Pituitary adenoma predisposition caused by germline mutations in the AIP gene

Jun 1 2006

A recent Finnish study identifies a low-penetrance gene defect which predisposes carriers to intracranial tumors called pituitary adenomas. In particular individuals carrying the gene defect are susceptible to such tumors which secrete growth hormone.

Excess of growth hormone results in conditions called acromegaly and gigantism. Identification of this gene defect using DNA-chip technologies is an example how genetic research can tackle more and more demanding tasks, such as identification of predisposition genes conferring a low absolute but high relative risk. The results are published in the journal Science.

The research group, lead by professor Lauri Aaltonen (University of Helsinki, Finland) and Dr Outi Vierimaa (Oulu University Hospital, Finland) providing the initial observations leading to the investigations, aimed at unravelling the genetic basis of susceptibility to pituitary adenomas. Pituitary adenomas are common benign neoplasms, accounting for approximately 15 % of intracranial tumors.

Most common hormone-secreting pituitary tumor types oversecrete prolactin or growth hormone (GH), which together with local compressive effects account for their substantial morbidity. Oversecretion of GH causes acromegaly or gigantism. Acromegaly is characterized by coarse facial features, protruding jaw, and enlarged extremities. The potentially severe symptoms of untreated acromegaly, develop slowly and the condition is difficult to diagnose early. Gigantism refers to excessive linear growth occurring due to GH oversecretion when epiphyseal growth plates are still open, in childhood and adolescence. Genetic predisposition to pituitary tumors has been believed to be rare.

The researchers detected three clusters of familial pituitary adenoma in Northern Finland. Genealogy data reaching back to 1700's was available. Two first clusters could be linked by genealogy. The researchers hypothesized that a previously uncharacterized form of low-penetrance pituitary adenoma predisposition (PAP) would contribute to the disease burden in the region. The researchers had previously characterized a population based cohort diagnosed with GH secreting pituitary adenoma (somatotropinoma) in Oulu University Hospital (OUH). These data were linked to the pedigree information, to identify additional affected distant relatives. The PAP phenotype - very low penetrance susceptibility to somatotropinoma and prolactinoma - did not fit well to any of the known familial pituitary adenoma syndromes. These syndromes are defined by familial occurrence of the disease, and the low penetrance of PAP appeared unique. Low penetrance means hereditary predisposition which relatively rarely leads to actual disease - but which may cause much more effect on population level than high-penetrance disease susceptibility which typically is very uncommon.

Utilizing modern chip-based technologies the research group identified mutations in the AIP gene as the underlying cause. Further work on the functional role of this gene should prove informative in revealing key cellular processes involved in genesis of pituitary adenomas, including potential drug targets.

It has not been previously realized that genetic predisposition to pituitary adenoma, in particular GH oversecreting type, can account for a significant proportion of cases. The study not only reveals this aspect of the disease, but also provides molecular tools for efficient identification of predisposed individuals. Without pre-existing risk awareness, the patients are typically diagnosed after years of delay, leading to significant morbidity. Simple tools for efficient clinical follow-up of predisposed individuals are available, such as monitoring GH in blood samples.

In a general sense, the results suggest that inherited tumor susceptibility may be more common than previously thought. The identification of the PAP gene indicates that with the new DNA-chip based technologies it is possible to identify the causative genetic defects in the low-penetrance conditions even in the absence of a strong family history.