nach oben

European Journal of Nuclear Medicine and Molecular Imaging

Erschienen in:

01.06.2020 | Original Article

Succinate detection using in vivo ¹H-MR spectroscopy identifies germline and somatic SDHx mutations in paragangliomas

verfasst von: Charlotte Lussey-Lepoutre, Alexandre Bellucci, Nelly Burnichon, Laurence Amar, Alexandre Buffet, Tom Drossart, Sébastien Fontaine, Olivier Clement, Paule Benit, Pierre Rustin, Lionel Groussin, Tchao Meatchi, Anne-Paule Gimenez-Roqueplo, Bertrand Tavitian, Judith Favier

Erschienen in: European Journal of Nuclear Medicine and Molecular Imaging | Ausgabe 6/2020

Einloggen, um Zugang zu erhalten

Abstract

Purpose

Germline mutations in genes encoding succinate dehydrogenase (SDH) are frequent in patients with pheochromocytoma and paraganglioma (PPGL). They lead to SDH inactivation, mediating a massive accumulation of succinate, which constitutes a highly specific biomarker of SDHx-mutated tumors when measured in vitro. In a recent pilot study, we showed that magnetic resonance spectroscopy (¹H-MRS) optimized for succinate detection (SUCCES) could detect succinate in vivo in both allografted mouse models and PPGL patients. The objective of this study was to prospectively assess the diagnostic performances of ¹H-MRS SUCCES sequence for the identification of SDH deficiency in PPGL patients.

Methods

Forty-nine patients presenting with 50 PPGLs were prospectively enrolled in our referral center for ¹H-MRS SUCCES. Two observers blinded to the clinical characteristics and genetic status analyzed the presence of a succinate peak and confronted the results to a composite gold standard combining PPGL genetic testing and/or in vitro protein analyses in the tumor.

Results

A succinate peak was observed in 20 tumors, all of which had proven SDH deficiency using the gold standard (17 patients with germline SDHx mutations, 2 with a somatic SDHD mutation, and 1 with negative SDHB IHC and SDH loss of function). A false negative result was observed in 3 tumors. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of ¹H-MRS SUCCES were respectively 87%, 100%, 100%, 90%, and 94%.

Conclusions

Detection of succinate using ¹H-MRS is a highly specific and sensitive hallmark of SDH-deficiency in PPGLs.

Nur mit Berechtigung zugänglich

Buffet A, Ben Aim L, Leboulleux S, Drui D, Vezzosi D, Libe R, et al. Positive impact of genetic test on the management and outcome of patients with paraganglioma and/or pheochromocytoma. J Clin Endocrinol Metab. 2019;104(4):1109–18. https://doi.org/10.1210/jc.2018-02411.CrossRefPubMed

Favier J, Amar L, Gimenez-Roqueplo AP. Paraganglioma and phaeochromocytoma: from genetics to personalized medicine. Nat Rev Endocrinol. 2015;11(2):101–11. https://doi.org/10.1038/nrendo.2014.188.CrossRefPubMed

Amar L, Baudin E, Burnichon N, Peyrard S, Silvera S, Bertherat J, et al. Succinate dehydrogenase B gene mutations predict survival in patients with malignant pheochromocytomas or paragangliomas. J Clin Endocrinol Metab. 2007;92(10):3822–8. https://doi.org/10.1210/jc.2007-0709.CrossRefPubMed

Gimenez-Roqueplo AP, Favier J, Rustin P, Rieubland C, Crespin M, Nau V, et al. Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas. Cancer Res. 2003;63(17):5615–21.PubMed

Favier J, Briere JJ, Burnichon N, Riviere J, Vescovo L, Benit P, et al. The Warburg effect is genetically determined in inherited pheochromocytomas. PLoS One. 2009;4(9):e7094. https://doi.org/10.1371/journal.pone.0007094.CrossRefPubMedPubMedCentral

Letouze E, Martinelli C, Loriot C, Burnichon N, Abermil N, Ottolenghi C, et al. SDH mutations establish a hypermethylator phenotype in paraganglioma. Cancer Cell. 2013;23(6):739–52. https://doi.org/10.1016/j.ccr.2013.04.018.CrossRefPubMed

Morin A, Letouze E, Gimenez-Roqueplo AP, Favier J. Oncometabolites-driven tumorigenesis: from genetics to targeted therapy. Int J Cancer. 2014;135(10):2237–48. https://doi.org/10.1002/ijc.29080.CrossRefPubMed

Selak MA, Armour SM, MacKenzie ED, Boulahbel H, Watson DG, Mansfield KD, et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell. 2005;7(1):77–85. https://doi.org/10.1016/j.ccr.2004.11.022.CrossRefPubMed

Pollard PJ, Briere JJ, Alam NA, Barwell J, Barclay E, Wortham NC, et al. Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations. Hum Mol Genet. 2005;14(15):2231–9. https://doi.org/10.1093/hmg/ddi227.CrossRefPubMed

10.

