Integrative genetic characterization and phenotype correlations in pheochromocytoma and paraganglioma tumours.
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.


OBJECTIVE
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.


CONCLUSIONS
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.
Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
Joakim
J
Crona
Department of Clinical Genetics, Sahlgrenska University Hospital, Göteborg, Sweden.
Margareta
M
Nordling
Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
Rajani
R
Maharjan
Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
Dan
D
Granberg
Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
Peter
P
Stålberg
Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
Per
P
Hellman
Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
Peyman
P
Björklund
D000310:Adrenal Gland Neoplasms / Q000235:genetics* / Q000473:pathology; D001483:Base Sequence; D015331:Cohort Studies; D052138:Genes, Neoplasm / Q000235:genetics*; D005820:Genetic Testing / Q000379:methods; D018095:Germ-Line Mutation / Q000235:genetics; D006801:Humans; D019656:Loss of Heterozygosity / Q000235:genetics; D008969:Molecular Sequence Data; D010235:Paraganglioma / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D010673:Pheochromocytoma / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA; D013548:Sweden