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We recently reported that miR-146a is differentially expressed in ALK+ and ALK− anaplastic large cell lymphoma (ALCL). In this study, the downstream targets of miR-146a in ALK+ ALCL were investigated by transcriptome analysis, identifying CD147 as potential target gene. Because CD147 is differentially expressed in ALK+ ALCL versus ALK− ALCL and normal T cells, this gene emerged as a strong candidate for the pathogenesis of this tumor. Here we demonstrate that CD147 is a direct target of miR-146 and contributes to the survival and proliferation of ALK+ ALCL cells in vitro and to the engraftment and tumor growth in vivo in an ALK+ ALCL-xenotransplant mouse model. CD147 knockdown in ALK+ ALCL cells resulted in loss of monocarboxylate transporter 1 (MCT1) expression, reduced glucose consumption and tumor growth retardation, as demonstrated by [18F]FDG-PET/MRI analysis. Investigation of metabolism in vitro and in vivo supported these findings, revealing reduced aerobic glycolysis and increased basal respiration in CD147 knockdown. In conclusion, our findings indicate that CD147 is of vital importance for ALK+ ALCL to maintain the high energy demand of rapid cell proliferation, promoting lactate export, and tumor growth. Furthermore, CD147 has the potential to serve as a novel therapeutic target in ALK+ ALCL, and warrants further investigation.

Funder: European Union’s Horizon 2020 Marie Skłodowska – Curie Innovative Training Networks (ITN - ETN) under grant agreement No.: 675712European Union’s Horizon 2020 Marie Skłodowska – Curie Innovative Training Networks (ITN - ETN) under grant agreement No.: 675712 Czech Science Foundation (GA CR), junior project no. 19-23424Y MEYS CZ project CEITEC 2020 (LQ1601), Funder: MEYS CZ project CEITEC 2020 (LQ1601) NCMG research infrastructure (LM22018132 funded by MEYS CR), Funder: European Union’s Horizon 2020 Marie Skłodowska – Curie Innovative Training Networks (ITN - ETN) under grant agreement No.: 675712., Funder: MH CZ-RVO 65269705

Further details on materials and methods used for this case study are provided as a supplement. (PDF 101 kb)

Background The PTEN-hamartoma-tumor-syndrome (PHTS) is caused by germline mutations in Phosphatase and Tensin homolog (PTEN) and predisposes to the development of several typical malignancies. Whereas PTEN mutations have been implicated in the occurrence of malignant mesotheliomas, the genetic landscape of verrucous carcinomas (VC) is largely uncharted. Both VC and malignant peritoneal mesotheliomas (MPM) are exceedingly rare and a potential link between these malignancies and PHTS has never been reported. Case presentation We here describe the clinical course of a PHTS patient who, in addition to a typical thyroid carcinoma at the age of 36 years, developed a highly-differentiated oral VC and an epithelioid MPM six years later. The patient with a history of occupational asbestos exposure underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for MPM. The clinical diagnosis of PHTS was consequently corroborated by a germline PTEN deletion. Sequencing of tumor tissue revealed a second hit in PTEN in the thyroid carcinoma and VC, confirmed by a PTEN loss and activation of the PI3K/AKT pathway in immunohistochemistry. Furthermore, additional somatic mutations in the thyroid carcinoma as well as in the VC were detected, whereas the genetics of MPM remained unrevealing. Discussion and conclusions We here report the very unusual clinical course of a patient with rare tumors that have a germline mutation first hit in PTEN in common. Since this patient was exposed to asbestos and current evidence suggests molecular mechanisms that might render PHTS patients particularly susceptible to mesothelioma, we strongly recommend PHTS patients to avoid even minimal exposure. Electronic supplementary material The online version of this article (10.1186/s12881-018-0651-4) contains supplementary material, which is available to authorized users.

