Deregulation of genetic pathways in neuroendocrine tumors

Alain Calender

Department of Genetics, Hôpital Edouard Herriot, Lyon and University of Lyon, School of Medicine
Place d'Arsonval 69437 Lyon Cedex 03 France
E-mail :


Gene, tumors, endocrine glands, pancreas, genetic predisposition,

December 2001



Neuroendocrine tumors (NET) are uncommon diseases occuring sporadically or in a familial context of autosomal dominant inherited syndromes such as Multiple Endocrine Neoplasia (MEN). During the last decade, at least six major genes involved in initial steps of NET have been characterized and one would expect that clinical screening syndromic forms of NET will include now genetic studies as a common tool for presymptomatic diagnosis (Calender, 2000). Four major MEN syndromes are MEN1 MEN2, von Hippel Lindau disease (VHL), and Carney Complex (CC) which represent the most common forms of inherited predisposition to NET with variable but high penetrance of proliferations in various neuroendocrine tissues. Less commonly, endocrine tumors of the pancreas , parathyroids and adrenal glands have been observed in phacomatosis such as Recklinghausen disease (NF1) , Tuberous sclerosis (TSC). Lastly, familial occurrence of a single endocrine lesion, such as primary hyperparathyroidism or pituitary adenoma have been identified as putative new genetic diseases fo which genetic pathways remain to be identified. Most NET predisposing diseases were related to inactivation of growth suppressor genes, according to the Knudson model, except MEN2, an inherited form of medullary thyroid carcinoma, which occur through dominant activation of a proto-oncogene, the RET tyrosine kinase receptor. Nevertheless, recent knowledges on the biological roles of most genes involved in cancer predisposition teaches us that a single gene might have pleiotropic effects at various stages of the cell physiology as for instance both a negative and a positive regulator function depending on the cellular context and sometimes the type of mutation (Zheng et al., 2000).

Cloning of genes involved in genetic diseases predisposing to NET has led to a better insight in the molecular nature of tumor initiation of (neuro)endocrine tissues in most endocrine glands. Even if the genes and related syndromes are presented separately, we would expect that genetic studies in patients with NET will now help to the differential diagnosis of syndromic diseases and that a single type of endocrine tumor may be related to the deregulation of distinct genes and related pathways. Major syndromes predisposing to NET and overlapping symptoms leading in some patients and/or families to adress the differential diagnosis by molecular genetic tools are presented in Figure 1.

Figure 1 : Overlapping lesions in genetic syndromes predisposing to neuroendocrine tumors. Major endocrine lesions described are MTC (medullary thyroid carcinoma), PHEO (pheochromocytoma), pHPT (primary hyperparathyroidism), pNET (pancreatic endocrine tumors), PiT (anterior pituiray tumors), cADR (adrenal cortical tumors), NET (bronchic or thymic 'carcinoids'), THYR (thyroid papillary or follicular carcinoma), NecT (neuroectodermic-derived tumors such as meningioma, paraganglioma, ependymoma), Carc midgut and hindgut carcinoids). Major genetic syndromes showed are MEN1 (Multiple Endocrine Neoplasia type 1), MEN2 (Multiple Endocrine Neoplasia type 2), VHL (von Hippel Lindau disease), NF-1 (Recklinghausen disease), TSC (Tuberous Sclerosis) and Fam. Isolated which represent genetic diseases with occurrence of a single and homogeneous lesion in probands and first or second degree relatives, such as familial isolated MTC or hyperparathyroidism. The most probable diagnosis suggested for each lesion are indicated inside the boxes. When designed by ? , the genes involved in these familial occurrences are unknown to date.


