Incidence and clinical relevance of RET proto-oncogene germline mutations in pheochromocytoma patients.
BACKGROUND
Autosomal dominant cancer syndrome--multiple endocrine neoplasia type 2 (MEN 2), may exist more often than expected in patients with pheochromocytoma. Germline mutations identified recently in MEN 2 can be revealed by genetic screening.


OBJECTIVE
To evaluate the frequency of RET (rearranged during transfection) mutations in patients with pheochromocytoma.


METHODS
We genetically screened germline mutations in the RET proto-oncogene and clinically re-evaluated patients with pheochromocytoma. A pentagastrin test and other biochemical studies were performed in all patients.


METHODS
Department of Internal Medicine and Hypertension, The Medical University of Warsaw, Warsaw, Poland and the Department of Nephrology and Hypertension, Albert Ludwigs University, Freiburg, Germany.


METHODS
Seventy seven unselected patients with pheochromocytoma (19 men, 58 women, mean age: 51.55 +/- 1.5 years; pheochromocytoma confirmed histopathologically) out of 162 diagnosed and treated in the years 1957-1998 in the Department of Internal Medicine and Hypertension in Warsaw, Poland. The other 85 patients did not respond to the written invitation.


METHODS
The finding of RET mutations and diagnosis of MEN 2 in patients with pheochromocytoma.


RESULTS
Genetic testing revealed germline mutations in the RET proto-oncogene in six patients (7.8%). All carriers had mutation of exon 11, codon 634: TGC to CGC. In four patients with this mutation, medullary thyroid carcinoma (MIC) was diagnosed and in three cases, surgically treated. Biochemical parameters: parathormone 31.88 +/- 2.87 pg/ml, calcitonin: 0 min 0.23 +/- 0.14 ng/ml; 2 min 0.49 +/- 0.21 ng/ml; 5 min 0.48 +/- 0.21 ng/ml, metoxycatecholamines: 601.62 +/- 42.71 microg/24h, epinephrine: 1.94 +/- 0.17 microg/24h, norepinephrine 13.96 +/- 1.3 microg/24h, carcinoembryonic antigen (CEA) 9.94 +/- 4.3 ng/ml. Ambulatory blood pressure monitoring (ABPM): systolic blood pressure (SBP): 116 +/- 1.9 mmHg, diastolic blood pressure (DBP): 73.7 +/- 0.9 mmHg. Clinical, biochemical and imaging procedures did not reveal any recurrence of pheochromocytoma in the 77 patients studied.


CONCLUSIONS
Patients with pheochromocytoma should be genetically screened for mutations of the RET proto-oncogene. These patients should undergo clinical screening for MEN 2. In addition, genetic studies can be useful for the screening of the families of the carriers.
Januszewicz
A
A
Department of Hypertension, Institute of Cardiology, Warsaw, Poland.
Neumann
H P
HP
Loń
I
I
Szmigielski
C
C
Symonides
B
B
Kabat
M
M
Apel
T W
TW
Wocial
B
B
Lapiński
M
M
Januszewicz
W
W
D000310:Adrenal Gland Neoplasms / Q000453:epidemiology / Q000235:genetics*; D000328:Adult; D018660:Blood Pressure Monitoring, Ambulatory; D029721:Drosophila Proteins; D005260:Female; D005787:Gene Frequency; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D008297:Male; D010281:Parathyroid Hormone / Q000097:blood; D010375:Pedigree; D010418:Pentagastrin; D010673:Pheochromocytoma / Q000453:epidemiology / Q000235:genetics*; D011044:Poland / Q000453:epidemiology; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*
D029721:Drosophila Proteins; C000715470:MAS1 protein, human; D010281:Parathyroid Hormone; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila; D010418:Pentagastrin