Anti-HPV16 E2 Protein T-Cell Responses and Viral Control in Women with Usual Vulvar Intraepithelial Neoplasia and Their Healthy Partners

T-cell responses (proliferation, intracellular cytokine synthesis and IFNγ ELISPOT) against human papillomavirus 16 (HPV16) E2 peptides were tested during 18 months in a longitudinal study in eight women presenting with HPV16-related usual vulvar intraepithelial neoplasia (VIN) and their healthy male partners. In six women, anti-E2 proliferative responses and cytokine production (single IFNγ and/or dual IFNγ/IL2 and/or single IL2) by CD4+ T lymphocytes became detectable after treating and healing of the usual VIN. In the women presenting with persistent lesions despite therapy, no proliferation was observed. Anti-E2 proliferative responses were also observed with dual IFNγ/IL2 production by CD4+ T-cells in six male partners who did not exhibit any genital HPV-related diseases. Ex vivo IFNγ ELISPOT showed numerous effector T-cells producing IFNγ after stimulation by a dominant E2 peptide in all men and women. Since the E2 protein is absent from the viral particles but is required for viral DNA replication, these results suggest a recent infection with replicative HPV16 in male partners. The presence of polyfunctional anti-E2 T-cell responses in the blood of asymptomatic men unambiguously establishes HPV infection even without detectable lesions. These results, despite the small size of the studied group, provide an argument in favor of prophylactic HPV vaccination of young men in order to prevent HPV16 infection and viral transmission from men to women

Méiose normale et perturbations de la première division méiotique

PARIS5-BU Méd.Cochin (751142101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Should the GCM2 gene be tested when screening for familial primary hyperparathyroidism?

International audienceObjective: Primary hyperparathyroism (PHPT) is a disease with either sporadic or inherited presentation. Germline mutations responsible for this disease can be found in different genes, the most frequently involved being MEN1, CDC73 = HRPT2 and CASR. During the last few years, new genes have been described as responsible for the development of PHPT such as GCM2. These genes are not systematically included in PHPT genetic screening yet. The aim of this work was to assess the importance of GCM2 genetic analysis in PHPT to determine if this gene should be included in gene panel investigated for this disease. Design and methods: The TENGEN network (French Oncogenetic Network of Neuroendocrine Tumors) collected and interpreted allelic variants according to the clinical characteristics of the GCM2-positive patients identified through genetic testing performed in French laboratories (713 patients with PHPT). Results: From 713 patients with PHPT included in this study, 85 (6.6%) carried at least one GCM2 variant. A total of 12 variants classified as uncertain significance or likely pathogenic were reported in 47 patients. Their mean age at PHPT diagnosis was 49 years. Additionally, the investigation of a large family showed that GCM2 variants could be associated with low penetrance. Conclusion: We provide a description and interpretation for GCM2 variants identified in a French population. We suggest that this gene should be included in genetic screening of patients with PHPT and propose the follow-up of asymptomatic patients carrying such variants for calcemia

Proposition of adjustments to the ACMG-AMP framework for the interpretation of MEN1 missense variants

International audienceIn 2015, the ACMG-AMP guidelines provided a general procedure for the objective and reproducible classification of genomic variants. While the benefits of this framework are of major importance, its adaptation for locus-specific use is needed. Multiple Endocrine Neoplasia type 1 (MEN1) occurs due to inactivating mutations in the tumour suppressor gene MEN1, including 20% of missense variants. The classification of these variants may be extremely challenging. Here, we compared the interpretation of the 122 MEN1 missense variants, identified in the French population over the past 15 years by the TENGEN network (French oncogenetics network of neuroendocrine tumors) versus by using the ACMG-AMP guidelines, and analyzed the causes of discordance. A total of 59.8% of missense variants were termed as (likely)-pathogenic variants by TENGEN versus only 28.7% using ACMG-AMP guidelines. Actually, 53.4% (39/73) of TENGEN (likely)-pathogenic variants were declassified in variant of uncertain significance (VUS) by using ACMG-AMP guidelines, thereby affecting the clinical management of patients and their families. Twenty of these ACMG-AMP VUS were found in patients with a clinically authentic MEN1 disease. Here, TENGEN proposes adjustments to the ACMG-AMP framework for the interpretation of MEN1 missense variants. These propositions merge both the classification systems, and are particularly interesting, as MEN1 is included in the ACMG secondary findings list for reporting in clinical genomic sequencing

UMD-MEN1 database: an overview of the 370 MEN1 variants present in 1,676 patients from the French population

IF 5.789International audienceContext: Multiple Endocrine Neoplasia type 1 (MEN1) is an autosomal dominant disease caused by mutations in the MEN1 gene characterized by a broad spectrum of clinical manifestations, of which the most frequent are primary hyperparathyroidism, pituitary adenomas, and neuroendocrine tumors. Objective: The aim of this work is to facilitate interpretation of variants and improve the genetic counseling and medical care of MEN1-patients’ families. Design, Setting, and Patients: The TENGEN network (French oncogenetics network of neuroendocrine tumors) has interpreted and collected all allelic variants and clinical characteristics of the MEN1-positive patients identified through genetic testing performed in the French population from 1997 to 2015. They were registered in a locus-specific database called the UMD-MEN1 database (www.umd.be/MEN1/). Main Outcomes: variant classification, age-related penetrance, odds ratio. Results: Three hundred seventy distinct variants reported in 1,676 patients, including 181 unpublished variants, have currently been registered. This database analysis pointed out the low frequency of benign or likely benign missense variants in MEN1 (only 6.6%). Eight families (1.9%) presented a familial isolated hyperparathyroidism and harbored the same mutation found in authentic MEN1-families. An association exists between large rearrangements and an earlier onset of the disease, whereas no difference was observed between truncating and non-truncating variants. Conclusion: UMD-MEN1 database provides an exhaustive overview of the MEN1 variants present in the French population. For each variant, a classification is publicly available. Clinical data collections allow the determination of genotype-phenotype correlation and age-related penetrance of lesions in the cohort

Carney complex predisposes to breast cancer: prospective study of 50 women.

