases has led to the identification of a predisposal syndrome to rhabdoid tumors. Herein we report extrarenal rhabdoid tumors observed in three infants between 3 and 6 months of age, underlining the misleading feature of the clinical presentation and the aggressiveness of the disease. Finally, we also report the genetic patient care management strategy.

[Genetic predisposition to childhood cancer]. / Oncogénétique en oncopédiatrie.

Tumor predisposition in children is rare, accounting for approximately 10% of all cancers in childhood. Tumor predisposition involves very rare tumors such as pleuropulmonary blastoma, adrenocortical carcinoma, hepatoblastoma, rhabdoid tumors, optic pathway glioma, as well as rare tumors such as retinoblastoma, medulloblastoma, nephroblastoma, or more frequent tumors such as sarcomas, neuroblastoma, and leukemias. The identification of these predispositions is important for improved management for both the child and relatives. Prenatal and preimplantation genetic diagnosis are options that could be considered for young parents in a perspective of future pregnancies. This manuscript describes the main tumor predispositions in childhood. From each histological subtype, the different diagnosis directions are discussed in view of these main tumor predispositions.

Acute lymphocytic leukaemia in a child with Beckwith-Wiedemann syndrome harbouring a CDKN1C mutation.

Beckwith-Wiedemann syndrome (BWS) is a rare overgrowth syndrome associated with an increased risk in childhood tumours. The phenotypic variability in BWS reflects its molecular heterogeneity. This syndrome is a multigenic disorder caused by dysregulation of imprinted growth regulatory genes in the 11p15.5 region. The most commonly reported tumours in this syndrome are tumours of embryologic origin such as Wilms tumours, hepatoblastomas, neuroblastomas, rhabdomyosarcomas and adrenocortical carcinomas. We report the case of a 10-year-old patient diagnosed with BWS, harbouring a CDKN1C (p57(KIP2)) mutation, who developed a T-type acute lymphoblastic leukaemia. To our knowledge it is the first report of an acute lymphoblastic leukaemia of T-type in a child with BWS. We discuss the possibility of a link between BWS and leukaemia via one of the few known negative regulator of hematopoiesis, the transforming growth factor beta pathway, depending upon the up-regulation of CDKN1C.

[Cowden syndrome, or multiple hamartomatous tumor syndrome, in clinical endocrinology]. / Le syndrome de Cowden ou syndrome des hamartomes multiples en endocrinologie clinique.

Cowden syndrome (CS) is the prototypic PTEN hamartoma tumor syndromes (PHTS), rare clinical syndromes characterized by germline mutations of the tumor suppressor PTEN. CS is characterized by association of macrocephaly, facial trichilemmomas, acral keratoses, papillomatous papules, with increased risk for breast, thyroid and endometrial cancer. PTEN, which is located on chromosome 10q23, regulates negatively the prosurvival PI3K/Akt/mTOR pathway through a lipid phosphatase activity. Loss of PTEN activates this pathway and leads to increased cellular growth, migration, proliferation, and survival. CS diagnosis is clinical, based on the association of pathognomonic, major and minor criteria. The association in a patient with thyroid cancer, rarely with multinodular goiter, of typical dermatological manifestations, easily identifiable by clinical examination (papillomatous papules, acral keratoses, trichilemmomas), with a history of breast, endometrial, or renal cancer, or hamartomatous tumors presence, should alert the clinician. Clinical management of patients with CS is multidisciplinary, to include early and frequent screening, surveillance, and preventive care for associated malignancies. The development of antineoplastic agents targeting PI3K/Akt/mTOR pathway, such as rapamycin, may be the opportunity of treatment in PHTS and CS patients, for whom no specific medical treatment exist.

Birt-Hogg-Dubé syndrome: clinical and genetic studies of 10 French families.

BACKGROUND: Birt-Hogg-Dubé syndrome (BHDS) is an autosomal dominant genodermatosis predisposing to the development of multiple fibrofolliculomas (FFs), pulmonary cysts, spontaneous pneumothorax and renal neoplasms. The association of BHDS with various nonrenal neoplasms has been reported but remains controversial. OBJECTIVES: To report the clinical features and germline mutations in 22 patients from 10 unrelated families with BHDS investigated during a 5-year prospective study by the Department of Dermatology at the University Hospital of Montpellier, France. Also, to define more clearly the characteristics of pulmonary, thyroid, renal and colorectal manifestations associated with BHDS. METHODS: Twenty-two patients with clinical and histological criteria of BHDS confirmed by FLCN (previously BHD) germline mutation were evaluated. Lung cysts and pneumothorax were detected by thoracic computed tomography (CT) scanning. Abdominal magnetic resonance imaging (MRI) or CT scans and/or renal ultrasonography were performed to screen for tumours. Thyroid nodules and goitres were assessed by clinical examination, ultrasound imaging and measurement of serum thyroid-stimulating hormone and thyrocalcitonin. RESULTS: Eighteen of the 22 individuals affected by BHDS (82%) were diagnosed with five or more FFs. Multiple epidermal cysts, severe facial hyperseborrhoea and oral papules were noted, respectively, in three of 22 (14%), nine of 22 (41%) and nine of 21 patients (43%). Spontaneous pneumothorax was reported in seven affected patients (32%). Cystic lesions were detected in 14 of 20 patients (70%) and mainly displayed a subpleural and basal location. Renal ultrasound, CT scan and/or MRI revealed renal cysts in 10 patients (45%), without renal carcinoma diagnosed thus far. Thyroid nodules and/or cysts were disclosed by ultrasound examination in 13 of 20 cases (65%). No medullary carcinoma or other thyroid carcinomas were detected. Colonoscopy failed to detect colorectal carcinoma. CONCLUSIONS: We report here the largest series to date of French patients with BHDS. We noted a high prevalence of thyroid nodules and renal cysts. However, the lack of a control group does not allow assessment of whether or not such association with BHDS is fortuitous.

