Sporadic and familial pituitary adenomas are being recognised and diagnosed with increasing frequency due to better diagnostic techniques and improving awareness.
Recently, a number of important steps have been taken to clarify the molecular pathological events leading to familial pituitary tumorigenesis, with the recognition of the tumour suppressor genes p27 and AIP as causes of familial pituitary tumours in addition to previously-established genes such as MEN1 and PRKAR1A. The abnormal expression of p27 (CDKN1B, which is under-expressed) and AIP (which is over-expressed) in sporadic pituitary tumours has been reported, but no somatic mutations have been recognised in these genes. Furthermore, germline mutations in apparently sporadic cases are extremely rare. The mechanism of p27 haploinsufficiency leading to tumorigenesis is supported by previous data showing p27 as an important cell cycle inhibitor. However, the mechanism whereby AIP causes tumorigenesis is unclear as this molecular co-chaperone has many potentially important partners. The most logical candidates are the phosphodiesterases due to their involvement in the cAMP pathway, which has in turn been previously implicated in somatotroph cell tumorigenesis via the gsp-mutation (GNAS1) and that of the PKA regulatory subunit (PRKAR1A). Nevertheless, there are increasing data that AIP acts as a classic tumour suppressor gene, regardless of its precise mode of action.
A number of outstanding questions remain regarding familial pituitary adenomas including (1) what are the causative genes in cases of AIP mutation-negative familial isolated pituitary adenomas, (2) what genes are responsible for the MEN1 and CDKN1B mutation-negative sporadic and familial MEN1-syndrome patients, and (3) what gene is behind ~40% of Carney complex cases without PRKAR1A but which segregate to the 2p16 area?
There are also exciting and novel developments in studies of the genesis of sporadic pituitary tumours. In addition to previously identified important players such as PTTG and HMGA2 (high mobility group A2 protein), recent studies have implicated the involvement of Akt and ERK pathways, MEG3, a non-coding RNA in non-functioning pituitary adenoma tumorigenesis, E-cadherin and the Wnt pathway, Pi-class glutathione-S-transferase (GSTP1), p21, p16, CXCL12 and its receptor CXCR4, DNA methyltransferase-3 (DNMT-3), Rab18 a protein involved in secretory granules, the folate receptor, pituitary microRNAs, and even the cooking spice curcumin.
Tumorigenesis seems to be a multifaceted process in the different type of pituitary adenomas, the increasing amount of information may lead to novel pathways and possibly novel treatments in the future, but the prime causative mechanisms remain elusive.
25 - 29 Apr 2009
European Society of Endocrinology