Molecular alterations to human chromosome 3p loci in neuroendocrine lung tumors

• Published in: Cancer 1998-09, Vol.83 (6), p.1109-1117
• Main Authors: Kovatich, Albert, Friedland, David M., Druck, Teresa, Hadaczek, Piotr, Huebner, Kay, Comis, Robert L., Hauck, Walter, McCue, Peter A.
• Format: Article
• Language: English
• Subjects: Acid Anhydride Hydrolases; Adult; Aged; Biological and medical sciences; Carcinoid Tumor - chemistry; Carcinoid Tumor - genetics; carcinoids; Carcinoma, Small Cell - chemistry; Carcinoma, Small Cell - genetics; Chromosomes, Human, Pair 3 - genetics; Female; FHIT; Humans; Loss of Heterozygosity; Lung; Lung Neoplasms - chemistry; Lung Neoplasms - genetics; Male; Medical sciences; Middle Aged; Neoplasm Proteins - analysis; neuroendocrine lung tumors; Pneumology; Proteins - analysis; small cell lung carcinoma; Tumors of the respiratory system and mediastinum
• ISSN: 0008-543X; 1097-0142
• DOI: 10.1002/(SICI)1097-0142(19980915)83:6<1109::AID-CNCR9>3.0.CO;2-2

BACKGROUND The origins of and interrelations between low grade and high grade neuroendocrine lung tumors, typical and atypical carcinoids, and small cell lung carcinoma (SCLC) have not been elucidated. Karyotypic and molecular genetic studies have demonstrated deletions in 3p in 100% of SCLCs and the candidate lung tumor suppressor gene, FHIT, at 3p14.2 is not expressed in the majority of SCLCs. Similar studies of typical and atypical carcinoids could clarify the interrelations among these tumors. METHODS For molecular genetic analyses, archival carcinoids and paired normal cells were microdissected from paraffin sections, deparaffinized, and DNA prepared. Oligonucleotide primer pairs for 12 microsatellite markers mapping between 3p14.2 and 3p21.3 were used to amplify allelic DNA fragments from 13 typical and 6 atypical carcinoids. In addition, an independent series of archival sections of carcinoids and SCLCs was tested by immunohistochemistry for expression of Fhit protein. RESULTS Of the six atypical carcinoids examined, three had lost an allele at all informative markers, whereas one had lost alleles in two distinct regions and two showed allele loss in a subregion of the chromosome region tested. Of the 13 typical carcinoids, 3 showed allele loss at only 1 or 2 loci each. Typical carcinoids, similar to normal lung epithelia, were strongly positive for the cytoplasmic Fhit protein, SCLCs were uniformly negative, and atypical carcinoids appeared to express an intermediate level of Fhit protein. CONCLUSIONS Loss of heterozygosity at 3p14.2‐p21.3 is significantly more extensive in all atypical carcinoids. Atypical carcinoids, which exhibit clinicopathologic features intermediate between typical carcinoids and small cell carcinomas and have been considered well differentiated neuroendocrine carcinomas, also are intermediate between typical carcinoids and SCLC on the basis of extent of loss of 3p alleles and reduced expression of Fhit protein. Cancer 1998;83:1109‐1117. © 1998 American Cancer Society. 3p allelic loss is minimal in typical lung carcinoids but extensive in atypical lung carcinoids; typical carcinoids are strongly positive for Fhit protein, small cell lung carcinomas are negative, and atypical carcinoids express an intermediate level of Fhit.