MEN1, a major genetic context predisposing to NET

From the disease to the gene

Multiple Endocrine Neoplasia type 1 (MEN1, OMIM 131100) is an autosomal dominant syndrome characterized by hyperplasia and/or multiple tumors of the parathyroid, endocrine pancreas, anterior pituitary, foregut-derived neuroendocrine tissues and adrenal cortical glands (Sheperd, 1991). Less common lesions have been associatedi wth MEN1 including cutaneous proliferations such as angiofibroma, collagenoma, lipoma and melanoma (Darling et al., 1997; Nord et al., 2000) and peripheral or central nervous system tumors such as ependymoma (Kato et al., 1996; Giraud et al.). The MEN1 locus has been localized to chromosome 11q13 in 1988 by linkage studies and the MEN1 gene itself was identified in 1997 after a 9 years-long period of extensive positionnal cloning (Larsson et al., 1988; Chandrasekharappa et al., 1997; The European Consortium on MEN1, 1997). The MEN1 gene consists of 10 exons, the first of which is untranslated, spanning around 7-10 Kb of genomic sequence and encoding menin, a protein of 610 amino acids. A major menin 2,8 Kb transcript and the protein were expressed in most human tissues analyzed, the menin RNA presenting a striking 4,2 Kb large form suggesting alternative promotor triggering and/or alternative splicing in 5', a question remaining to date unresolved (The European Consortium on MEN1, 1997).

Menin does not reveal homologies to any other known proteins nor includes consensus motifs from which the putative function of the protein could be deduced. Nevertheless, menin was characterized as a nuclear protein containing two nuclear localization signals (NLS) in exon 10 (Guru et al., 1998) which have been functionnally defined by in vitro expression of deletion constructs labelled by epitope-tagging with enhanced green fluorescent protein (EGFP). Despite the nuclear localization suggesting a major role of menin in the regulation of genome expression, the MEN1 protein was recently shown to move from nucleus to cytoplasm during the cell cycle and mainly the mitotic process (Huang et al., 1999). These data contrast with the absence of any variation of size and amount of menin throughout the cell cycle as studied in synchronized cells (Wautot et al., 2000).

Major function of menin in normal and MEN1-related conditions

Major function of the MEN1 gene product might be related to the ability of menin to bind JunD, a transcription factor belonging to the multimeric AP1 transcription regulation complex (Agarwal et al., 1999). Deletion constructs and natural mutants of menin have shown that interaction with JunD needs three major domains of the menin protein, the first 40 aminoacids of the N-terminal region and two central sequences at positions 139-242 and 323-428 respectively. The menin-JunD interaction seemed to be specific and established through the N- terminal sequences (amino acids 1-70) of JunD and a co-activator, JAB1, involved in the transcriptionnal regulation activity of JunD in the AP1 complex (Agarwal et al., 1999). Specific JunD missense mutants in the N- terminal domain failed to bind menin with a subsequent activation of their transcriptionnal activity suggesting escape of menin control (Knapp et al., 2000). Wild-type menin repressed transcriptionnal activation mediated by JunD upon in vitro co-transfection assays. Independantly, some authors have confirmed these data and showed that menin mediated repression of JunD activity was related to histone deacetylation mechanisms which are involved in chromatin-mediated regulation of gene expression (Gobl et al., 1999).

Despite extensive characterization of menin-JunD interaction, the physiopathogeny of MEN1-related endocrine and non- endocrine lesions remains poorly understood, mainly considering the fact that AP1 is an ubiquitous factor in all tissues which regulates most of cellular process such as, mitosis, DNA replication, transcription, apoptosis and response to physical or chemical stress (Calender, 2000). JunD was considered as a transcriptionnal activator but paradoxical observations showed that overexpression of JunD in NIH3T3 cells suppresses cell growth. This suggests that JunD might be both a co-repressor and a co-activator in AP1 depending the cellular context. Recent studies showed that overexpression of menin in ras- transformed NIH3T3 cells inhibits cell growth supporting the hypothesis that menin is a growth-suppressor through complex interactions within the JunD-AP1 complex (Kim et al., 1999).

