Typical and atypical carcinoid tumors of the lung are characterized by 11q deletions as detected by comparative genomic hybridization

摘要

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.