Analysis of cyclin D1 (CCND1) allelic imbalance and overexpression in sporadic human pituitary tumors

Cyclin D1 plays an important role in the regulation of cell progression thr ough G(1) of the cell cycle and has been demonstrated to have oncogenic pro perties. Using RFLP-PCR, an A/G polymorphism within the cyclin D1 (CCND1) g ene was analyzed in 151 sporadic human pituitary tumors, of which 60 were i nformative at this locus. Further analysis showed that in 15 of 60 (25%) tu mors, there was evidence of allelic imbalance, which is indicative of gene amplification. Allelic imbalance was observed more frequently in invasive t umors (11 of 29 tumors; 38%) than in their noninvasive counterparts (4 of 3 1 tumors; 13%; P = 0.02). Forty-six of the tumors informative for the polym orphism were available for immunohistochemical analysis. Cyclin D1 expressi on (nuclear and/or cytoplasmic) was detected in 25 of 46 (54%) tumors. Of t hese cases, expression of nuclear cyclin D1 was detected in 9 of 46 (20%) t umors, whereas 16 of 46 (35%) tumors showed cyclin D1 staining exclusively confined to the cytoplasm, Neither nuclear staining nor cytoplasmic stainin g was observed in any of the normal pituitaries or in the negative control. Expression of cyclin D1 was observed in significantly more nonfunctional t umors (18 of 27 tumors; 67%) than in somatotrophinomas (7 of 19 tumors; 37% ; P = 0.046), Nuclear cyclin D1 expression was observed more frequently in nonfunctional tumors (8 of 27 tumors; 30%) than in somatotrophinomas (1 of 19 tumors; 5%; P = 0.04). There was no correlation between cyclin D1 expres sion and tumor grade or between allelic imbalance of CCND1 and cyclin D1 ex pression. We conclude that amplification of CCND1 occurs in pituitary tumor s and that the overexpression of cyclin D1 may be an early event in tumorig enesis. Cyclin D1 overexpression occurring in the absence of CCND1 allelic imbalance suggests that additional mechanisms responsible for deregulated c yclin D1 expression are involved in human pituitary tumorigenesis.