Abstract
BackgroundAbout 60% of Pheochromocytoma (PCC) and Paraganglioma (PGL) patients have either germline or somatic mutations in one of the 12 proposed disease causing genes; SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, EPAS1, RET, NF1, TMEM127, MAX and H-RAS. Selective screening for germline mutations is routinely performed in clinical management of these diseases. Testing for somatic alterations is not performed on a regular basis because of limitations in interpreting the results.AimThe purpose of the study was to investigate genetic events and phenotype correlations in a large cohort of PCC and PGL tumours.MethodsA total of 101 tumours from 89 patients with PCC and PGL were re-sequenced for a panel of 10 disease causing genes using automated Sanger sequencing. Selected samples were analysed with Multiplex Ligation-dependent Probe Amplification and/or SNParray.ResultsPathogenic genetic variants were found in tumours from 33 individual patients (37%), 14 (16%) were discovered in constitutional DNA and 16 (18%) were confirmed as somatic. Loss of heterozygosity (LOH) was observed in 1/1 SDHB, 11/11 VHL and 3/3 NF1-associated tumours. In patients with somatic mutations there were no recurrences in contrast to carriers of germline mutations (P = 0.022). SDHx/VHL/EPAS1 associated cases had higher norepinephrine output (P = 0.03) and lower epinephrine output (P<0.001) compared to RET/NF1/H-RAS cases.ConclusionSomatic mutations are frequent events in PCC and PGL tumours. Tumour genotype may be further investigated as prognostic factors in these diseases. Growing evidence suggest that analysis of tumour DNA could have an impact on the management of these patients.
Highlights
Pheochromocytoma (PCC) and paraganglioma (PGL) are rare neural crest-derived tumours arising in the adrenal medulla (PCC) or autonomic ganglia (PGL)
In patients with somatic mutations there were no recurrences in contrast to carriers of germline mutations (P = 0.022)
Translational studies show that approximately 60% of PCC and PGL cases have either germline or somatic mutations in one of 13 suggested disease causing loci; SDH subunits A, B, C and D, SDHAF2, Von Hippel Lindau syndrome (VHL), EPAS1, RET, Neurofibromatosis type 1 (NF1), TMEM127, MAX and H-RAS [8,9,10,11,12,13,14,15,16,17,18,19,20]
Summary
Pheochromocytoma (PCC) and paraganglioma (PGL) are rare neural crest-derived tumours arising in the adrenal medulla (PCC) or autonomic ganglia (PGL). Translational studies show that approximately 60% of PCC and PGL cases have either germline or somatic mutations in one of 13 suggested disease causing loci; SDH subunits A, B, C and D, SDHAF2, VHL, EPAS1, RET, NF1, TMEM127, MAX and H-RAS [8,9,10,11,12,13,14,15,16,17,18,19,20]. The aim of this study was, to describe the genetic landscape of PCC and PGL tumours and to correlate tumour genotype with patient characteristics and disease outcome. About 60% of Pheochromocytoma (PCC) and Paraganglioma (PGL) patients have either germline or somatic mutations in one of the 12 proposed disease causing genes; SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, EPAS1, RET, NF1, TMEM127, MAX and H-RAS. Testing for somatic alterations is not performed on a regular basis because of limitations in interpreting the results
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