Frequent inactivation of thep16 gene in human pituitary tumors by gene methylation

Abstract

Rodent models of pituitary tumorigenesis have implicated the retinoblastoma (Rb) pathway in the development of pituitary tumors. Previously, we reported that loss of p16 expression rather than loss of Rb occurs in most human pituitary adenomas. This alteration in these tumors is not associated with p16 mutation or frequent homozygous p16 gene loss. Our laboratory has now demonstrated that in most human pituitary tumors, the 5' CpG island of the p16 gene is extensively methylated. The high frequency of p16 gene methylation in human pituitary tumors suggests that this alteration is an early and perhaps required event in pituitary cell transformation.

CDKN2A/p16 inactivation is related to pituitary adenoma type and size

“…Compared with non‐neoplastic adenohypophysis, staining was reduced in another ten adenomas, suggesting that p16 is down‐regulated in the vast majority of adenomas of all major types. Our p16 expression data largely confirm previous findings in the normal and neoplastic pituitary gland7–9, 18. For example, strong expression of p16 has been described in the normal pituitary by using immunoblotting and immunohistochemistry7, 9, 18, while p16 protein was undetectable by immunoblotting in two series of 20 and 25 adenomas of various types, including somatotroph adenomas7, 8.…”

“…Our p16 expression data largely confirm previous findings in the normal and neoplastic pituitary gland7–9, 18. For example, strong expression of p16 has been described in the normal pituitary by using immunoblotting and immunohistochemistry7, 9, 18, while p16 protein was undetectable by immunoblotting in two series of 20 and 25 adenomas of various types, including somatotroph adenomas7, 8. However, our data on somatotroph adenomas differ from the findings of another study9, where p16 negativity was seen in only 4 of 21 (19%) ‘STH‐secreting adenomas’, whereas p16 was absent in 10 of 13 (77%) somatotroph adenomas in our series.…”

“…Since immunohistochemical adenoma types were not detailed in the latter study, it is unclear whether (clinically inactive) corticotroph adenomas were included among the non‐functioning adenomas. On the other hand, two other studies reported methylation in 18 of 208 and in 20 of 24 cases10, respectively, but the involvement of adenoma types was different. One of these studies described methylation in 9 of 11 STH‐producing adenomas, but not in the single corticotroph adenoma10, while the other study included three corticotroph adenomas, all of them being methylated8.…”

“…On the other hand, two other studies reported methylation in 18 of 208 and in 20 of 24 cases10, respectively, but the involvement of adenoma types was different. One of these studies described methylation in 9 of 11 STH‐producing adenomas, but not in the single corticotroph adenoma10, while the other study included three corticotroph adenomas, all of them being methylated8. Reasons for these inconsistencies among studies may be related to the small numbers of cases, different techniques for revealing methylation, and differences in the DNA regions analysed.…”

p16 INK4a andp15INK4b gene methylations in plasma cells from monoclonal gammopathy of undetermined significance

“…4 Results of MS-PCR in MGUS and MM samples are summarized in Table 1 10 Inactivation of p16 INK4a gene has been reported in benign tumors like adenomas and in premalignant lesions. [18][19][20] Loss of p16 INK4a gene expression by methylation occurs early in the establishment of cell lines from primary culture. These data suggest that p15 INK4b INK4b gene has only been described in MM, Burkitt lymphoma, acute leukemia, and myelodysplastic syndromes (MDS).…”