Analyses transcriptomiques et fonctionnelles des anomalies moléculaires récurrentes des sarcomes du stroma endométrial

In about half of cases, endometrial stromal sarcomas (ESS) are characterized in by a JAZF1-SUZ12 or YWHAE-NUTM2 fusion transcript, which is involved in carcinogenesis. The exploration by RNA sequencing of a retrospective series of 42 uterine sarcomas diagnosed as ESS but negative for JAZF1 and/or YWHAE rearrangement in FISH shows that ESS actually represent a heterogeneous disease both in terms of clinical behavior and molecular genetics. Cluster analyses on the expression profiles indicated that tumors could be gather in three distinct subgroups: one mainly composed of BCOR-rearranged samples; one mainly composed of JAZF1-fused ESS and the last composed of various molecular subtypes. These three subgroups display different gene signatures, different in silico cell cycle score, and very different clinical presentation, natural history and survival. While YWHAE-NUTM2 fusion genes may be present in both high and low grade ESS, the high-grade presenting with an additional BCOR or BCORL1 gene mutations. RNAseq brings clinically relevant molecular classification, enabling to reclassify diseases and to guide therapeutic strategy. The functional similarities between the classical JAZF1-SUZ12 and the alternative transcripts (most commonly chromosomal translocations that frequently involve chromatin remodeling genes) may suggest that they activate a similar oncogenic pathway.Les sarcomes du stroma endométrial (SSE) sont caractérisés dans 50% des cas par une transcrit de fusion JAZF1-SUZ12 ou YWHAE-NUTM2, impliqué dans la carcinogenèse. L'exploration par séquençage ARN (RNAseq) d'une série rétrospective de 42 tumeurs utérines diagnostiquées « SSE » mais sans transcrit de fusion classique JAZF1-SUZ12 et/ou YWHAE-NUTM2 a permis de montrer que les SSE représentent en fait une pathologie hétérogène à la fois sur le plan clinique, moléculaire et immunitaire. L’analyse de l’expression des gènes en RNAseq a permis de classer ces tumeurs en 3 groupes ou « clusters » : un groupe de haut grade (principalement composé de tumeurs avec réarrangement du gène BCOR), un groupe de bas grade (principalement composé de tumeurs avec réarrangements du gène JAZF1) et le dernier groupe de grade intermédiaire (composé de divers sous-types moléculaires). Cette classification était directement corrélée à la survie des patientes. De plus, nous avons mis en évidence que le transcrit de fusion YWHAE-NUTM2 n’était pas systématiquement synonyme de haut grade. Enfin, le RNAseq a permis de reclasser un quart des tumeurs de la série et de découvrir de nouvelles anomalies moléculaires dans les SSE. Nous avons également noté que les anomalies moléculaires retrouvées par RNAseq comprenaient dans la grande majorité des cas des gènes impliqués dans le remodelage de la chromatine (notamment via les complexes PRC1 et 2), ce qui peut suggérer qu'ils activent une voie oncogénique analogue

Transcriptomic and functional analyses of recurrent molecular abnormalities in endometrial stromal sarcomas

Les sarcomes du stroma endométrial (SSE) sont caractérisés dans 50% des cas par une transcrit de fusion JAZF1-SUZ12 ou YWHAE-NUTM2, impliqué dans la carcinogenèse. L'exploration par séquençage ARN (RNAseq) d'une série rétrospective de 42 tumeurs utérines diagnostiquées « SSE » mais sans transcrit de fusion classique JAZF1-SUZ12 et/ou YWHAE-NUTM2 a permis de montrer que les SSE représentent en fait une pathologie hétérogène à la fois sur le plan clinique, moléculaire et immunitaire. L’analyse de l’expression des gènes en RNAseq a permis de classer ces tumeurs en 3 groupes ou « clusters » : un groupe de haut grade (principalement composé de tumeurs avec réarrangement du gène BCOR), un groupe de bas grade (principalement composé de tumeurs avec réarrangements du gène JAZF1) et le dernier groupe de grade intermédiaire (composé de divers sous-types moléculaires). Cette classification était directement corrélée à la survie des patientes. De plus, nous avons mis en évidence que le transcrit de fusion YWHAE-NUTM2 n’était pas systématiquement synonyme de haut grade. Enfin, le RNAseq a permis de reclasser un quart des tumeurs de la série et de découvrir de nouvelles anomalies moléculaires dans les SSE. Nous avons également noté que les anomalies moléculaires retrouvées par RNAseq comprenaient dans la grande majorité des cas des gènes impliqués dans le remodelage de la chromatine (notamment via les complexes PRC1 et 2), ce qui peut suggérer qu'ils activent une voie oncogénique analogue.In about half of cases, endometrial stromal sarcomas (ESS) are characterized in by a JAZF1-SUZ12 or YWHAE-NUTM2 fusion transcript, which is involved in carcinogenesis. The exploration by RNA sequencing of a retrospective series of 42 uterine sarcomas diagnosed as ESS but negative for JAZF1 and/or YWHAE rearrangement in FISH shows that ESS actually represent a heterogeneous disease both in terms of clinical behavior and molecular genetics. Cluster analyses on the expression profiles indicated that tumors could be gather in three distinct subgroups: one mainly composed of BCOR-rearranged samples; one mainly composed of JAZF1-fused ESS and the last composed of various molecular subtypes. These three subgroups display different gene signatures, different in silico cell cycle score, and very different clinical presentation, natural history and survival. While YWHAE-NUTM2 fusion genes may be present in both high and low grade ESS, the high-grade presenting with an additional BCOR or BCORL1 gene mutations. RNAseq brings clinically relevant molecular classification, enabling to reclassify diseases and to guide therapeutic strategy. The functional similarities between the classical JAZF1-SUZ12 and the alternative transcripts (most commonly chromosomal translocations that frequently involve chromatin remodeling genes) may suggest that they activate a similar oncogenic pathway