More than 300 unique germline mutations have now been identified in MEN1 family probands analyzed throughout the world (Agarwal et al., 1997; Shimizu et al., 1997; Bassett et al., 1998; Giraud et al., 1998; Teh et al., 1998; Poncin et al., 1999; Mutch et al., 1999). Somatic mutations have also been reported in sporadic forms of endocrine tumors with variable incidence of 20-30% in parathyroid, endocrine pancreas ( gastrinomas, insulinomas), lung carcinoids and less than 1% in pituitary and adrenal cortical tumors (Heppner et al., 1999; Toliat et al., 1997; Zhuang et al., 1997; Debelenko et al., 1997; Zhuang et al., 1997; Prezant et al., 1998). All these mutations were recently included in an unpublished mutation database developped in the frame of UMD (Universal Mutation database) software allowing an easy evaluation of genotype-phenotype corralations (Beroud et al., 2000). Over 70% of germline mutations related to the MEN1 disease are nonsense and frameshifts predicting truncation and/or absence of the abnormal protein. Missenses, in-frame deletions or insertions and splice-site alterations account for the remaining ♠ 30% mutations described in the clinical context of MEN1. A putative effect of truncating mutations might be a premature degradation of the truncated menin through the protein catabolism pathway as suggested by the failure of Western-Blot detection of mutant protein in most cases analyzed (Wautot et al., 2000)]. This observation do not exclude a transient and abnormal effect of the truncated menin within the nucleus and cytoplasm, a question which will be further adressed by immunohistochemical competent monoclonal antibodies against menin. Intronic and splice-site mutations were shown to alter RNA splicing with abnormal exon skipping and/or intronic retention (Mutch et al., 1999; Engelbach et al., 1999; Roijers et al., 2000).

Homologs of MEN1 sequences in other species

The murine Men1 gene was mapped and cloned in the pericentromeric region of murine chromosome 19 which is syntenic to human 11q13 [37]. The genomic organization of Men1 is similar to that of the human gene including 10 exons and a noncoding region covering ♠ 6,7 Kb of genomic DNA. Suggestive of what might happen in humans, two major transcripts of 2,8 and 3,2 Kb were detected in most embryonic and adult tissues, resulting from alternative splicing of intron 1 (Bassett et al., 1999). The predicted protein is 611 amino acids in length and characterized by 97% homology with the human sequence. Two independant teams subsequently cloned the murine and rat Men1 and showed similar data on structure and expression (Bassett et al., 1999; Karges et al., 1999). The expression of Men1 is detected as earlier as gestationnal day 7 in the whole embryo, and a strong expression limited to thymus, liver, nervous system and gonads at day 17. Hence, the expression of Men1 was not confined to organs affected in MEN1. In testis, Men1 expression was found to be higher in Sertoli cells than in germ cells (Stewart et al., 1998). These data assess independant observations suggesting that menin-JunD related pathways within the AP1 complex might directly control the transition of granulosa cells to terminally differentiated, non-dividing luteal cells in ovarian gland (Sharma et al., 2000). Lastly, the zebrafish and drosophila homologs of MEN1 have been recently identified and show respectively ♠ 75% and ♠ 47% homologies with the human sequence (Khodaei et al., 1999; Maruyama et al., 2000). Among the amino acid residue substitutions reported as disease-associated missense mutations, most of them (70%) were completely conserved either in zebrafish and drosophila menin, indicating an evolutionnary conserved protein with a fundamental role in biological processes.

Animal model of MEN1 and pathogenic effect of MEN1 gene inactivation

According to the Knudson model, MEN1 appears to be a growth suppressor gene with tumors in MEN1 affected patients showing somatic loss of the wild-type allele, so-called loss of heterozygosity (LOH) at 11q13 (Bystrom et al., 1990; Knudson, 1971). Functionnally, all truncating mutations affect one or both NLS in the C-terminal domain of menin. Conversely, missense mutations have never been observed inside the menin NLSs sequences, suggesting that the functionnal role of these sequences might be critical for cell survival and mainly at the embryonic level. Recently, the first mouse model of MEN1 was produced through homologous recombination of the mouse Men1 gene (Crabtree et al., 2001). A major mice strain lacking exons 3-8 of the Men1 gene was produced and heterozygous Men1+/- were bred to generate Men1-/- homozygotes. Homozygous inactivation of the Men1 gene was lethal at around days 10-14 of embryogenesis with developmental delay, defects in cranial and facial developments. Interestingly, Men1+/- heterozygotes develop hyperplastic pancreatic islets and first small tumors after 9 months of age and significantly larger tumors with capsular invasion after 16 months of age. Other tumors observed in heterozygous Men1+/- mices were parathyroid hyperplasia/adenoma, pituitary adenoma and adrenal cortical carcinomas in 24, 26 and 20% of cases analyzed throughout the course of the time study. Most of the tumors observed in this animal model showed loss of heterozygosity on the wild-type allele (Crabtree et al., 2001).

