Open AccessIntegrative Genetic Characterization and Phenotype Correlations in Pheochromocytoma and Paraganglioma Tumours
Author(s) -
Joakim Crona,
Margareta Nordling,
Rajani Maharjan,
Dan Granberg,
Peter Stålberg,
Per Hellman,
Peyman Björklund
Publication year - 2014
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0086756
Subject(s) - sdhd , sdhb , paraganglioma , pheochromocytoma , germline mutation , loss of heterozygosity , sdha , sanger sequencing , biology , germline , somatic cell , multiplex ligation dependent probe amplification , cancer research , multiple endocrine neoplasia type 2 , genetics , genotype , mutation , pathology , gene , medicine , endocrinology , allele , exon , gene expression
Background 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 . 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. Aim The purpose of the study was to investigate genetic events and phenotype correlations in a large cohort of PCC and PGL tumours. Methods A 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. Results Pathogenic 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. Conclusion Somatic 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.