Oncogenèse et différenciation des léiomyocarsomes (rôle de l'amplification du chromosome 17p dans la biologie de ces tumeurs)

Les léiomyosarcomes (LMS) sont des sarcomes des tissus mous de l'adulte extrêmement agressifs malgré leur différenciation musculaire lisse très marquée. Ils présentent des profils génomiques très complexes, caractérisés par de nombreux remaniements chromosomiques proches de ceux observés dans les sarcomes pléomorphes indifférenciés. Cette thèse montre qu'un sous-groupe de LMS, rétropéritonéaux pour la plupart, présentent une amplification et une surexpression du gène MYOCD, gène localisé sur le bras court du chromosome 17. La myocardine est un cofacteur du SRF, essentiel à la différenciation musculaire lisse. Son amplification pourrait donc être responsable de la différenciation de ces tumeurs. L'inhibition de l'expression du gène MYOCD dans une lignée de LMS a montré que la myocardine est impliquée dans la différenciation musculaire lisse, la prolifération et la migration de ces tumeurs. Enfin, des altérations des gènes TPS3 et COPS3, situés sur le chromosome 17p, pourraient également être impliquées dans l'oncogenèse de ces tumeurs.Leiomyosarcomas (LMS) are aggressive soft tissue sarcomas despite a marked smooth muscle differentiation. They present with complex genomic profiles similar to those observed in pleomorphic undifferentiated sarcomas. This thesis shows that a sub-group of predominantly retroperitoneal LMS amplifly and overexpress the MYOCD gene on the short arm of chromosome 17. Myocardin is an SRF cofactor which is essential for smooth muscle differentiation. Therefore, its amplification could be responsible of these LMS smooth muscle differentiation. By inhibiting MYOCD expression in an LMS cell line I show that LMS smooth muscle differentiation is concomitantly inhibited as is tumor proliferation and migration. Finally, TP53 and COPS3 - two additional genes located at 17p are also misregulated and may contribute to the development of LMS.PARIS5-BU Méd.Cochin (751142101) / SudocSudocFranceF

Chimeric oncogene regulates the EGR2 sarcoma susceptibility gene via a GGAA-microsatellite

International audienceDeciphering the ways in which somatic mutations and germline susceptibility variants cooperate to promote cancer is challenging. Ewing sarcoma is characterized by fusions between EWSR1 and members of the ETS gene family, usually EWSR1-FLI1, leading to the generation of oncogenic transcription factors that bind DNA at GGAA motifs. A recent genome-wide association study identified susceptibility variants near EGR2. Here we found that EGR2 knockdown inhibited proliferation, clonogenicity and spheroidal growth in vitro and induced regression of Ewing sarcoma xenografts. Targeted germline deep sequencing of the EGR2 locus in affected subjects and controls identified 291 Ewing-associated SNPs. At rs79965208, the A risk allele connected adjacent GGAA repeats by converting an interspaced GGAT motif into a GGAA motif, thereby increasing the number of consecutive GGAA motifs and thus the EWSR1-FLI1-dependent enhancer activity of this sequence, with epigenetic characteristics of an active regulatory element. EWSR1-FLI1 preferentially bound to the A risk allele, which increased global and allele-specific EGR2 expression. Collectively, our findings establish cooperation between a dominant oncogene and a susceptibility variant that regulates a major driver of Ewing sarcomagenesi

Effect of chemoprevention by low-dose aspirin of new or recurrent colorectal adenomas in patients with Lynch syndrome (AAS-Lynch): study protocol for a multicenter, double-blind, placebo-controlled randomized controlled trial

Abstract Lynch syndrome (LS) is the most common cause of inherited colorectal cancer (CRC) and confers a high lifetime risk of CRC estimated to be up to 60%. Colonoscopy is recommended every 2 years in LS patients above the 20–25-year-old age bracket, and every year when colonic neoplasia has been detected. Efficient chemoprevention has the potential to represent a cost-effective intervention in these high-risk patients and could allow a delay in colonoscopy surveillance. Several epidemiological studies have shown that regular use of low dose aspirin is associated with a 20 to 30% reduction in the risk of sporadic colonic adenomas and colorectal cancer regardless of family risk. However, in recent large randomized trials in specific populations, aspirin use showed no protection for colorectal cancer. A prospective randomized CAPP-2 trial evaluated the effect of aspirin use in LS patients. The primary analysis of this trial showed no significant decrease in CRC in LS patients under daily aspirin. However, a preplanned secondary analysis after an extended follow-up showed a significant reduced risk of CRC in the aspirin group in the per-protocol analysis. The real effect and clinical benefit of aspirin are still to be consolidated in this population. The AAS-Lynch trial—a prospective, multicentric, double-blind, placebo-controlled, randomized clinical trial—was designed to investigate if daily aspirin therapy, at a dose of 100 or 300 mg, would decrease the occurrence or recurrence of colorectal adenomas in patients under 75 years of age, compared with placebo. Trial registration ClinicalTrials.gov NCT02813824 . Registered on 27 June 2016. The trial was prospectively registered