In the past, our research was stricklty dedicated to the study of pheochromocytoma and paraganglioma (PPGL), rare neuroendocrine tumors causing secondary hypertension. PPGL are characterized by a very strong genetic component and we have particularly focused our research on PPGL susceptibility genes encoding a mitochondrial enzyme, succinate dehydrogenase (SDH), with the aim of improving the understanding of PPGL as a model to decipher the mechanisms linking cell metabolism, angiogenesis, epigenetic reprogramming and carcinogenesis.
For the 2019-2024 period, the team, while continuing its on-going projects on PPGL, will extend its research interests to other types of rare cancers such as renal cancers and gastro-intestinal stroma tumors (GIST). The team tackles both basic science with the study of oncogenic pathways associated with mitochondrial deficiencies, and translational research with human genetics, biomarker identification and therapeutic proof-of-concepts. In order to achieve these extended goals in a rare and therefore poorly studied disease, our strategy has been to develop numerous but strong and long lasting collaborations, to investigate these wide questions using cutting-edge technologies and with a unique access to patients and biosamples. This state-of-the-art multidisciplinary approach has led us to collaborate with several clinical departments (from HEGP and other hospitals) and with research teams involved in in vivo imaging, metabolomics or fluxomics .
Our team is currently recognized as a top-level research team at national and international level. Judith FAVIER is the co-chair of the international Pheochromocytoma and paraganglioma RESearch Support ORganization (PRESSOR). Anne-Paule Gimenez-Roqueplo is the former head of the PPGL working group of the European Network for the Study of Adrenal Tumours (ENS@T).
Telomerase activation and ATRX mutations are independent risk factors for metastatic pheochromocytoma and paraganglioma.
PURPOSE : Pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumors. While most PPGL are benign, up to 20% may become metastatic with – and -mutated tumors showing the higher risk. We aimed at determining the contribution of immortalization mechanisms to metastatic progression.
EXPERIMENTAL DESIGN : Immortalization mechanisms were investigated in 200 tumors. To identify telomerase (+) tumors we analyzed genomic alterations leading to transcriptional activation of comprising promoter mutations, hypermethylation and gain copy number. To identify tumors that activated the alternative lengthening of telomere (ALT) mechanism, we combined analyses of telomere length by slot blot, telomere heterogeneity by telomere FISH, and mutations by next-generation sequencing. Univariate/multivariate and metastasis-free survival (MFS) and overall survival (OS) analyses were carried out for assessment of risk factors and clinical outcomes.
RESULTS : Only 37/200 (18.5%) tumors achieved immortalization. Telomerase activation occurred in 12 metastatic tumors, and was prevalent in -mutated paragangliomas ( = 2.42e-09). ALT features were present in 25 tumors, mostly pheochromocytomas, regardless of metastatic status or molecular group ( = .169), yet mutations were found preferentially in /-mutated metastatic ( = .0014). Telomerase activation and mutations were independent factors of poor prognosis: MFS (hazard ratio, 48.2 and 33.1; = 6.50E-07 and 1.90E-07, respectively); OS (hazard ratio, 97.4 and 44.1; = 4.30E-03 and 2.00E-03, respectively) and were associated with worse MFS and OS (logrank tests < .0001).
CONCLUSION : Assessment of telomerase activation and mutations could be used to identify metastatic PPGL, particularly in tumors at high-risk of progression.
Clin Can Res 2018More