International audienceCarney complex (CNC) is a rare genetic syndrome, mostly due to germline loss-of-function pathogenic variants in PRKAR1A. Carney complex includes pigmented skin lesions, cardiac myxomas, primary pigmented nodular adrenocortical dysplasia, and various breast benign tumors

Multiple endocrine neoplasia type 1 caused by mosaic mutation: clinical follow-up and genetic counseling?

International audienceMEN1 is an autosomal dominant hereditary syndrome characterized by several endocrine tumors, in most cases affecting the parathyroid glands, pancreas, and anterior pituitary. It is the result of inactivating mutations in the tumor suppressor gene MEN1. More than 1300 different mutations have been identified in this gene. Mosaic MEN1 mutations have been previously described in only a few patients in the literature. In this paper, we provide a review of six cases of MEN1 mosaicism reported in the literature supplemented with six additional cases described by the French TENgen network of laboratories. This review highlights that (i) MEN1 mosaicism is not associated with a mild phenotype and results in the same natural history as heterozygous MEN1 mutation and (ii) that more systematic detection of MEN1 mosaic mutation enables improvements in both patient monitoring and genetic counseling

Value of Somatostatin Receptor PET/CT in Patients With MEN1 at Various Stages of Their Disease

International audienceAbstract Context Despite the growing evidence of the clinical value of somatostatin receptor (SSTR) positron emission tomography (PET) in the evaluation of neuroendocrine tumors (NETs), its role remains to be clarified at different time points in the journey of patients with multiple endocrine neoplasia type 1 (MEN1). The rarity of the disease is however a significant impediment to prospective clinical trials. Objective The goals of the study were to assess the indications and value of SSTR PET/computed tomography (CT) in patients with MEN1. Methods We retrospectively included patients from 7 French expert centers for whom data on SSTR PET/CT and morphological imaging performed at the same period were available. Detection rates of PET study were analyzed. Results One hundred and 8 patients were included. SSTR PET/CT was performed at screening (n = 33), staging (n = 34), restaging (n = 37), and for peptide receptor targeted radiotherapy selection (n = 4). PET detected positive pancreatic lesions in 91% of cases at screening, with results comparable with magnetic resonance imaging but superior to CT (P = .049). Metastases (mostly lymph node [LN]) were present at the screening phase in 28% of cases, possibly due to the suboptimal value of screening morphological imaging in the assessment of nodal metastases and/or a long delay between imaging studies. SSTR PET/CT was considered superior or complementary to the reference standard in the assessment of LN or distant metastases in the vast majority of cases and regardless of the clinical scenario. Conclusion This study shows the potential added value of SSTR PET in the assessment of MEN1-associated NETs and provides great impetus toward its implementation in the evaluation of patients with MEN1

Transcriptome in paraffin samples for the diagnosis and prognosis of adrenocortical carcinoma

DESIGN: Molecular classification is important for the diagnosis and prognosis of adrenocortical tumors (ACT). Transcriptome profiles separate adrenocortical adenomas ‘C2’ from carcinomas, and identify two groups of carcinomas ‘C1A’ and ‘C1B’, of poor and better prognosis respectively. However, many ACT cannot be profiled because of improper or absent freezing procedures, a mandatory requirement so far. The main aim was to determine transcriptome profiles on formalin-fixed paraffin-embedded (FFPE) samples, using the new 3’-end RNA-sequencing technology. A secondary aim was to demonstrate the ability of this technique to explore large FFPE archives, by focusing on the rare oncocytic ACT variants. METHODS: We included 131 ACT: a training cohort from Cochin hospital and an independent validation cohort from Wuerzburg hospital. The 3’ transcriptome was generated from FFPE samples using QuantSeq (Lexogen, Vienna, Austria) and NextSeq500 (Illumina, San Diego, CA, USA). RESULTS: In the training cohort, unsupervised clustering identified three groups: ‘C1A’ aggressive carcinomas (n = 28, 29%), ‘C1B’ more indolent carcinomas (n = 28, 29%), and ‘C2’ adenomas (n = 39, 41%). The prognostic value of FFPE transcriptome was confirmed in the validation cohort (5-year OS: 26% in ‘C1A’ (n = 26) and 100% in ‘C1B’ (n = 10), P  = 0.003). FFPE transcriptome was an independent prognostic factor in a multivariable model including tumor stage and Ki-67 (OS HR: 7.5, P  = 0.01). Oncocytic ACT (n = 19) did not form any specific cluster. Oncocytic carcinomas (n = 6) and oncocytic ACT of uncertain malignant potential (n = 4) were all in ‘C1B’. CONCLUSIONS: The 3’ RNA-sequencing represents a convenient solution for determining ACT molecular class from FFPE samples. This technique should facilitate routine use and large retrospective studies