Genomic Alterations in Well-Differentiated Gastrointestinal and Bronchial Neuroendocrine Tumors (Carcinoids)

Abstract

Neuroendocrine tumors (carcinoids) are a heterogeneous group of neoplasms arising from the diffuse neuroendocrine system. Genetic changes underlying their tumorigenesis are primarily unknown. We used comparative genomic hybridization to screen 32 well-differentiated neuroendocrine tumors (21 gastrointestinal and 11 bronchial) and three associated metastases for genomic alterations. There were striking differences of genomic imbalances between the two subgroups of neuroendocrine tumors. Losses of chromosome 18q and 18p were shown in eight (38%) and seven (33%), respectively, out of 21 gastrointestinal tumors and in none of the 11 bronchial tumors. Conversely, deletions of 11q occurred in four of 11 (36%) bronchial tumors but only in one gastrointestinal tumor. These comparative genomic hybridization findings were confirmed by interphase cytogenetics. Our data indicate that neuroendocrine tumors of the two subgroups develop via different molecular pathways. Inactivation of one or several tumor suppressor genes on chromosome 18 may be important for the biological behavior of gastrointestinal tumors, whereas gene inactivation on 11q seems to be associated with tumor development of the bronchi.

High-resolution genomic profiling reveals gain of chromosome 14 as a predictor of poor outcome in ileal carcinoids

“…Only one of our patients displayed segmental loss on chromosome 18 (18q22.2-qter). This is in line with previous studies demonstrating losses of 18q12-qter, 18q21-qter, 18q21.1 or 18q22-qter in ileal carcinoids using chromosome-based CGH or SNP analysis (Zhao et al 2000, Kytölä et al 2001, Kulke et al 2008.…”

“…Using microsatellite markers, chromosome-based comparative genomic hybridization (CGH) and single nucleotide polymorphism (SNP) analysis, recurrent copy number alterations (CNAs) have been identified. The most common CNA is loss of chromosome 18 (Terris et al 1998, Zhao et al 2000, Kytölä et al 2001, Löllgen et al 2001, Tönnies et al 2001, Stancu et al 2003, Wang et al 2005, Kim do et al 2008, Kulke et al 2008. Other recurrent CNAs include losses involving chromosomes 9, 11q and/or 16q, and gains involving chromosomes 4, 5, 7, 14 and/or 20.…”

Comparison of genetic alterations in neuroendocrine tumors: frequent loss of chromosome 18 in ileal carcinoid tumors

“…3,13,14,32 Interestingly, a higher frequency of allelic loss of 18q was reported for classical midgut carcinoids 14,32 but not for lung carcinoid tumors. 13,27 In our study, the high frequency of loss of the entire chromosome 18 in ileal carcinoid tumors suggest that there are multiple tumor suppressor genes in chromosome 18 involving both the short and the long arms that play an important role in the tumorigenesis of ileal carcinoid tumors. Among the tumor suppressor genes harbored on chromosome 18q, the most extensively studied are the DCC gene localized at 18q21.2 and the DPC4 (Smad4) gene localized at 18q21.1.…”

“…Allelic loss of chromosomes 11q, 16q and 18q is reported in typical midgut carcinoids. 3,[11][12][13][14] Allelic loss of chromosome 18q is frequent in colorectal carcinomas. 15 DPC4 (Smad4) gene, present on chromosome 18q, has mutations in about 50% of pancreatic 16 and in about 20% of colorectal carcinomas.…”

Metastatic Carcinoid Tumors: A Clinical Review

“…In sporadic midgut carcinoids, a high frequency of deletions on chromosome 18 is described [11]. These findings might indicate different pathways in the development of carcinoid tumors from the foregut and midgut [12].…”