Multiple endocrine neoplasias: advances and challenges for the future

Abstract

Several important advances have been made over the last 2 years, since the last international workshop on multiple endocrine neoplasias (MENs) that was held in Marseilles, France (MEN2006). The series of articles that are included in this issue summarize the most important of these advances as they were presented in Delphi, Greece, during the 11th International Workshop on MENs, September 25–27, 2008 (MEN2008). This editorial summarizes some of these advances: the identification of the AIP, and the PDE11A and PDE8B genes by genome-wide association (GWA) studies as predisposing genes for pituitary and adrenal tumours, respectively, the discovery of p27 mutations in a new form of MEN similar to MEN type 1 (MEN 1) that is now known as MEN 4, the molecular investigations of Carney triad (CT), a disorder that associates paragangliomas (PGLs), gastrointestinal stromal tumour (GISTs), and pulmonary chondromas (PCH) with pheochromocytomas and adrenocortical adenomas and other lesions, and the molecular elucidation of the association of GISTs with paragangliomas (Carney–Stratakis syndrome) that is now known to be because of SDHB, SDHC, and SDHD mutations. Molecular investigations in Carney complex (another MEN also described by Dr. Carney, who during the meeting, along with Dr. Charles E. (‘Gene’) Jackson was honoured for his life-long and many contributions to the field) have also revealed the role of cyclic AMP signalling in tumorigenesis. As our knowledge of the molecular causes of MENs increases, the challenge is to translate these discoveries in better treatments for our patients. Indeed, new advances in the preventive diagnosis and molecular treatment of MEN 1 and MEN 2, respectively, continued unabated, and an update on this front was also presented at MEN2008 and is included in this issue.

In their classical definition, multiple endocrine neoplasias (MEN) syndromes type 1 and type 2 (MEN 1 and MEN 2 respectively) included combinations of co-presenting tumours of the endocrine glands: the MEN 1 syndrome was defined as the combination of parathyroid, pituitary and gastrointestinal neuroendocrine tumours, and the MEN 2 as the combination of pheochromocytomas, medullary thyroid carcinoma and parathyroid tumours [1]. In the last decade of the 20th century, the molecular basis of these inherited tumour syndromes was elucidated and the RET and menin genes were found to be responsible for the genetic transmission of the MEN 2 and MEN 1 syndromes respectively [1, 2]. However, several patients or even families with combinations of endocrine tumours did not meet the diagnostic criteria for the MEN 1 and MEN 2 syndromes or did not harbour genetic defects of these two genes. It also became apparent that these syndromes might occasionally be associated with atypical endocrine neoplasias or even lesions in nonendocrine tissues, as the mutated genes were expressed and had functions in other tissues as well [2]. Conditions such as Carney complex (CNC), Von Hippel Lindau and Cowden disease (CD) were added to the list of MENs [3]. CNC, in particular, which causes a variety of endocrine tumours (in the adrenal cortex, pituitary, the thyroid and the gonad) by its molecular elucidation (caused by PRKAR1A mutations) revealed the role of cyclic AMP (cAMP) signalling in endocrine (and other) tumorigenesis. The ten international workshops on MEN syndromes that have taken place in the United States and Europe over the last 20 years tracked these developments [4, 5].

Over the last 2 years, and since the last meeting in Marseilles, France (MEN2006), several exciting developments have taken place in the field of MENs, including the identification of several new genes and even the description of new disorders. Genome-wide association (GWA) studies identified the aryl hydrocarbon receptor-binding protein (AIP) as the gene responsible for inherited growth-hormone (GH)-producing pituitary tumours [6], and the phosphodiesterases 11A and 8B (PDE11A and PDE8B) genes responsible for a predisposition to a variety of adrenal tumours, mainly inherited adrenal hyperplasias leading to Cushing syndrome [7, 8]. Another genetic linkage study, this time first in rodents and then in humans with pituitary tumours and an MEN 1-like condition, identified mutations in the CDKN1B/p27^Kip1 gene [9, 10]. Patients with this condition were labelled as having MEN type X (MEN X) [9] now preferentially named MEN type 4 (MEN 4) [11]. Genetic studies identified mutations in the succinate dehydrogenease (SDH) subunit B, C and D genes (SDHB, SDHC, and SDHD) in a condition that is actually a new entity now known as Carney–Stratakis syndrome (CSS): it describes the association of paragangliomas (PGL), pheochromocytomas, and gastrointestinal stromal tumours (GIST) [12, 13]. These genes are also involved in inherited paragangliomas only [14]. Carney triad (CT) on the other hand is an atypical MEN disorder that associates PGLs, GISTs, and pulmonary chondromas (PCH) with pheochromocytomas and adrenocortical adenomas and other lesions. The genetic defect in CT remains elusive despite extensive genetic searches [15] and current data suggest that it may not represent a familial syndrome [16].