Clinical implications of MEN1 gene analysis

Taken together, updated data on MEN1 suggest that inactivation or absence of both MEN1 alleles is a critical factor in MEN1-related endocrine tumors initiation. Identification of nonsense or any other truncating mutations in a MEN1 suspected patient clearly assess the diagnosis. With missense or intronic mutations, we might consider that pathogenic effects may be related to disturbances in menin-JunD (or forthcoming new functionnal interactions) related pathway or abnormal splicing respectively. In such cases, in vitro functionnal tests will be required to assess for instance that an amino acid substitution must be considered as a mutation and not a rare polymorphism. Clinical criteria used for diagnosis of MEN1 are crucial and in our experience, MEN1 germline mutations were found in 95% of probands/families with as a patient sharing at least three major lesions of the syndrome and a first-degree relatives affected by one (or more) MEN1-related lesions (Giraud et al., 1998). Most families without demonstrable MEN1 mutations display an atypical clinical pattern, which might suggest genetic heterogeneity of the disease or the occurrence of phenocopies with lesions which are commonly observed in the non-MEN1 individuals, such as primary hyperparathyroidism and prolactinoma (Teh et al., 1987; Stock et al., 1997). Lastly, when MEN1 is strongly suspected, mutations might occur in unknown part of the MEN1 sequence, as the 5' regulatory region for which functionnal characterization is in progress (Khodaei-O'Brien et al., 2000). Large intragenic rearrangements and/or deletions, either within or encompassing the MEN1 gene might have been missed by routine PCR and sequencing procedures. A MEN1 deletion has been suggested in a japanese MEN1 pedigree by quantitative Southern-Blot analysis and shown recently in a large french MEN1 family using molecular cytogenetics procedures (Kishi et al., 1998; Lespinasse et al, in preparation). Finally, we might conclude that clinical screening of patients remains a prerequisite of genetic analysis and that functionnal knowledges on menin-related pathways must be kept in mind of clinicians following MEN1 affected patients.


Oncogenic activation of RET, a tyrosine-kinase membrane receptor, induces MEN2

Clinical expression of RET germline mutations

The two major variants of Multiple Endocrine Neoplasia type 2 (MEN2A or Sipple's syndrome, OMIM 171400 ; MEN2B or Gorlin syndrome, OMIM 162300) result from missense activating (or oncogenic) mutations of RET, a gene localized on chromosome 10q11-2 and encoding a transmembrane tyrosine-kinase (TK) receptor (Donis-Keller et al., 1993; Mulligan et al., 1993). MEN2 might be considered as the inherited form of medullary thyroid carcinoma (MTC) , a constant lesion in MEN2, associated or not with pheochromocytoma and/or primary hyperparathyroidism. MEN2B is a rare variant characterized by an early-occurrence and aggressive MTC, pheochromocytoma, mucosal neuromas on the gastrointestinal tract and a marfanoid habitus. FMTC (Familial isolated Medullary Thyroid Carcinoma) might be considered as the classical MENA syndrome with very low penetrance of pheochromocytoma and hyperparathyroidism (Farndon et al., 1986; Moers et al., 1996).