Pediatric-type follicular lymphoma (PTFL) is a B-cell lymphoma with distinctive clinicopathological features. Recently, recurrent genetic alterations of potential importance for its pathogenesis that disrupt pathways associated with the germinal center reaction (

BACKGROUND: Systemic Anaplastic Large Cell Lymphoma (sALCL) is comprised of two distinct T-cell non-Hodgkin lymphoma entities: ALK-positive (ALK+) ALCL and ALK-negative (ALK-) ALCL. These entities are characterized by either the presence of absence of an ALK-translocation. It has been reported that ALK+ ALCL has a better prognosis compared to ALK- ALCL, with a 5-year overall survival (OS) of 70-80% versus 15-45%, respectively. Furthermore, more than 25% of ALK+ ALCL patients undergo relapse. sALCL is a genetically heterogeneous disease whose genomic characterization has been improved through the implementation of high-throughput technologies. Despite this, the prognostic value of somatic mutations has been poorly described. Here we present the analysis of genetic aberrations of sALCL, shedding light on disease pathogenesis, novel diagnostic biomarkers and prognostic markers for the detection of refractory and/or relapsed patients which could hold clinical implications. METHODS: Formalin-fixed paraffin-embedded (FFPE) and/or fresh frozen tissue and related clinical information for 82 sALCL patients (47 ALK+ and 35 ALK-) were obtained after written informed consent from 5 centres across Europe. Using deep targeted DNA sequencing, the entire coding region of 275 selected genes (QIAseq Targeted DNA - Human Comprehensive Cancer Panel, Qiagen, Germany) was investigated in our retrospective cohort of patient' samples as well as 6 ALCL cell lines (Karpas-299, SU-DHL-1, DEL, SR786, FEPD and MAC2a). The average depth achieved across all the sequenced samples was approximately 2000x allowing the detection of aberrations with low allele frequencies ( RESULTS: ALK- patients in our cohort have a worse prognosis than ALK+, whereby the 7y-OS was 45.1% and 73.2%, respectively, although the 7 year progression free survival (PFS) was comparable at 57.1% for ALK+ and 42.4% for ALK- patients. As previously reported, ALK+ patients were significantly younger in our series than ALK- patients with an average age of 23.5 and 55.2 years, respectively. Among the 275 genes sequenced, 148 (53.8%) genes harbor at least one mutation throughout the entire patient and cell line cohort; almost 1/3 of mutated genes were shared between ALK- and ALK+ ALCL patients. On average 4.2 mutations per patient were detected in ALK- ALCL, a higher level than observed in ALK+ samples (2.7), most likely due to the oncogenic-driving role of the ALK-translocation in this group. Seventy-two out of 82 (88%) patients carried at least one single mutation within the genes analysed in our panel. The most recurrent genes mutated were TP53 in both sALCL categories (16% of sALCL patients), followed by LRP1B being prevalently mutated in ALK+ disease (15% of sALCL patients). As expected, STAT3 and JAK1 were mutated solely in the ALK- ALCL cohort and represent the most commonly mutated genes in this group. Prognostically, the most recurrent genes mutated in patients with a dismal outcome (dead and/or relapsed patients) were TP53, STAT3, EPHA5, JAK1, LRP1B, KMT2D, PRDM1 and SOCS1. Comparing samples at diagnosis versus relapse highlighted two key findings: firstly, the clonal expansion of TP53 mutated clones in relapsed ALCL patients and secondly, the acquired mutations in EPHA5 which were only detected at relapse. These data suggest their possible use as biomarkers associated with clonal evolution. CONCLUSION: This study provides information regarding the genetic landscape in sALCL across 275 select genes. We have confirmed the importance of known frequently mutated genes (STAT3 and JAK1) and describe novel recurrently mutated genes (LRP1B, EPHA5 and KMT2D). Mutations in STAT3 were more recurrent in ALK- ALCL patients with shorter OS, and clones harboring mutated TP53 and EPHA5 were detectable more often in relapsed sALCL thereby suggesting a possible driving role. Disclosures Gambacorti-Passerini: Bristol-Meyers Squibb: Consultancy; Pfizer: Honoraria, Research Funding.