Different patterns of allelic loss (loss of heterozygosity) in recurrent human pituitary tumors provide evidence for multiclonal origins

Sporadic human pituitary tumors are benign adenomas of monoclonal origin. T his implies that they arise from de novo somatic mutation(s) within a singl e pituitary cell. The availability of original and recurrent/regrown tumors from the same patient allowed testing of the prediction that recurrent/reg rown tumors have identical genetic abnormalities as the original tumor samp le, We used PCR amplification, from archival slide-extracted DNA, to allelo type microsatellite polymorphisms as an indication of clonality and confirm ed this by X chromosome inactivation analysis in samples from women. Tumors from 33 of 49 (67%) patients with two or more specimens showed loss of het erozygosity (LOH) of at least one marker in at least one of their samples. Two patterns of LOH were observed. In pattern A in 14 of 33 (42%) of patien ts, the LOH pattern of the first tumor was preserved in the second recurren t sample, with some recurrent tumors also showing additional LOH. In these patients, the original and second tumors are presumed to arise from the sam e original clone with or without progressive accumulation of LOH. In patter n B [19 of 33 (58%) patients], LOH seen in the first tumor was not preserve d in the second or subsequent tumors, as evidenced by retention of heterozy gosity compared with the first tumor. The simplest explanation is that the second tumor, although still monoclonal, arises from another independently abnormal clone, This was confirmed by X chromosome inactivation analysis in all 11 women where this was informative, These results show that initial a nd recurrent tumors, of a benign tumor type, are frequently derived from se parate independent clones, This suggests that either: (a) more than one abn ormal clone is present from the outset though only one dominates; or (b) se veral clones arise independently at different times. In both scenarios, the initiating event(s) that predisposes to transformation might result in mul ticlonal hyperplasia, possibly as a consequence of exogenous stimulation.