Functionnal insights on the c-ret protein

RET genomic size is 60 Kb and the gene contains 21 exons (Takahashi et al., 1988). The c-ret protein is characterized by an extracellular cysteine-rich homodimerization domain and an intracellular TK catalytic site. The N-terminal part of the extracellular region contains a cadherin-like domain which mediates calcium-dependant cell-cell adhesion. This receptor bounds at least four ligands, GDNF (Glial cell line Derived Neurotrophic Factor), neurturin, artemin and persephrin, all of them inducing homodimerization of the c-ret protein through the cysteine-rich region, thereby triggering the TK catalytic site (Airaksinen et al., 1999; Taraviras et al., 1999). Intracellular events after ligand binding and c-ret dimerization involve cross-phosphorylation of TK domains and the downstream activation of Ras-MAP-kinase and PI3/AKT transduction pathways (Ohiwa et al., 1997; Segouffin-Cariou and Billaud, 2000). Biological properties of c-ret and ligands is related to the genesis of the peripheral and central nervous sytem and renal excretory tract. Strikingly, both GDNF -/- and c-ret -/- knock-out mices share the same phenotype with an early death after birth, lack of neurons in the whole digestive tract and kidney agenesis (Schuchardt et al., 1994; Sanchez et al., 1996; Enomoto et al., 1998). The c-ret protein is highly expressed in many normal endocrine tissues, developping kidney and in human tumors of the neural crest derivatives, such as MTC, neuroblastoma and pheochromocytoma (Nakamura et al., 1994; Avantaggiato et al., 1994). Recently, it has been proven that a constitutively activated RET-MEN2A allele promotes cell survival in vitro in the absence of any growth factors and that this effect might be controlled by a specific domain around c-ret tyrosine 1062 through the PI3/AKT / MAP kinase pathways (De Vita et al., 2000).

Germline RET mutations in MEN2 and downstream deregulated pathways

All germline mutations of RET observed in MEN2 were missense mutations affecting either the cystein-rich extracellular dimerization domain (exons 8 to 13) or intracellular TK catalytic sites (exons 15 and 16) (Pasini et al., 1996; Eng et al., 1996). Genotype- phenotype correlations have been clearly established, mutations occuring in exons 8 to 14 being mostly related to MEN2A and FMTC variants, mutations observed in exons 15 and 16 being always related to a MEN2B phenotype. Conversely, transgenic mice expressing an activating MEN2A-related mutation in exon 11 develop bilateral MTC as in humans but never pheochromocytoma (Michiels et al., 1997; Kawai et al., 2000). Mutations occuring in exons 8 to 11 induce spontaneous homodimerization of the c-ret protein in absence of the ligand(s) (Santoro et al., 1995). Mutations described in exon 13 and 14 affect the catalytic site by inducing an inappropriate binding to substrates of the intracellular signalling pathway (Santoro et al., 1995; Rossel et al., 1997). Lastly, MEN2B-related mutations in exons 15 and 16 switch the substrate specificity of the c-ret TK from a membrane receptor towards an intracellular tyrosine-kinase, thus inducing abnormal signalling pathways (Santoro et al., 1995; Iwashita et al., 1999).

Clinical implications of RET sequencing in MEN2

To date, germline RET mutations were found in ♠ 100% of MEN2A, ♠ 90% of FMTC and ♠ 95-100% of MEN2B families. In terms of clinical use, we might conclude that routine screening of exons 8, 10, 11, 12, 13, 14, 15 and 16 of RET is now an useful tool for an accurate presymptomatic diagnosis in this disease. Germline RET mutations were also found in 5-7% of sporadic cases of MTC (Eng et al., 1995; Wohllk et al., 1996), mostly in patients for which clinical and genetic informations have been less informative at initial diagnosis, suggesting de novo mutations or missed familial cases. MEN2 syndrome represents a model in genetic predisposition to cancer by the fact that molecular genetic analysis of RET might be considered as an early preventive action, leading to prophylactic thyroidectomy in (young) asymptomatic gene-carriers (Lallier et al., 1998).


Mutations in the VHL gene predisposes to pancreatic NET

Clinical features

In a recent series of 158 patients affected by VHL (von Hippel Lindau or OMIM 193300) disease, Hammel et al showed pancreatic involvement in 77% of cases, including true cysts, serous cystadenomas and neuroendocrine tumors in 12% of VHL patients (Hammel et al., 2000). None of the patients with pancreatic NET had symptoms of hormonal hypersecretion suggesting that VHL-related pancreatic NET are mostly non-functionnal. VHL-related pancreatic NET might be distinguished from MEN1-related tumors based on 1) the absence of primitive duodenal tumors 2) frequent non-functionnal lesions with focal positivity for pancreatic polypeptide, somatostatin, glucagon and insulin 3) a clear-cell morphology related to intracytoplasmic lipid and myelin accumulation and 4) the frequent occurrence of microcystic adenomas around the clear-cell tumors. VHL disease is an autosomal dominant disease which main lesions are retinal hemangioblastomas, retinal hemangioblastomas and/or cerebellar hemangioblastomas, renal cancers, pheochromocytoma, pancreatic lesions and auricular endolymphatic epithelial proliferations (Richard et al., 1998; Couch et al., 2000).