Richter S, Peitzsch M, Rapizzi E, Lenders JW, Qin N, de Cubas AA, et al. Krebs cycle metabolite profiling for identification and stratification of pheochromocytomas/paragangliomas due to succinate dehydrogenase deficiency. J Clin Endocrinol Metab. 2014;99(10):3903–11. https://doi.org/10.1210/jc.2014-2151.CrossRefPubMedPubMedCentral

11.

Rao JU, Engelke UF, Rodenburg RJ, Wevers RA, Pacak K, Eisenhofer G, et al. Genotype-specific abnormalities in mitochondrial function associate with distinct profiles of energy metabolism and catecholamine content in pheochromocytoma and paraganglioma. Clin Cancer Res. 2013;19(14):3787–95. https://doi.org/10.1158/1078-0432.CCR-12-3922.CrossRefPubMedPubMedCentral

12.

Lussey-Lepoutre C, Bellucci A, Morin A, Buffet A, Amar L, Janin M, et al. In vivo detection of succinate by magnetic resonance spectroscopy as a Hallmark of SDHx mutations in paraganglioma. Clin Cancer Res. 2016;22(5):1120–9. https://doi.org/10.1158/1078-0432.CCR-15-1576.CrossRefPubMed

13.

Lenders JW, Duh QY, Eisenhofer G, Gimenez-Roqueplo AP, Grebe SK, Murad MH, et al. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014;99(6):1915–42. https://doi.org/10.1210/jc.2014-1498.CrossRefPubMed

14.

Plouin PF, Gimenez-Roqueplo AP, Bertagna X. COMETE, a network for the study and management of hypersecreting adrenal tumors. Bull Acad Natl Med. 2008;192(1):73–82 discussion 3-5.PubMed

15.

Webb PG, Sailasuta N, Kohler SJ, Raidy T, Moats RA, Hurd RE. Automated single-voxel proton MRS: technical development and multisite verification. Magn Reson Med. 1994;31(4):365–73.CrossRef

16.

Korpershoek E, Favier J, Gaal J, Burnichon N, van Gessel B, Oudijk L, et al. SDHA immunohistochemistry detects germline SDHA gene mutations in apparently sporadic paragangliomas and pheochromocytomas. J Clin Endocrinol Metab. 2011;96(9):E1472–6. https://doi.org/10.1210/jc.2011-1043.CrossRefPubMed

17.

Menara M, Oudijk L, Badoual C, Bertherat J, Lepoutre-Lussey C, Amar L, et al. SDHD immunohistochemistry: a new tool to validate SDHx mutations in pheochromocytoma/paraganglioma. J Clin Endocrinol Metab. 2015;100(2):E287–91. https://doi.org/10.1210/jc.2014-1870.CrossRefPubMed

18.

van Nederveen FH, Gaal J, Favier J, Korpershoek E, Oldenburg RA, de Bruyn EM, et al. An immunohistochemical procedure to detect patients with paraganglioma and phaeochromocytoma with germline SDHB, SDHC, or SDHD gene mutations: a retrospective and prospective analysis. Lancet Oncol. 2009;10(8):764–71. https://doi.org/10.1016/S1470-2045(09)70164-0.CrossRefPubMedPubMedCentral

19.

Benit P, Goncalves S, Philippe Dassa E, Briere JJ, Martin G, Rustin P. Three spectrophotometric assays for the measurement of the five respiratory chain complexes in minuscule biological samples. Clin Chim Acta. 2006;374(1–2):81–6. https://doi.org/10.1016/j.cca.2006.05.034.CrossRefPubMed

20.

Ben Aim L, Pigny P, Castro-Vega LJ, Buffet A, Amar L, Bertherat J, et al. Targeted next-generation sequencing detects rare genetic events in pheochromocytoma and paraganglioma. J Med Genet. 2019. https://doi.org/10.1136/jmedgenet-2018-105714.

21.

Group NGSiPS, Toledo RA, Burnichon N, Cascon A, Benn DE, Bayley JP, et al. Consensus statement on next-generation-sequencing-based diagnostic testing of hereditary phaeochromocytomas and paragangliomas. Nat Rev Endocrinol. 2017;13(4):233–47. https://doi.org/10.1038/nrendo.2016.185.CrossRef

22.

