TYPICAL AND ATYPICAL CARCINOID-TUMORS OF THE LUNG ARE CHARACTERIZED BY 11Q DELETIONS AS DETECTED BY COMPARATIVE GENOMIC HYBRIDIZATION

Neuroendocrine tumors of the lung represent a wide spectrum of phenoty pically distinct entities with different biological characteristics su ch as typical carcinoid tumor (TC), atypical carcinoid tumor (AC), lar ge-cell neuroendocrine carcinoma (LCNEC), and small-cell lung carcinom a (SCLC), The histogenetic relationships between TC, AC, LCNEC, and SC LC are still unclear. This study was carried out to provide cytogeneti c data about pulmonary neuroendocrine tumors and to evaluate their cha racteristic alterations and histogenetic relations for an improved und erstanding of the mechanisms of tumor development. Twenty-nine paraffi n-embedded tumor samples of TC (n = 17), AC (n = 6), LCNEC (n = 3), an d SCLC (n = 3) were selected for isolation of tumor DNA and subsequent comparative genomic hybridization (CGH) analysis. To confirm the comp arative genomic hybridization results for characteristic chromosomal i mbalances, selected cases were additionally investigated by loss of he terozygosity analysis. For statistical evaluation, we also used compar ative genomic hybridization data from 45 published SCLC cases. DNA und errepresentations of 11q were the most frequent findings in TC (8 of 1 7) 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 cha racterized by a different pattern of DNA losses (3p-, 4q-, 5q-, 13q-, and 15q-) and gains (5p+, 17p+, and +20). Statistical analysis reveale d significantly different occurrences of 11q deletions in TC/AC vel su s 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 i ncluding the MEN1 gene locus, which represents a characteristic geneti c alteration in these tumors. Losses of 10q and 13q sequences allow a further cytogenetic differentiation between TC and AC. These additiona l 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 rel ationship, they differ remarkably in their cytogenetic characteristics , highlighting an early fundamental molecular divergence during the de velopment of these tumors.