VHL gene and function

The VHL gene was cloned in 1993 on chromosome 3p35-36 and contains only three exons encoding a protein with pleiotropic functions (Latif et al., 1993). The VHL protein interacts with the elongin family involved as regulators of transcriptionnal elongation (Aso et al., 1995; Kibel et al., 1995). Other functions of the VHL protein have been related to the hypoxia-induced cell regulation by enhanced expression of VEGF (Vascular Endothelial Growth Factor), regulation of extracellular matrix fibronectin expression and stabilization and lastly, VHL protein interacts with Cullin-2 and Rbx1, two major components of the cellular ubiquitination or protein catabolism machinery (Mukhopadhyay et al., 1997; Ohh et al., 1998; Iwai et al., 1999). Many naturally occuring mutations in VHL have either been shown or are predicted to abrogate assembly with elongins and Cullin-2, suggesting a functionnal role for these interactions in VHL-related tumors and digestive NET (Bonicalzi et al., 2001; Libutti et al., 2000).

Clinical implications of VHL gene analysis

VHL gene sequencing has been useful in VHL disease presymptomatic diagnosis and in some clinical states suggesting differential diagnosis with MEN1 and MEN2. In fact, germline mutations of the VHL gene have been shown in patients with pancreatic endocrine tumors without any lesions suggesting MEN1 (Aubert-Petit et al., 1999) and in rare cases of familial occurrence of pheochromocytomas (Garcia et al;, 1997).


Forthcoming genes involved in neuroendocrine tumors through the Carney Complex

Carney complex (CC or OMIM 160980) is an autosomal dominant disease predisposing to various types of tumors including cardiac and cutaneous myxomas, spotty pigmentation of the skin and nonneoplastic hyperfunctioning endocrine states, as nodular adrenocortical hyperplasia associated with Cushing syndrome, pituitary and thyroid adenomas (Carney et al., 1985). Clinical evaluation and genetic linkage analysis of families affected by Carney complex suggested at least two distinct loci for disease genes, the first on chromosome 2p16, the second on chromosome 17q24 (Stratakis et al., 1996; Casey et al., 1998). Recent positional cloning studies demonstrate that 17q-linked Carney disease was caused by mutations in the R1α regulatory subunit of cAMP-dependant protein kinase A (PKA), so- called the PPKAR1αgene (Kirschner et al., 2000; Casey et al., 2000). Most mutations were nonsense or frameshifts inducing haploinsufficiency of the PPKAR1α subunit. This protein acts as a tumor suppressor gene in most tissues by down-regulating the PKA activity. Loss of the PPKAR1α regulatory subunit promotes cell proliferation and growth of benign tumors in multiple tissues. Hyperendocrine states are likely to be a result of increased PKA activity and cAMP levels by disruption of the tetrameric inactive form of the enzyme (McKnight et al., 1998). The second gene involved in Carney complex and localized on 2p16 remains to be identified.



Apart from well-defined genes involved in genetic predisposition to NET, we were not able to show a common pathway leading to the proliferation of neuroendocrine cells. We might expect that various mechanisms occur depending the embryological origins of the organs concerned. Figure 2 summarizes the mechanisms related to MEN1, MEN2, VHL, CC and NF1/TSC mutations in the genetic syndromes described previously. The genetic mechanisms underlying malignant progression of benign neuroendocrine tumors remain unknown. Some genes, as NF1 (Neurofibromatosis type 1) and TSC1/2 (Tuberous Sclerosis) have been suggested as putative loci involved in tumoral progression from the fact that both genetic syndromes related to mutations in these genes, either Recklinghausen Neurofibromatosis (NF1) and Tuberous Sclerosis (TSC) might rarely predispose to endocrine tumors such as pheochromocytomas, primary hyperparathyrodism and pancreatic somatostatinomas or insulinomas (Van Basten et al., 1994; Kim et al., 1995). The NF1 (chromosome 17) and both TSC1 (chromosome 9) and TSC2 (chromosome 16) genes are involved in the membrane signal transduction pathway by acting as negative regulators of ras (NF1) or rab-5 (TSC1/2)-related small G-proteins (van Slegtenhorst et al., 1997; Xiao et al., 1997). NF1, TSC1/2 disrupt GTP-ras or rab-5 complex and are considered as GTPase-activating proteins (GAP), an independant class of growth-suppressor genes.

