ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2019) 16 8.12 | DOI: 10.1530/ey.16.8.12

Genetics department, Assistance Publique-Hôpitaux de Paris, Hôpitaleuropéen Georges Pompidou, F-75015, Paris, France


To read the full abstract: J Med Genet. 2019 Mar 15. pii: jmedgenet-2018-105714. [Epub ahead of print].

Paragangliomas and pheochromocytomas (PPGL) are rare neuroendocrine tumours that can arise either from the adrenal medulla (pheochromocytomas, PCC) or from extra-adrenal paraganglia (paragangliomas, PGL). PPGLs are considered to be the most heritable of human tumours with at least 35% having inherited forms of the disease (13). Driver mutations can also be identified at somatic level, and overall, germline or somatic mutations in one of the 18 known genes involved in PPGL pathogenesis are present in ~60% of tumours (14). These PPGL genes include VHL, NF1, RET, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, FH, MAX, EPAS1, HRAS, EGLN1, ATRX, MET, MDH2 and SLC25A11, demonstrating a high degree of genetic heterogeneity in the aetiology of these tumours. Published guidelines recommend that genetic testing should be considered in all patients with PPGL.

This study aimed to validate a unique customized ‘MASTR Plus SDHv2’ PPGL gene panel using next generation sequencing (NGS) of germline and tumour DNAs, including DNA extracted from formalin-fixed paraffin-embedded (FFPE) tissues in order to rapidly identify driver mutations in patients and tumours for guiding follow-up, targeted therapies in case of metastatic PPGL and familial genetic counselling.

The NGS custom-designed targeted panel significantly improved the diagnostic accuracy for mutation detection in PPGL compared with former genetic approaches. In total, the NGS panel assessed in both retrospective and prospective cohorts, encompassing 768 patients’ germline and/or tumour DNA, showed higher accuracy for PPGL genetic testing than conventional methods with a significant increase of the mutation detection rate (78% vs. 65%). Furthermore, the NGS panel brought an additional value in diagnosing co-occurring variants and mosaicism, both genetic mechanisms not easily identified so far. These data are essential for guiding genetic counselling, which indicates or exempts (in the presence or the absence of a germline mutation) specific management and follow-up, as well as predictive genetic testing in the relatives or to reassure (in front of truly somatic mutations) patients about the risk of relapse.

References: 13. Toledo RA, Burnichon N, Cascon A, Benn DE, Bayley JP, Welander J, Tops CM, Firth H, Dwight T, Ercolino T, Mannelli M, Opocher G, Clifton-Bligh R, Gimm O, Maher ER, Robledo M, Gimenez-Roqueplo AP, Dahia PLM. Consensus Statement on next generation-sequencing-based diagnostic testing of hereditary phaeochromocytomas and paragangliomas. Nat Rev Endocrinol 2017; 13:233–47.

14. Favier J, Amar L, Gimenez-Roqueplo AP. Paraganglioma and phaeochromocytoma: from genetics to personalized medicine. Nat Rev Endocrinol 2015; 11:101–11.

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