Abstract
BackgroundSmall intestinal neuroendocrine tumors (SI-NETs) are typically slow-growing tumors that have metastasized already at the time of diagnosis. The purpose of the present study was to further refine and define regions of recurrent copy number (CN) alterations (CNA) in SI-NETs.MethodsGenome-wide CNAs was determined by applying array CGH (a-CGH) on SI-NETs including 18 primary tumors and 12 metastases. Quantitative PCR analysis (qPCR) was used to confirm CNAs detected by a-CGH as well as to detect CNAs in an extended panel of SI-NETs. Unsupervised hierarchical clustering was used to detect tumor groups with similar patterns of chromosomal alterations based on recurrent regions of CN loss or gain. The log rank test was used to calculate overall survival. Mann–Whitney U test or Fisher’s exact test were used to evaluate associations between tumor groups and recurrent CNAs or clinical parameters.ResultsThe most frequent abnormality was loss of chromosome 18 observed in 70% of the cases. CN losses were also frequently found of chromosomes 11 (23%), 16 (20%), and 9 (20%), with regions of recurrent CN loss identified in 11q23.1-qter, 16q12.2-qter, 9pter-p13.2 and 9p13.1-11.2. Gains were most frequently detected in chromosomes 14 (43%), 20 (37%), 4 (27%), and 5 (23%) with recurrent regions of CN gain located to 14q11.2, 14q32.2-32.31, 20pter-p11.21, 20q11.1-11.21, 20q12-qter, 4 and 5. qPCR analysis confirmed most CNAs detected by a-CGH as well as revealed CNAs in an extended panel of SI-NETs. Unsupervised hierarchical clustering of recurrent regions of CNAs revealed two separate tumor groups and 5 chromosomal clusters. Loss of chromosomes 18, 16 and 11 and again of chromosome 20 were found in both tumor groups. Tumor group II was enriched for alterations in chromosome cluster-d, including gain of chromosomes 4, 5, 7, 14 and gain of 20 in chromosome cluster-b. Gain in 20pter-p11.21 was associated with short survival. Statistically significant differences were observed between primary tumors and metastases for loss of 16q and gain of 7.ConclusionOur results revealed recurrent CNAs in several candidate regions with a potential role in SI-NET development. Distinct genetic alterations and pathways are involved in tumorigenesis of SI-NETs.
Highlights
Small intestinal neuroendocrine tumors (SI-NETs) are typically slow-growing tumors that have metastasized already at the time of diagnosis
Overall findings of copy number alterations detected by array comparative genomic hybridization (CGH) (a-CGH) We determined genome-wide CN aberrations (CNAs) in 30 tumors representing 19 primary tumors and 11 metastases from 29 patients with SI-NET using a-CGH
Overall the CNAs detected by a-CGH in this study were consistent with those detected for the 17 cases analyzed by metaphase CGH in our previous study [12] as well as with those samples analyzed by the 1 Mb resolution array
Summary
Small intestinal neuroendocrine tumors (SI-NETs) are typically slow-growing tumors that have metastasized already at the time of diagnosis. The purpose of the present study was to further refine and define regions of recurrent copy number (CN) alterations (CNA) in SI-NETs. Small intestinal neuroendocrine tumor (SI-NET) arising from enterochromaffin cells is the most common type of gastrointestinal endocrine tumor. SI-NETs are mostly sporadic, a few small families with a history of the disease have recently been characterized [5,6]. The clinical picture of the carcinoid syndrome, which usually occur in patients with liver metastases, is due to excessive production and release of hormones and substances such as serotonin, tachykinins and prostaglandins [9]. Surgery is the first treatment of choice, in patients with metastatic disease surgical treatment seldom leads to cure [11]
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