Figure 2 : Schematic summary of the complexity of pathways involved in genetic predisposition to neuroendocrine tumors. All proteins, membrane receptors, pathways and interactions are detailed in the text. When designed by +, the gene involved in the syndrome (such as MEN2) acts as an oncogene with a dominant mechanism. When designed by -, the genes related to syndromes (such as MEN1, NF1, TSC, Carney complex and VHL) are considered as growth suppressors, acting by negative regulation of various pathways shown in this figure.

Most cancers result from multistep scenarios and we might consider that many other genes are involved in the progression of benign NET towards a fully malignant phenotype. Mutations of well-known growth-suppressor or onco-genes, such as p53, Ki-RAS , HER2/NEU, C-MYC, N-MYC , N-RAS , C-JUN, PRAD-1, have been excluded as major events in NET progression even if some studies showed upregulation of gene expression in tumor tissues (Calender, 2000). Up-regulation of genes such as bcl-2, an apoptosis-regulating function and p53 or down or de-regulation of adhesion molecules such as CD44 have been suggested to be of importance as prognostic markers in pancreatic and bronchial carcinoid tumors (Granberg et al., 2000). Nuclear nm23 and Ki-67 proliferation-associated markers have also been considered as useful tools for valuable prognostic information and identification of patients at risk of disease-related death (Farley et al., 1993; Solcia et al., 1998). Nevertheless, more hopes on this topic remain related to the identification of loci-specific loss of heterozygosity (LOH) mainly on chromosomes 1p and 1q (Chung et al., 1997), 3p25-26 (Ebrahimi et al., 1999; Chung et al., 1997), 11q13 and 18q (Chakrabarti et al., 1998; Hessmann et al., 1999). Loss of the MEN1 loci might induce latent genomic and/or chromosomal instability as suggested by a few reports but the basic mechanism leading to this instability has not been proven to date (Calender, 2000). Most of the genes involved in such LOH's remain to be identified and their implications in neuroendocrine cell proliferation must be demonstrated by in vitro functional tests. Malignant progression of neuroendocrine tumors might also be triggered by overexpression of growth factors involved in endocrine and endothelial cell proliferation such as TGFα, EGF, NGF and VEGF/VEGF-related factors ( Nilsson et al., 1995; Bold et al., 1995; Grimmond et al., 1996; Liu et al. 1995).

Finally, most of the genes involved in the initiation of endocrine tumors have been now discovered and are involved in genetic predisposition to NET. In sporadic and malignant forms of neuroendocrine tumors, other genes remain to be found and their respective roles during the multistep progression of tumors to be identified. Genetic studies have contributed to the development of animal models of neuroendocrine tumors in the context of genetic syndromes closed to what have been observed in humans. This represents a powerful tool for therapeutical assays in the future and mainly by understanding the mechanisms leading a normal endocrine cell towards a fully malignant and metastatic clone.


