[596] Endocrine Tumors Display Site-Specific Alterations in Wnt Signaling, the mTOR Pathway, and Chromatin Remodeling

Paula S Ginter, Nicole C Panarelli, Rhonda K Yantiss, Theresa Scognamiglio, Yao-Tseng Chen. Weill Cornell Medical College, New York

Background: Endocrine tumors (ET) comprise a heterogeneous group of neoplasms that affect multiple organ systems, yet genetic alterations in these sporadic tumors are poorly defined. Some ET of the bronchi, gastrointestinal (GI) tract, and adrenal cortex show B-catenin mutations, whereas mTOR pathway activation and mutations in the chromatin remodeling genes, ATRX and DAXX, are thought to be crucial to pancreatic ET pathogenesis. In this study, we evaluated the expression of B-catenin, mTOR pathway proteins, ATRX and DAXX in ET from various organs to determine their potential roles in the pathogenesis of ET.
Design: Tissue microarrays were constructed from low-to-intermediate grade ET (Ki-67 index <20%), including 50 parathyroid adenomas, 50 adrenocortical adenomas, 46 pituitary adenomas, 51 bronchial carcinoid tumors, and 60 well-differentiated ET of the GI tract [27 small intestinal, 10 appendiceal, and 23 pancreatic]. TMAs were stained for B-catenin, p-mTOR, PTEN, TSC2, ATRX and DAXX. Aberrant staining was defined as nuclear staining for B-catenin, increased (2+ to 3+) cytoplasmic mTOR staining, decreased (0 to 1+) cytoplasmic staining for TSC2 and PTEN, and staining of <50% of nuclei for ATRX and DAXX.
Results:

Immunohistochemical Analysis of Endocrine Tumors (in percentages)

	Small Intestinal ET (n=27)	Appendiceal ET (n=10)	Pancreatic ET (n=23)	Bronchial Carcinoid (n=51)	Adrenocortical Adenoma (n=50)	Pituitary Adenoma (n=46)	Parathyroid adenoma (n=50)
Nuclear B-catenin	0	0	0	0	86	0	0
Increased mTOR	78	100	38	52	6	52	52
Decreased PTEN	89	50	74	24	98	28	96
Decreased TSC2	100	50	74	90	94	48	92
Decreased ATRX	77	50	57	51	88	4	14
Decreased DAXX	81	80	65	49	24	6	4

Nuclear B-catenin was only noted in adrenocortical adenoma (86%). Increased mTOR was most frequent in small intestinal and appendiceal ET (>75%), lower in others. PTEN and TSC2 showed parallel losses in ET of most organs except the bronchi. Loss of ATRX or DAXX was found in the majority of GI and bronchial ET, but not in pituitary or parathyroid adenoma.
Conclusions: Alterations in the mTOR pathway are globally present in ET of multiple organs, but aberrant Wnt-signaling is limited to adrenocortical adenomas. Small intestinal ET most frequently exhibit alterations in the mTOR pathway and chromosome remodeling proteins, which less commonly involve the foregut-derived bronchial and pancreatic ET. Loss of chromosome remodeling proteins was often seen in ET of the diffuse endocrine system (GI, pancreas, bronchi), but was much less common in ET from endocrine organs (adrenal, pituitary, parathyroid).
Category: Endocrine

Tuesday, March 20, 2012 1:00 PM

Poster Session IV # 42, Tuesday Afternoon