Low-frequency variation near common germline susceptibility loci are associated with risk of Ewing sarcoma

Background: Ewing sarcoma (EwS) is a rare, aggressive solid tumor of childhood, adolescence and young adulthood associated with pathognomonic EWSR1-ETS fusion oncoproteins altering transcriptional regulation. Genome-wide association studies (GWAS) have identified 6 common germline susceptibility loci but have not investigated low-frequency inherited variants with minor allele frequencies below 5% due to limited genotyped cases of this rare tumor. Methods We investigated the contribution of rare and low-frequency variation to EwS susceptibility in the largest EwS genome-wide association study to date (733 EwS cases and 1,346 unaffected controls of European ancestry). Results We identified two low-frequency variants, rs112837127 and rs2296730, on chromosome 20 that were associated with EwS risk (OR = 0.186 and 2.038, respectively;P-value < 5x10(-8)) and located near previously reported common susceptibility loci. After adjusting for the most associated common variant at the locus, only rs112837127 remained a statistically significant independent signal (OR = 0.200, P-value = 5.84x10(-8)). Conclusions: These findings suggest rare variation residing on common haplotypes are important contributors to EwS risk. Impact Motivate future targeted sequencing studies for a comprehensive evaluation of low-frequency and rare variation around common EwS susceptibility loci

Génomique comparée et développement de nouveaux outils bioinformatiques permettant l'analyse de la diversité métabolique des Eumycota

Bien que les Eumycota soient étudiés depuis de nombreuses années, les raisons de leur diversité métabolique restent à ce jour largement inexpliquées. Afin d'étudier cette diversité, j'ai commencé par identifier les protéines orthologues d'une cinquantaine d'espèces en utilisant une approche innovante qui tient compte des résultats prédits par différentes méthodes. Les groupes d' orthologues ont ensuite été annotés et les fonctions enzymatiques ont été reportées sur des voies métaboliques de référence. Afin de pouvoir visualiser facilement la conservation d'une voie métabolique donnée, j'ai développé un outil, FUNGIpath (www.fungipath.u-psud.fr). En analysant la conservation des différentes voies métaboliques de KEGG, j'ai essayé de comprendre comment le métabolisme fongique a pu évoluer et se diversifier au cours de l'évolution. A coté d'un petit nombre de voies métaboliques très bien conservées, l'analyse semble indiquer une moindre conservation et une plus grande diversité pour un grand nombre de ces voies. Étonnement, cette diversification ne semble être en accord ni avec la phylogénie, ni avec les milieux ou les modes de vie des champignons étudiés ici.Even if the Eumycota have been studied since a long time, the origin of their metabolic diversity are still unknown. ln order to better understand this diversity, 1 begun to identify orthologous genes in about fifty fungal genomes. To predict orthologous groups, 1 used an innovative approach which takes into account the results predicted by different methods. Then, the orthologous groups were annotated and the enzymatic activities were mapped to known metabolic pathways. These results were integrated in a database and 1 developed a new tool, FUNGIpath (www.fungipath.u-psud.fr). which allows to visualize the level of conservation of metabolic pathways. During the analysis of the KEGG pathways, 1 tried to understand how the fungal metabolism evolved during the Evolution. Apart from a small number of highly conserved metabolisms, the results show a lower conservation and a wide diversity for a lot of pathways. Surprisingly, this diversity doesn't seem to agree with the phylogeny, the lifestyle or the habitat of the studied Fungi.ORSAY-PARIS 11-BU Sciences (914712101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Clonally Expanded T Cells Reveal Immunogenicity of Rhabdoid Tumors

International audienceRhabdoid tumors (RTs) are genomically simple pediatric cancers driven by the biallelic inactivation of SMARCB1, leading to SWI/SNF chromatin remodeler complex deficiency. Comprehensive evaluation of the immune infiltrates of human and mice RTs, including immunohistochemistry, bulk RNA sequencing and DNA methylation profiling studies showed a high rate of tumors infiltrated by T and myeloid cells. Single-cell RNA (scRNA) and T cell receptor sequencing highlighted the heterogeneity of these cells and revealed therapeutically targetable exhausted effector and clonally expanded tissue resident memory CD8+ T subpopulations, likely representing tumor-specific cells. Checkpoint blockade therapy in an experimental RT model induced the regression of established tumors and durable immune responses. Finally, we show that one mechanism mediating RTs immunogenicity involves SMARCB1-dependent re-expression of endogenous retroviruses and interferon-signaling activation

Genome-wide association study identifies multiple new loci associated with Ewing sarcoma susceptibility.

Ewing sarcoma (EWS) is a pediatric cancer characterized by the EWSR1-FLI1 fusion. We performed a genome-wide association study of 733 EWS cases and 1346 unaffected individuals of European ancestry. Our study replicates previously reported susceptibility loci at 1p36.22, 10q21.3 and 15q15.1, and identifies new loci at 6p25.1, 20p11.22 and 20p11.23. Effect estimates exhibit odds ratios in excess of 1.7, which is high for cancer GWAS, and striking in light of the rarity of EWS cases in familial cancer syndromes. Expression quantitative trait locus (eQTL) analyses identify candidate genes at 6p25.1 (RREB1) and 20p11.23 (KIZ). The 20p11.22 locus is near NKX2-2, a highly overexpressed gene in EWS. Interestingly, most loci reside near GGAA repeat sequences and may disrupt binding of the EWSR1-FLI1 fusion protein. The high locus to case discovery ratio from 733 EWS cases suggests a genetic architecture in which moderate risk SNPs constitute a significant fraction of risk