Br J Haematol

International audienc

Caractérisation des cancers pulmonaires chez des patients présentant une mutation germinale de BRCA

Introduction: BRCA germline mutations are responsible for a cancer predisposition syndrome for which the lung cancer data are inconsistent. The objective of this study is to describe the phenotype of a cohort of patients with a BRCA germline mutation and lung cancer.Methods: multi-center retrospective observational study carried out on medico-administrative and care data collected prospectively in the hospital computer system and entered in the Health Data Warehouse of the whole AP-HP. Results: Between 01/01/2012 and 31/12/2018, 17 patients with lung cancer and BRCA1/2 germinal mutation were identified. The median age at diagnosis of lung cancer was 55 years (32-75 years) with a majority of women (12/17, 71%), former smokers (11/17, 65%) with an average of 20 pack years, BRCA2 mutations (12/17, 71%) and localized forms (13/20, 65%). The median time from the first BRCA spectrum cancer to lung cancer was 20 years. A 2nd lung cancer with a significant delay compared to the first occurred in 3 patients. The median follow-up time was 34 months (2-204). Univariate overall survival and progression-free survival analyses by BRCA status did not find significant differences.Conclusion: our population seems to present specific characteristics that could justify an individualized follow-up with a management integrating onco-geneticists in order to allow a personalized management of lung cancer risk.Introduction : les mutations germinales de BRCA 1 et 2 sont responsables d’un syndrome de prédisposition au cancer pour lequel les données concernant les cancers pulmonaires sont discordantes. L’objectif de cette étude est de décrire le phénotype d’une cohorte de patients présentant une mutation germinale de BRCA et un cancer du poumon.Méthodes : étude observationnelle rétrospective multicentrique réalisée sur données médico-administratives et données de soins collectées prospectivement dans le système informatique hospitalier et versées dans l’Entrepôt de Données de Santé de l’ensemble de l’AP–HP.Résultats : entre le 01/01/2012 et le 31/12/2018, 17 patients présentant un cancer pulmonaire et mutation germinale de BRCA1/2 ont été identifiés. L’âge médian au diagnostic de cancer pulmonaire était de 55 ans (32-75 ans) avec une majorité de femme (12/17, 71%), de patients anciens fumeurs (11/17, 65%) à 20PA en moyenne, de mutations BRCA2 (12/17, 71%) et de formes localisées (13/20, 65%). Le délai médian entre le 1er cancer du spectre BRCA et le cancer pulmonaire était de 20 ans. Un 2e cancer pulmonaire avec un délai important par rapport au premier est survenu chez 3 patients. La médiane de suivi était de 34 mois (2-204). Les analyses de survie globale et de survie sans progression univariées selon le statut BRCA ne retrouvent pas de différences significatives.Conclusion : notre population semble présenter des caractéristiques propres qui pourraient justifier d’un suivi individualisé avec une prise en charge intégrant les onco-généticiens afin de permettre une gestion personnalisée du risque de cancer pulmonaire

Metabolomic profiling of cardiac allografts after controlled circulatory death

International audienc

Heterogeneity of mutational mechanisms and modes of inheritance in auriculocondylar syndrome

<p>Background Auriculocondylar syndrome (ACS) is a rare craniofacial disorder consisting of micrognathia, mandibular condyle hypoplasia and a specific malformation of the ear at the junction between the lobe and helix. Missense heterozygous mutations in the phospholipase C, beta 4 (PLCB4) and guanine nucleotide binding protein (G protein), a inhibiting activity polypeptide 3 (GNAI3) genes have recently been identified in ACS patients by exome sequencing. These genes are predicted to function within the G protein-coupled endothelin receptor pathway during craniofacial development.</p><p>Results We report eight additional cases ascribed to PLCB4 or GNAI3 gene lesions, comprising six heterozygous PLCB4 missense mutations, one heterozygous GNAI3 missense mutation and one homozygous PLCB4 intragenic deletion. Certain residues represent mutational hotspots; of the total of 11 ACS PLCB4 missense mutations now described, five disrupt Arg621 and two disrupt Asp360. The narrow distribution of mutations within protein space suggests that the mutations may result in dominantly interfering proteins, rather than haploinsufficiency. The consanguineous parents of the patient with a homozygous PLCB4 deletion each harboured the heterozygous deletion, but did not present the ACS phenotype, further suggesting that ACS is not caused by PLCB4 haploinsufficiency. In addition to ACS, the patient harbouring a homozygous deletion presented with central apnoea, a phenotype that has not been previously reported in ACS patients.</p><p>Conclusions These findings indicate that ACS is not only genetically heterogeneous but also an autosomal dominant or recessive condition according to the nature of the PLCB4 gene lesion.</p>