MOLECULAR ALTERATIONS TO HUMAN-CHROMOSOME 3P LOCI IN NEUROENDOCRINE LUNG-TUMORS

BACKGROUND. The origins of and interrelations between low grade and hi gh grade neuroendocrine lung tumors, typical and atypical carcinoids, and small cell lung carcinoma (SCLC) have not been elucidated Karyotyp ic and molecular genetic studies have demonstrated deletions in 3p in 100% of SCLCs and the candidate lung tumor suppressor gene, FHIT, at 3 p14.2 is not expressed in the majority of SCLCs. Similar studies of ty pical and atypical carcinoids could clarify the interrelations among t hese tumors. METHODS. For molecular genetic analyses, archival carcino ids and paired normal cells were microdissected from paraffin sections , deparaffinized, and DNA prepared. Oligonucleotide primer pairs for 1 2 microsatellite markers mapping between 3p14.2 and 3p21.3 were used t o amplify allelic DNA fragments from 13 typical and 6 atypical carcino ids. In addition, an independent series of archival sections of carcin oids and SCLCs was tested by immunohistochemistry for expression of Fh it protein. RESULTS. Of the six atypical carcinoids examined, three ha d lost an allele at all informative markers, whereas one had lost alle les in two distinct regions and two showed allele loss in a subregion of the chromosome region tested. Of the 13 typical carcinoids, 3 showe d allele loss at only 1 or 2 loci each. Typical carcinoids, similar to normal lung epithelia, were strongly positive for the cytoplasmic Fhi t protein, SCLCs were uniformly negative, and atypical carcinoids appe ared to express an intermediate level of Fhit protein. CONCLUSIONS, Lo ss of heterozygosity at 3p14.2-p21.3 is significantly more extensive i n all atypical carcinoids. Atypical carcinoids, which exhibit clinicop athologic features intermediate between typical carcinoids and small c ell carcinomas and have been considered well differentiated neuroendoc rine carcinomas, also are intermediate between typical carcinoids and SCLC on the basis of extent of loss of 3p alleles and reduced expressi on of Fhit protein. (C) 1998 American Cancer Society.