Radiotherapy in bone sarcoma: the quest for better treatment option

Abstract Bone sarcomas are rare tumors representing 0.2% of all cancers. While osteosarcoma and Ewing sarcoma mainly affect children and young adults, chondrosarcoma and chordoma have a preferential incidence in people over the age of 40. Despite this range in populations affected, all bone sarcoma patients require complex transdisciplinary management and share some similarities. The cornerstone of all bone sarcoma treatment is monobloc resection of the tumor with adequate margins in healthy surrounding tissues. Adjuvant chemo- and/or radiotherapy are often included depending on the location of the tumor, quality of resection or presence of metastases. High dose radiotherapy is largely applied to allow better local control in case of incomplete primary tumor resection or for unresectable tumors. With the development of advanced techniques such as proton, carbon ion therapy, radiotherapy is gaining popularity for the treatment of bone sarcomas, enabling the delivery of higher doses of radiation, while sparing surrounding healthy tissues. Nevertheless, bone sarcomas are radioresistant tumors, and some mechanisms involved in this radioresistance have been reported. Hypoxia for instance, can potentially be targeted to improve tumor response to radiotherapy and decrease radiation-induced cellular toxicity. In this review, the benefits and drawbacks of radiotherapy in bone sarcoma will be addressed. Finally, new strategies combining a radiosensitizing agent and radiotherapy and their applicability in bone sarcoma will be presented

Novel Therapeutic Options for Solitary Fibrous Tumor: Antiangiogenic Therapy and Beyond

International audienceSFT is an ultrarare mesenchymal ubiquitous tumor, with an incidence rate <1 case/million people/year. The fifth WHO classification published in April 2020 subdivided SFT into three categories: benign (locally aggressive), NOS (rarely metastasizing), and malignant. Recurrence can occur in up to 10–40% of localized SFTs, and several risk stratification models have been proposed to predict the individual risk of metastatic relapse. The Demicco model is the most widely used and is based on age at presentation, tumor size, and mitotic count. Total en bloc resection is the standard treatment of patients with a localized SFT; in case of advanced disease, the clinical efficacy of conventional chemotherapy remains poor. In this review, we discuss new insights into the biology and the treatment of patients with SFT. NAB2–STAT6 oncogenic fusion, which is the pathognomonic hallmark of SFT, is supposedly involved in the overexpression of vascular endothelial growth factor (VEGF). These specific biological features encouraged the successful assessment of antiangiogenic drugs. Overall, antiangiogenic therapies showed a significant activity toward SFT in the advanced/metastatic setting. Nevertheless, these promising results warrant additional investigation to be validated, including randomized phase III trials and biological translational analysis, to understand and predict mechanisms of efficacy and resistance. While the therapeutic potential of immunotherapy remains elusive, the use of antiangiogenics as first-line treatment should be considered

Impact of KIT exon 10 M541L allelic variant on the response to imatinib in aggressive fibromatosis: analysis of the desminib series by competitive allele specific Taqman PCR technology.

International audienceBACKGROUND:Aggressive fibromatosis (AF) is a rare fibroblastic proliferative disease with a locally aggressive behavior and no distant metastasis, characterized by driver mutations in CTNNB1 or the APC gene. When progressive and/or symptomatic AF is not amenable to local management, a variety of medical treatments may be efficient, including imatinib mesylate. The phase II "Desminib trial" included 40 patients with AF to evaluate the toxicity and efficacy of imatinib resulting in a 65% tumor control rate at 1 year. We investigated a potential predictive value of KIT exon 10 M541L variant (KITL541) on this prospective series.METHODS:DNA was extracted in sufficient quantity from 33 patients included in the Desminib trial. The detection of KITL541 was performed by Competitive Allele-Specific Taqman® PCR technology. Chi-2 analyses were performed to search for a correlation between KIT status and tumor response. Progression free (PFS) and overall survival (OS) were compared by log-rank test after Kaplan-Meier analysis.RESULTS:In 6 out of 33 cases (18%), the technique failed to determine the mutational status; 5 patients (19%) harboured KITL541 and 22 patients (81%) were classified as KIT wild type. Compared with total cohort, KITL541 frequency did not distinguish between different clinical characteristics. In the KITL541 and the KITWT subgroups, the tumor control rate at 1 year was 100% and 68%, respectively (p = 0.316). The median PFS of patients harboring KITL541 or not is 29.9 and 24.5 months, respectively (p = 0.616), and the median OS is not reached, in any of the groups.CONCLUSION:Our results do not support a predictive effect of KITL541 on the efficacy of imatinib for patients with AF

Sclerosing Encapsulating Peritonitis: Solving the Diagnosis Challenge of a Rare Entity

Sclerosing encapsulating peritonitis (SEP) is an unusual fibroinflammatory disease of the peritoneum marked by the development of a fibrous membrane enveloping generally the small intestines. The knowledge around this subject is not completely understood. And the etiology can be either idiopathic or secondary to several diseases, treatments, and/or medications. We present a case of a 52-year-old man suffering from atypical clinical symptoms including recurrent abdominal ascites and intestinal obstruction. An abdominal computed tomography showed findings typical of SEP. Therefore, the patient benefited from exploratory laparotomy, which confirmed the diagnosis of idiopathic SEP. Postoperatively, he again had an episode of bowel obstruction, but this was controlled with steroids. Diagnosis of SEP is a real challenge to surgeons, gastroenterologists, and radiologists. And imagery is very helpful to make the diagnosis. Consequently, it is imperative that all hospital practitioners should distinguish between this lesion and other etiology of acute peritonitis