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Analysis of PTEN mutation in non-familial pheochromocytoma
Janusz Puc1, Grzegorz Placha, Bozenna Wocial
1Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA. jpuc@ucsd.edu
Abstract:
PTEN, a tumor suppressor gene, is frequently mutated in a variety of human tumors. In mice, monoallelic inactivation of this gene predisposes animals to neoplasia of multiple organs. Interestingly, Pten heterozygous mice develop bilateral hyperplasia of the adrenal medulla. In this report we demonstrate that these neoplasms are hormonally active pheochromocytomas that secrete increased amounts of bioactive catecholamines: norepinephrine and epinephrine. To test a possibility that PTEN might be one of the genes responsible for human sporadic pheochromocytoma, we performed mutation analysis of DNA obtained from tumors of 29 patients. However, direct sequencing of all nine exons of the PTEN gene, including the splice junctions, revealed no mutations. Examination of protein expression by immunohistochemistry using 8 normal adrenals and 11 sporadic pheochromocytomas showed no decrease in the PTEN protein expression in the tumor tissue, but upregulation of insulin-like growth factor II, a peptide implicated in growth of adrenal tissue, was observed in four cases (36%).
Insights
The tumor suppressor gene PTEN, when inactivated in mice, causes adrenal medulla hyperplasia and hormonally active pheochromocytomas. Human sporadic pheochromocytomas showed no PTEN mutations but increased insulin-like growth factor II.
Area of Science:
- Oncology
- Endocrinology
- Molecular Biology
Background:
- The tumor suppressor gene PTEN is frequently mutated in human cancers.
- Monoallelic inactivation of PTEN in mice leads to neoplasia in multiple organs.
- Pten heterozygous mice exhibit bilateral adrenal medulla hyperplasia.
Purpose of the Study:
- To investigate if PTEN mutations are responsible for human sporadic pheochromocytoma.
- To characterize the hormonal activity of Pten-induced pheochromocytomas in mice.
- To examine PTEN protein expression and IGF-II levels in human pheochromocytomas.
Main Methods:
- Mutation analysis (direct sequencing) of the PTEN gene in 29 human pheochromocytoma tumors.
- Immunohistochemistry to assess PTEN protein expression in normal adrenal tissue and pheochromocytomas.
- Analysis of insulin-like growth factor II (IGF-II) expression in pheochromocytoma tissues.
Main Results:
- Pten heterozygous mice developed hormonally active pheochromocytomas secreting norepinephrine and epinephrine.
- No PTEN gene mutations were detected in the 29 human sporadic pheochromocytoma tumors.
- PTEN protein expression was not decreased in human pheochromocytomas; however, IGF-II was upregulated in 36% of cases.
Conclusions:
- PTEN inactivation in mice leads to pheochromocytomas with increased catecholamine secretion.
- PTEN mutations are unlikely to be a primary cause of human sporadic pheochromocytoma.
- Upregulation of IGF-II may play a role in the growth of human sporadic pheochromocytomas.
