Typical and Atypical Carcinoid Tumors of the Lung Are Characterized by 11q Deletions as Detected by Comparative Genomic Hybridization

Abstract

Neuroendocrine tumors of the lung represent a wide spectrum of phenotypically distinct entities with different biological characteristics such as typical carcinoid tumor (TC), atypical carcinoid tumor (AC), large-cell neuroendocrine carcinoma (LCNEC), and small-cell lung carcinoma (SCLC). The histogenetic relationships between TC, AC, LCNEC, and SCLC are still unclear. This study was carried out to provide cytogenetic data about pulmonary neuroendocrine tumors and to evaluate their characteristic alterations and histogenetic relations for an improved understanding of the mechanisms of tumor development. Twenty-nine paraffin-embedded tumor samples of TC (n = 17), AC (n = 6), LCNEC (n = 3), and SCLC (n = 3) were selected for isolation of tumor DNA and subsequent comparative genomic hybridization (CGH) analysis. To confirm the comparative genomic hybridization results for characteristic chromosomal imbalances, selected cases were additionally investigated by loss of heterozygosity analysis. For statistical evaluation, we also used comparative genomic hybridization data from 45 published SCLC cases. DNA underrepresentations of 11q were the most frequent findings in TC (8 of 17) and AC (4 of 6), whereas these aberrations were rare in LCNEC (1 of 3) and SCLC (0 of 3). Furthermore, AC showed DNA underrepresentation of 10q (3 of 6) and 13q (3 of 6). In contrast, SCLC and LCNEC were characterized by a different pattern of DNA losses (3p-, 4q-, 5q-, 13q-, and 15q-) and gains (5p+, 17p+, and +20). Statistical analysis revealed significantly different occurrences of 11q deletions in TC/AC versus SCLC (45 published cases of SCLC and our 3 cases; P = 0.002; Fisher's exact test). Thus, TC and AC display frequent loss of 11q material including the MEN1 gene locus, which represents a characteristic genetic alteration in these tumors. Losses of 10q and 13q sequences allow a further cytogenetic differentiation between TC and AC. These additional changes might be responsible for the more aggressive behavior of AC. Three cases of LCNEC, the first to be analyzed by comparative genomic hybridization, exhibited similar complex abnormal patterns (4q-, 5q-, 10q-, 13q-, 15q-) to those of SCLC. Although neuroendocrine tumors of the lung share common phenotypic features, suggesting a genotypic relationship, they differ remarkably in their cytogenetic characteristics, highlighting an early fundamental molecular divergence during the development of these tumors.

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.…”

“…24 In previous reports, allelic loss of 11q was identified in pancreatic endocrine tumors, and ileal and lung carcinoid tumors but was not found in any appendiceal or rectal carcinoid tumors. 14,[25][26][27] Another study reported a high frequency of allelic loss at 11q13 locus (62%) in midgut carcinoid tumors, but a low frequency of succinate-ubiquinone oxireductase subunit D gene mutations, suggesting that other tumor suppressor genes may be targets for allelic loss at this region. 28 In our study, pancreatic endocrine tumors and carcinoid tumors demonstrated occasional loss of chromosome 16q with loss of loci at 16q11.2-q24.2.…”

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

“…pancreatic endocrine tumours and lung carcinoids. In the latter tumours, losses on chromosome 11, including the MEN1 locus, have been shown to be a primary tumour oncogenic event (Walch et al 1998, Zhao et al 2001. When comparing carcinoid tumours with an intact chromosome 18 and tumours with loss of chromosome 18, two distinct patterns of CNAs appeared.…”

Pulmonary and extrapulmonary poorly differentiated large cell neuroendocrine carcinomas

“…3 The question of whether LCNEC should be considered as part of the NET spectrum remains unanswered. [15][16][17][18][19][20][21] Previous studies suggested several distinctive clinical features of LCNEC compared with well-differentiated NEC, including: tobacco use, male gender, advanced stage at presentation, and more frequent peripheral presentation. 10,11,13,[22][23][24] Historic LCNEC series have suggested a natural aggressive course with a median survival < 1 year.…”