The TP53 Arg72Pro and MDM2 309G>T polymorphisms are not associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers.

BACKGROUND: The TP53 pathway, in which TP53 and its negative regulator MDM2 are the central elements, has an important role in carcinogenesis, particularly in BRCA1- and BRCA2-mediated carcinogenesis. A single nucleotide polymorphism (SNP) in the promoter region of MDM2 (309T>G, rs2279744) and a coding SNP of TP53 (Arg72Pro, rs1042522) have been shown to be of functional significance. METHODS: To investigate whether these SNPs modify breast cancer risk for BRCA1 and BRCA2 mutation carriers, we pooled genotype data on the TP53 Arg72Pro SNP in 7011 mutation carriers and on the MDM2 309T>G SNP in 2222 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analysed using a Cox proportional hazards model within a retrospective likelihood framework. RESULTS: No association was found between these SNPs and breast cancer risk for BRCA1 (TP53: per-allele hazard ratio (HR)=1.01, 95% confidence interval (CI): 0.93-1.10, P(trend)=0.77; MDM2: HR=0.96, 95%CI: 0.84-1.09, P(trend)=0.54) or for BRCA2 mutation carriers (TP53: HR=0.99, 95%CI: 0.87-1.12, P(trend)=0.83; MDM2: HR=0.98, 95%CI: 0.80-1.21, P(trend)=0.88). We also evaluated the potential combined effects of both SNPs on breast cancer risk, however, none of their combined genotypes showed any evidence of association. CONCLUSION: There was no evidence that TP53 Arg72Pro or MDM2 309T>G, either singly or in combination, influence breast cancer risk in BRCA1 or BRCA2 mutation carriers.

An unusual succinate dehydrogenase gene mutation C in a case of laryngeal paraganglioma.

OBJECTIVE: To report a rare case of a laryngeal paraganglioma related to succinate dehydrogenase gene mutation C. METHOD: A case report and a review of the world literature concerning succinate dehydrogenase mutations and laryngeal paraganglioma are presented. RESULTS: We identified a laryngeal paraganglioma in a 38-year-old woman, related to a very rare, deleterious in exon 4 of the succinate dehydrogenase mutation C. This mutation was a non-sense mutation: c.183G >A leading to p.Trp61X. No other neuroendocrine tumour was identified in this case, but a thyroid papillary carcinoma was concomitantly discovered and cured. CONCLUSION: To our knowledge, this is the first report in the world literature of laryngeal paraganglioma related to a succinate dehydrogenase mutation C. The case presented underlines the fact that every patient with paraganglioma should be tested for succinate dehydrogenase genetic mutations, even if a family history of paraganglioma is absent, in order to enable appropriate clinical management and to improve our knowledge of familial paraganglioma.

[Hereditary predispositions to gynaecological cancers]. / Prédispositions héréditaires aux cancers gynécologiques.

The breast, ovary and endometrial cancers are hereditary in 5 to 10% of the cases. These genetic predisposition syndromes can be classified into two major classes: ovarian cancer and breast cancer predisposition family cases (genes BRCA1 and BRCA2) and family cases of colon cancer, endometrial cancer and ovarian cancer (Lynch syndrome or HNPCC) (genes hMLH1, hMSH2, hMLH6). The estimate of the family and individual risk can contribute in a determining manner to the management of these patients, by the practice of screening or an adapted prevention. Indeed, the risk of cancer of an individual having a positive test for a gene of predisposition to breast cancer (BRCA1, BRCA2) or to the colon cancer (hMLH1, hMSH2, hMLH6) lies between 50 and 70% at the age of 70 years. The indication of a genetic test must be discussed within the framework of an oncogenetic consultation. An individual and family medical management ranging from simple monitoring to prophylactic surgery is proposed to these predisposed people.

Structural and numerical aberrations of chromosome 22 in a case of follicular variant of papillary thyroid carcinoma revealed by conventional and molecular cytogenetics.

This study reports a case of papillary carcinoma with vesicular components showing multiclonal aberrations of chromosome 22 as revealed by RHG-banding cytogenetics and by fluorescence in situ hybridization (FISH; whole chromosome 22 and BCR-ABL-specific locus probes, multi-FISH). Four clones with chromosome 22 changes as the sole abnormality were seen. The main abnormal clone lacked the whole chromosome 22. A del(22)(q11) was observed in a second group of cells. The third clone had an idic(22). Finally, FISH revealed a fourth abnormal cell population with a der(17)t(?17;22). Some of these chromosome 22 alterations have been described in other solid tumors such as meningiomas and neurinomas, suggesting a common genetic pathway of tumor progression occurring in a multistep process. Chromosome 22 changes do not seem to be involved in pure papillary thyroid tumors and therefore could be related to the maintenance of a follicular-type histological pattern.