Curras-Freixes M, Inglada-Perez L, Mancikova V, Montero-Conde C, Leton R, Comino-Mendez I, et al. Recommendations for somatic and germline genetic testing of single pheochromocytoma and paraganglioma based on findings from a series of 329 patients. J Med Genet. 2015;52(10):647–56. https://doi.org/10.1136/jmedgenet-2015-103218.CrossRefPubMed

23.

van Nederveen FH, Korpershoek E, Lenders JW, de Krijger RR, Dinjens WN. Somatic SDHB mutation in an extraadrenal pheochromocytoma. N Engl J Med. 2007;357(3):306–8. https://doi.org/10.1056/NEJMc070010.CrossRefPubMed

24.

Boikos SA, Pappo AS, Killian JK, LaQuaglia MP, Weldon CB, George S, et al. Molecular subtypes of KIT/PDGFRA wild-type gastrointestinal stromal tumors: a report from the National Institutes of Health Gastrointestinal Stromal Tumor Clinic. JAMA Oncol. 2016;2(7):922–8. https://doi.org/10.1001/jamaoncol.2016.0256.CrossRefPubMedPubMedCentral

25.

Evenepoel L, Papathomas TG, Krol N, Korpershoek E, de Krijger RR, Persu A, et al. Toward an improved definition of the genetic and tumor spectrum associated with SDH germ-line mutations. Genet Med. 2015;17(8):610–20. https://doi.org/10.1038/gim.2014.162.CrossRefPubMed

26.

Mason EF, Hornick JL. Conventional risk stratification fails to predict progression of succinate dehydrogenase-deficient gastrointestinal stromal tumors: a clinicopathologic study of 76 cases. Am J Surg Pathol. 2016;40(12):1616–21. https://doi.org/10.1097/PAS.0000000000000685.CrossRefPubMed

27.

Ricketts C, Woodward ER, Killick P, Morris MR, Astuti D, Latif F, et al. Germline SDHB mutations and familial renal cell carcinoma. J Natl Cancer Inst. 2008;100(17):1260–2. https://doi.org/10.1093/jnci/djn254.CrossRefPubMed

28.

Casey RT, McLean MA, Madhu B, Challis BG, ten Hoopen R, Roberts T, et al. Translating in vivo metabolomic analysis of succinate dehydrogenase deficient tumors into clinical utility. JCO Precis Oncol. 2019;2:1–12. https://doi.org/10.1200/PO.17.00191.CrossRef

29.

Taieb D, Jha A, Treglia G, Pacak K. Molecular imaging and radionuclide therapy of paraganglioma and pheochromocytoma. Endocr Relat Cancer. 2019. https://doi.org/10.1530/ERC-19-0165.

30.

Varoquaux A, le Fur Y, Imperiale A, Reyre A, Montava M, Fakhry N, et al. Magnetic resonance spectroscopy of paragangliomas: new insights into in vivo metabolomics. Endocr Relat Cancer. 2015;22(4):M1–8. https://doi.org/10.1530/ERC-15-0246.CrossRefPubMedPubMedCentral

Titel: Succinate detection using in vivo 1H-MR spectroscopy identifies germline and somatic SDHx mutations in paragangliomas
verfasst von: Charlotte Lussey-Lepoutre
Alexandre Bellucci
Nelly Burnichon
Laurence Amar
Alexandre Buffet
Tom Drossart
Sébastien Fontaine
Olivier Clement
Paule Benit
Pierre Rustin
Lionel Groussin
Tchao Meatchi
Anne-Paule Gimenez-Roqueplo
Bertrand Tavitian
Judith Favier
Publikationsdatum: 01.06.2020
Verlag: Springer Berlin Heidelberg
Erschienen in: European Journal of Nuclear Medicine and Molecular Imaging / Ausgabe 6/2020
Print ISSN: 1619-7070
Elektronische ISSN: 1619-7089
DOI: https://doi.org/10.1007/s00259-019-04633-9

Springer Medizin

Abstract

Purpose

Methods

Results

Conclusions

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 6/2020

Tumor uptake in glioblastoma multiforme after IV injection of [177Lu]Lu-PSMA-617

TSPO PET, tumour grading and molecular genetics in histologically verified glioma: a correlative 18F-GE-180 PET study

FDG-PET assessment and metabolic patterns in Lafora disease

Assessment of treatment responses in children and adolescents with Ewing sarcoma with metabolic tumor parameters derived from 18F-FDG-PET/CT and circulating tumor DNA

18F-Fluciclovine (18F-FACBC) PET imaging of recurrent brain tumors

18F-Fluorocholine PET uptake correlates with pathologic evidence of recurrent tumor after stereotactic radiosurgery for brain metastases