Nomenclature continues to be a problem, of course; this is not unexpected in a rapidly evolving field. During the meeting, MEN X [9] – was almost unanimously renamed and accepted as MEN 4, as mentioned above. And, the conditions that are named after Dr. Carney, should not be confused with each other, or with the more widely known syndrome, CNC, or the ‘complex of endocrine overactivity, myxomas and spotty skin pigmentation’. Some times, the complex is being referred to as ‘Carney syndrome’ – again, this condition, is caused by PRKAR1A mutations and has nothing to do with either Carney Triad or the dyad (CSS). In fact, during the MEN2008 meeting, Dr. Carney was honoured for his life-long contributions to the field of MENs: at least three disorders that all predispose to various endocrine tumours today bear his name!

Modern technology has allowed not only the elucidation of genetic defects and delineation of new disorders within the MEN field, but also has led to the discovery of other genes, involved in common intracellular signalling pathways and every day cellular functions which – when dysregulated – could lead to the development of endocrine tumours [17, 18]. Secondary ‘hits’, in the form of mutations or epigenetic changes that lead to dysregulation of these functions could lead to proliferation, hyperplasia or neoplasia; it has also become apparent that sporadic tumours of the same type frequently harbour defects in the same genes and/or pathways [19]. One noteworthy aspect of the importance of the discovery of the MEN genes, like for instance menin, is that this led to the elucidation of other important pathways to which menin function is linked like the cyclin dependent kinase inhibitor and Hox genes; this discovery may eventually lead to the development of further molecular targeted therapies, which could plausibly be applied for MEN1 pancreatic tumours for which we now lack efficient therapies [20].

The discoveries of AIP, PDE11A and PDE8B, along with earlier identification of GNAS and PRKAR1A genes highlight the importance of the cAMP pathway in endocrine tumorigenesis. Whole- and tissue-specific knock out (KO) mouse models of the PRKAR1A gene were recently created; these are described in this issue [21]. These mouse models, and other gene KOs, are invaluable tools in the investigations of MENs and in the unraveling of molecular pathways leading to endocrine tumours.

Genetic counselling is another important aspect in our field. Primary hyperparathyroidism for instance is a component of distinct MEN syndromes but it is even more frequently encountered in its sporadic form. The indications for genetic counseling in this disease are discussed in a nice review by Falchetti et al. [22]. Except for the hyperparathyroidism forms associated with classical MEN syndromes, one further hereditary form concerns parathyroid carcinoma and the hyperparathyroidism-jaw tumour syndrome. The role of parafibromin, a new suppressor gene which is mutated in these families, is the object of a detailed review by Newey et al. [23].

These important developments in the field of endocrine tumorigenesis have also opened new roads in the development of new therapeutic agents of these tumours. These are all molecularly designed therapies, and aim at interfering with activated pathways that are involved in tumorigenesis. The most important of these pathways (drugs for which are already on clinical trials) is the tyrosine kinase pathway activated by RET mutations; it is quite appropriate, indeed that the first MEN to be molecularly elucidated (MEN 2) is also the first where molecularly targeted drugs are applied. It has also recently become apparent that except for RET activation there are further intracellular signalling pathways which interact with the signalling cascade after RET activation; these pathways and molecules may become targeted in further combination treatments for MTC [24].

The molecular delineation of the responsible gene has also allowed the preclinical diagnosis of the disease which is very important indeed, especially in view of the prognosis of clinical medullary carcinoma of the thyroid (MTC) [25]. Medullary carcinoma of the thyroid also occurs in a sporadic form in 75% of the cases. Calcitonin represents a good tumour marker for MTC; however the need for further biomarkers has become apparent. These biomarkers, which are currently being developed, are factors that may indicate response to treatment or progression of disease and may become clinically useful in prognosis and decision to more aggressive treatment; they include detection of somatic RET mutations and immunocytochemistry markers in tumour tissue, as well as molecular imaging techniques [26].

These are fascinating developments in a field that really started with the intense investigations and discoveries by Dr. Jackson: Dr. Charles E (‘Gene’) Jackson worked with Nancy Simpson to establish the MEN2 Workshops and the first one that was held in Kingston, Ontario in 1983 provided the initiative for mapping the RET oncogene as the gene responsible for the MEN2 syndromes. Dr. Jackson, who was honoured during the MEN2008 meeting for his contributions, was instrumental in the organization of the successive workshops that were held biennially thereafter in Cambridge, Heidelberg, Houston, Stockholm, Utrecht, Gubbio, Grand Rapids, Bethesda, Marseilles, and now in Delphi.

The reports that follow represent the ‘state of the art’ in the field of MENs; these are data that were presented by the leaders in the field at the Delphi meeting. We all agreed that despite the significant advances of the recent years, challenges remain and the answers to old questions have led to new ones: How do we design molecular pathways for the non-MEN 2- related syndromes? What pathways should be targeted? And, in basic research: what determines tissue-specific tumorigenesis in these syndromes that are caused by ubiquitously expressed genes? And what about sporadic endocrine tumours in the same tissues? The vast majority of these tumours are caused by unknown somatic mutations or epigenetic phenomena, or… are they? We are sure the next two years will be equally or even more exciting and we are all looking forward to the next MEN worskshop (MEN2010), which will be held in Italy.