CYTOGENETIC AND MICROSATELLITE ALTERATIONS IN TUMORS FROM PATIENTS WITH THE SYNDROME OF MYXOMAS, SPOTTY SKIN PIGMENTATION, AND ENDOCRINE OVERACTIVITY (CARNEY COMPLEX)

Carney complex (CC) is a familial multiple neoplasia and lentiginosis syndrome, transmitted in an autosomal dominant manner. It is the only familial form of cardiac and skin myxomas known and in eludes endocrin e neoplasms causing Cushing's syndrome [primary pigmented nodular adre nocortical disease (PPNAD)] and acromegaly (GH-producing adenoma). The molecular defect leading to CC remains unknown, but was recently mapp ed to chromosome 2p16 by linkage analysis. This region has exhibited c ytogenetic aberrations in atrial myxomas from patients with CC and har bors the hMSH2 and hMSH6 genes, which are involved in the preservation of microsatellite length stability of replicating human cells. In the present study, we examined 15 tumor and normal tissue specimens from 13 patients with CC [GH-producing adenoma (n = 1), adrenal tumors (PPN AD: n = 8), thyroid cancer (n = 1), normal adrenal gland (n = 1)] and 4 cultured cell lines [heart myxoma (n = 3) and eyelid myxoma(n = 1)]. Chromosome analysis was obtained by standard cytogenetic techniques. One of the myxoma cell lines and 3 PPNAD specimens contained multiple telomeric associations (tas). The normal adrenocortical tissue from a patient with PPNAD contained no apparent chromosomal anomalies, wherea s the neighboring PPNAD tissue demonstrated tas. DNA was extracted fro m peripheral blood, tumor cell lines, and frozen or paraffin-embedded tissues and subjected to PCR amplification with primers from 64 micros atellite locations covering chromosomes 1 and 3-22 and 14 loci coverin g chromosome 2. The alterations detected were loss and gain of heteroz ygosity (LOH and GOH; 49% and 26%, respectively), deletions of both al leles (DEL; 10%), and microsatellite length instability (15%). GOH and LOH were the most frequent changes, with telomeric markers significan tly overrepresented (P < 0.05). Chromosomes 6, 11, 22, 10, and 19 demo nstrated mostly LOH, GOH, or DEL in over 40% of the informative loci t ested (73%, 59%, 47%, 46%, and 44%, respectively), whereas markers on chromosome 2 showed only microsatellite length instability (10%). The degree of genomic instability and its type were independent of tumor t ype (P > 0.1). We conclude that tumors and tumor cell lines from patie nts with CC demonstrate significant genomic, but not microsatellite le ngth, instability. Thus, the CC gene(s) on chromosome 2p16 is differen t from the hMSH2 and hMSH6 genes and has dominant, rather than recessi ve, tumorigenic function. This gene(s) appears to be involved in the r egulation of genomic stability of dividing cells, in particular the st ructure of telomeres in replicating chromosomes and/or the function of the mitotic apparatus.