Le suivi à long terme des adultes guéris d'un cancer pédiatrique. État des lieux des connaissances et des pratiques en médecine générale. Enquête descriptive auprès des médecins généralistes de Seine-Maritime et de l'Eure ayant au moins un adulte guéri d'un cancer pédiatrique dans sa patientèle

Les cancers pédiatriques sont rares, mais avec 82 % de survie à 5 ans, les survivants représentent une population croissante en France. Le suivi à long terme apparaît comme une nécessité étant donné leur risque accru de morbi-mortalité. Actuellement, des organisations de suivi sont en train de se développer et le rôle du médecin généraliste est mal connu. L’objectif de ce travail est d’établir un état des lieux des connaissances et des pratiques des médecins généralistes sur le suivi à long terme des patients guéris d’un cancer pédiatrique en Seine-Maritime et dans l’Eure.De Juin à Décembre 2018, 731 médecins généralistes de Seine-Maritime et de l’Eure ont été contactés par téléphone afin de retrouver ceux ayant dans leur patientèle au moins un patient adulte guéri d’un cancer pédiatrique. Ces derniers ont été sollicités pour répondre à un questionnaire.Sur les 460 médecins répondeurs à l’enquête téléphonique, 81 médecins (soit 17,6%) avaient dans leur patientèle au moins un adulte guéri d’un cancer pédiatrique. 61 questionnaires ont pu être exploités. Les médecins ont des connaissances incomplètes sur la nécessité de ce suivi. Seuls 22,9% des médecins sont au courant de l’existence de consultations de suivi au CHU de Rouen. 59% déclarent participer au suivi, deux tiers le font en collaboration avec d’autres professionnels de santé. Les principales difficultés rencontrées par les médecins généralistes sont le manque de connaissances, d’outils et les difficultés de communication avec l’oncologue et avec le patient.Le rôle du médecin généraliste dans le suivi n’est pas encore bien établi, la proximité avec son patient en fait l’acteur de soins le mieux placé pour coordonner et expliquer l’intérêt du suivi au patient. Une sensibilisation des médecins sur l’existence de consultations de suivi à long terme au CHU de Rouen et le développement d’outils d’aide permettraient d’améliorer les connaissances et les pratiques des médecins sur la prise en charge à effectuer

L1 chimeric transcripts are expressed in healthy brain and their deregulation in glioma follows that of their host locus

International audienceBesides the consequences of retrotransposition, long interspersed element 1 (L1) retrotransposons can affect the host genome through their antisense promoter. In addition to the sense promoter, the evolutionarily recent L1 retrotransposons, which are present in several thousand copies, also possess an anti-sense promoter that can produce L1 chimeric transcripts (LCT) composed of the L1 5′ UTR followed by the adjacent genomic sequence. The full extent to which LCT expression occurs in a given tissue and whether disruption of the defense mechanisms that normally control L1 retrotransposons affects their expression and function in cancer cells, remain to be established. By using CLIFinder, a dedicated bioinformatics tool, we found that LCT expression was widespread in normal brain and aggressive glioma samples, and that approximately 17% of recent L1 retrotransposons, from the L1PA1 to L1PA7 subfamilies, were involved in their production. Importantly, the transcriptional activities of the L1 antisense promoters and of their host loci were coupled. Accordingly, we detected LCT-producing L1 retrotransposons mainly in transcriptionally active genes and genomic loci. Moreover, changes in the host genomic locus expression level in glioma were associated with a similar change in LCT expression level, regardless of the L1 promoter methylation status. Our findings support a model in which the host genomic locus transcriptional activity is the main driving force of LCT expression. We hypothesize that this model is more applicable when host gene and LCT are transcribed from the same strand

L1 chimeric transcripts are expressed in healthy brain and their deregulation in glioma follows that of their host locus

International audienceBesides the consequences of retrotransposition, long interspersed element 1 (L1) retrotransposons can affect the host genome through their antisense promoter. In addition to the sense promoter, the evolutionarily recent L1 retrotransposons, which are present in several thousand copies, also possess an anti-sense promoter that can produce L1 chimeric transcripts (LCT) composed of the L1 5′ UTR followed by the adjacent genomic sequence. The full extent to which LCT expression occurs in a given tissue and whether disruption of the defense mechanisms that normally control L1 retrotransposons affects their expression and function in cancer cells, remain to be established. By using CLIFinder, a dedicated bioinformatics tool, we found that LCT expression was widespread in normal brain and aggressive glioma samples, and that approximately 17% of recent L1 retrotransposons, from the L1PA1 to L1PA7 subfamilies, were involved in their production. Importantly, the transcriptional activities of the L1 antisense promoters and of their host loci were coupled. Accordingly, we detected LCT-producing L1 retrotransposons mainly in transcriptionally active genes and genomic loci. Moreover, changes in the host genomic locus expression level in glioma were associated with a similar change in LCT expression level, regardless of the L1 promoter methylation status. Our findings support a model in which the host genomic locus transcriptional activity is the main driving force of LCT expression. We hypothesize that this model is more applicable when host gene and LCT are transcribed from the same strand

15q11.2 microdeletion (BP1–BP2) and developmental delay, behaviour issues, epilepsy and congenital heart disease: A series of 52 patients

International audienceProximal region of chromosome 15 long arm is rich in duplicons that, define five breakpoints (BP) for 15q rearrangements. 15q11.2 microdeletion between BP1 and BP2 has been previously associated with developmental delay and atypical psychological patterns. This region contains four highly-conserved and non-imprinted genes: NIPA1, NIPA2, CYFIP1, TUBGCP5. Our goal was to investigate the phenotypes associated with this microdeletion in a cohort of 52 patients. This copy number variation (CNV) was prevalent in 0.8% patients presenting with developmental delay, psychological pattern issues and/or multiple congenital malformations. This was studied by array-CGH at six different French Genetic laboratories. We collected data from 52 unrelated patients (including 3 foetuses) after excluding patients with an associated genetic alteration (known CNV, aneuploidy or known monogenic disease). Out of 52 patients, mild or moderate developmental delay was observed in 68.3%, 85.4% had speech impairment and 63.4% had psychological issues such as Attention Deficit and Hyperactivity Disorder, Autistic Spectrum Disorder or Obsessive-Compulsive Disorder. Seizures were noted in 18.7% patients and associated congenital heart disease in 17.3%. Parents were analysed for abnormalities in the region in 65.4% families. Amongst these families, 'de novo' microdeletions were observed in 18.8% and 81.2% were inherited from one of the parents. Incomplete penetrance and variable expressivity were observed amongst the patients. Our results support the hypothesis that 15q11.2 (BP1-BP2) microdeletion is associated with developmental delay, abnormal behaviour, generalized epilepsy and congenital heart disease. The later feature has been rarely described. Incomplete penetrance and variability of expression demands further assessment and studies

Identification of three clinical neurofibromatosis 1 subtypes: Latent class analysis of a series of 1351 patients

International audienc

Identification of three clinical neurofibromatosis 1 subtypes: Latent class analysis of a series of 1351 patients

International audienc

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

BackgroundWe previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15-20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in similar to 80% of cases.MethodsWe report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded.ResultsNo gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5-528.7, P=1.1x10(-4)) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR=3.70[95%CI 1.3-8.2], P=2.1x10(-4)). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR=19.65[95%CI 2.1-2635.4], P=3.4x10(-3)), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR=4.40[9%CI 2.3-8.4], P=7.7x10(-8)). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD]=43.3 [20.3] years) than the other patients (56.0 [17.3] years; P=1.68x10(-5)).ConclusionsRare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old