Intestinal microbiota influences clinical outcome and side effects of early breast cancer treatment.

The prognosis of early breast cancer (BC) relies on cell autonomous and immune parameters. The impact of the intestinal microbiome on clinical outcome has not yet been evaluated. Shotgun metagenomics was used to determine the composition of the fecal microbiota in 121 specimens from 76 early BC patients, 45 of whom were paired before and after chemotherapy. These patients were enrolled in the CANTO prospective study designed to record the side effects associated with the clinical management of BC. We analyzed associations between baseline or post-chemotherapy fecal microbiota and plasma metabolomics with BC prognosis, as well as with therapy-induced side effects. We examined the clinical relevance of these findings in immunocompetent mice colonized with BC patient microbiota that were subsequently challenged with histo-compatible mouse BC and chemotherapy. We conclude that specific gut commensals that are overabundant in BC patients compared with healthy individuals negatively impact BC prognosis, are modulated by chemotherapy, and may influence weight gain and neurological side effects of BC therapies. These findings obtained in adjuvant and neoadjuvant settings warrant prospective validation

TRANSFERT DE GENES DANS LES CELLULES SOUCHES HEMATOPOIETIQUES HUMAINES (ETUDE DE L'INFLUENCE DE LA STRUCTURE RETROVIRALE SUR L'EXPRESSION DES TRANSGENES)

LE TRANSFERT DE GENES DANS LES CELLULES SOUCHES HEMATOPOIETIQUES (CSH) A DE NOMBREUSES APPLICATIONS, POUR LA THERAPIE GENIQUE COMME POUR LA COMPREHENSION DES MECANISMES DE REGULATION DE L'HEMATOPOIESE. EN RAISON DU FORT POUVOIR PROLIFERATIF DES CSH, UN TRANSFERT DE GENE STABLE A LONG TERME NECESSITE L'INTEGRATION DU TRANSGENE DANS LE GENOME DE LA CELLULE. EN OUTRE, DEUX PROBLEMES MAJEURS DOIVENT ETRE RESOLUS : LA TRANSDUCTION EFFICACE DES CSH, MAJORITAIREMENT QUIESCENTES, ET L'EXPRESSION A LONG TERME DES TRANSGENES. LES LENTIVIRUS AYANT LA PARTICULARITE D'INFECTER LES CELLULES INDEPENDAMMENT DU CYCLE CELLULAIRE, LES VECTEURS DERIVES DE CES VIRUS SONT MAINTENANT PREFERES A CEUX, DERIVES DES ONCORETROVIRUS, DONT LA TRANSDUCTION EST DEPENDANTE DU CYCLE CELLULAIRE. DANS CE TRAVAIL, NOUS AVONS MONTRE QU'UN VECTEUR LENTIVIRAL PERMETTAIT LE TRANSFERT DE GENES DANS LES CELLULES HEMATOPOIETIQUES D'AUTANT PLUS EFFICACEMENT QU'IL INCLUAIT LES SEQUENCES CONTROLANT LA FORMATION DE LA STRUCTURE ADN TRIPLEX CENTRAL. NOUS AVONS EGALEMENT MONTRE QUE LE VECTEUR TRIP AINSI OBTENU PERMETTAIT DE TRANSDUIRE AVEC LA MEME EFFICACITE TOUTE LA HIERARCHIE DES CELLULES HEMATOPOIETIQUES, INCLUANT LES CELLULES LES PLUS PRIMITIVES AYANT DES CAPACITES DE COLONISATION A LONG TERME DE LA MOELLE OSSEUSE DES SOURIS NOD-SCID. POUR AMELIORER L'EXPRESSION DU TRANSGENE ET LA SECURITE D'UTILISATION DU VECTEUR LENTIVIRAL, LE VECTEUR INITIAL A ETE MODIFIE EN DELETANT LES SEQUENCES PROMOTRICES ET ACTIVATRICES CONTENUES DANS LES LTR ET EN PLACANT LE TRANSGENE SOUS LA DEPENDANCE DU PROMOTEUR DU FACTEUR D'ELONGATION DE LA TRANSCRIPTION EF1-ALPHA, UN PROMOTEUR CELLULAIRE UBIQUITAIRE FORT. AVEC CE NOUVEAU VECTEUR, NOUS AVONS OBTENU UNE EXPRESSION FORTE, HOMOGENE, STABLE A LONG TERME DU TRANSGENE DANS TOUTES LES LIGNEES HEMATOPOIETIQUES ET DANS LES CELLULES PRIMITIVES. CE NOUVEAU VECTEUR OUVRE DE NOMBREUSES APPLICATIONS AUSSI BIEN POUR LA THERAPIE GENIQUE QUE POUR LA RECHERCHE FONDAMENTALE.PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Penetrance estimation of Alzheimer disease in SORL1 loss-of-function variant carriers using a family-based strategy and stratification by APOE genotypes

International audienceAbstract Background Alzheimer disease (AD) is a common complex disorder with a high genetic component. Loss-of-function (LoF) SORL1 variants are one of the strongest AD genetic risk factors. Estimating their age-related penetrance is essential before putative use for genetic counseling or preventive trials. However, relative rarity and co-occurrence with the main AD risk factor, APOE -ε4, make such estimations difficult. Methods We proposed to estimate the age-related penetrance of SORL1 -LoF variants through a survival framework by estimating the conditional instantaneous risk combining (i) a baseline for non-carriers of SORL1- LoF variants, stratified by APOE-ε4 , derived from the Rotterdam study ( N = 12,255), and (ii) an age-dependent proportional hazard effect for SORL1- LoF variants estimated from 27 extended pedigrees (including 307 relatives ≥ 40 years old, 45 of them having genotyping information) recruited from the French reference center for young Alzheimer patients. We embedded this model into an expectation-maximization algorithm to accommodate for missing genotypes. To correct for ascertainment bias, proband phenotypes were omitted. Then, we assessed if our penetrance curves were concordant with age distributions of APOE -ε4-stratified SORL1- LoF variant carriers detected among sequencing data of 13,007 cases and 10,182 controls from European and American case-control study consortia. Results SORL1- LoF variants penetrance curves reached 100% (95% confidence interval [99–100%]) by age 70 among APOE -ε4ε4 carriers only, compared with 56% [40–72%] and 37% [26–51%] in ε4 heterozygous carriers and ε4 non-carriers, respectively. These estimates were fully consistent with observed age distributions of SORL1- LoF variant carriers in case-control study data. Conclusions We conclude that SORL1- LoF variants should be interpreted in light of APOE genotypes for future clinical applications