Molecular genetics of neuroendocrine tumors.
Calender A
Digestion. 2000 ; 62 Suppl 1 : 3-18.
PMID 10940682
Lessons learned from BRCA1 and BRCA2.
Zheng L, Li S, Boyer TG, Lee WH
Oncogene. 2000 ; 19 (53) : 6159-6175.
PMID 11156530
The natural history of multiple endocrine neoplasia type 1. Highly uncommon or highly unrecognized?
Shepherd JJ
Archives of surgery (Chicago, Ill. : 1960). 1991 ; 126 (8) : 935-952.
PMID 1677802
Multiple facial angiofibromas and collagenomas in patients with multiple endocrine neoplasia type 1.
Darling TN, Skarulis MC, Steinberg SM, Marx SJ, Spiegel AM, Turner M
Archives of dermatology. 1997 ; 133 (7) : 853-857.
PMID 9236523
Malignant melanoma in patients with multiple endocrine neoplasia type 1 and involvement of the MEN1 gene in sporadic melanoma.
Nord B, Platz A, Smoczynski K, Kytölä S, Robertson G, Calender A, Murat A, Weintraub D, Burgess J, Edwards M, Skogseid B, Owen D, Lassam N, Hogg D, Larsson C, Teh BT
International journal of cancer. Journal international du cancer. 2000 ; 87 (4) : 463-467.
PMID 10918183
Multiple endocrine neoplasia type 1 associated with spinal ependymoma.
Kato H, Uchimura I, Morohoshi M, Fujisawa K, Kobayashi Y, Numano F, Goseki N, Endo M, Tamura A, Nagashima C
Internal medicine (Tokyo, Japan). 1996 ; 35 (4) : 285-289.
PMID 8739783
A large multiple endocrine neoplasia type 1 family with clinical expression suggestive of anticipation.
Giraud S, Choplin H, Teh BT, Lespinasse J, Jouvet A, Labat-Moleur F, Lenoir G, Hamon B, Hamon P, Calender A
The Journal of clinical endocrinology and metabolism. 1997 ; 82 (10) : 3487-3492.
PMID 9329390
Multiple endocrine neoplasia type 1 gene maps to chromosome 11 and is lost in insulinoma.
Larsson C, Skogseid B, Oberg K, Nakamura Y, Nordenskjö M
Nature. 1988 ; 332 (6159) : 85-87.
PMID 2894610
Positional cloning of the gene for multiple endocrine neoplasia-type 1.
Chandrasekharappa SC, Guru SC, Manickam P, Olufemi SE, Collins FS, Emmert-Buck MR, Debelenko LV, Zhuang Z, Lubensky IA, Liotta LA, Crabtree JS, Wang Y, Roe BA, Weisemann J, Boguski MS, Agarwal SK, Kester MB, Kim YS, Heppner C, Dong Q, Spiegel AM, Burns AL, Marx SJ
Science (New York, N.Y.). 1997 ; 276 (5311) : 404-407.
PMID 9103196
Identification of the multiple endocrine neoplasia type 1 (MEN1) gene. The European Consortium on MEN1.
Lemmens I, Van de Ven WJ, Kas K, Zhang CX, Giraud S, Wautot V, Buisson N, De Witte K, Salandre J, Lenoir G, Pugeat M, Calender A, Parente F, Quincey D, Gaudray P, De Wit MJ, Lips CJ, Höppener JW, Khodaei S, Grant AL, Weber G, Kytölä S, Teh BT, Farnebo F, Thakker RV
Human molecular genetics. 1997 ; 6 (7) : 1177-1183.
PMID 9215690
Menin, the product of the MEN1 gene, is a nuclear protein.
Guru SC, Goldsmith PK, Burns AL, Marx SJ, Spiegel AM, Collins FS, Chandrasekharappa SC
Proceedings of the National Academy of Sciences of the United States of America. 1998 ; 95 (4) : 1630-1634.
PMID 9465067
Nuclear/cytoplasmic localization of the multiple endocrine neoplasia type 1 gene product, menin.
Huang SC, Zhuang Z, Weil RJ, Pack S, Wang C, Krutzsch HC, Pham TA, Lubensky IA
Laboratory investigation; a journal of technical methods and pathology. 1999 ; 79 (3) : 301-310.
PMID 10092066
Expression analysis of endogenous menin, the product of the multiple endocrine neoplasia type 1 gene, in cell lines and human tissues.
Wautot V, Khodaei S, Frappart L, Buisson N, Baro E, Lenoir GM, Calender A, Zhang CX, Weber G
International journal of cancer. Journal international du cancer. 2000 ; 85 (6) : 877-881.
PMID 10709111
Menin interacts with the AP1 transcription factor JunD and represses JunD-activated transcription.
Agarwal SK, Guru SC, Heppner C, Erdos MR, Collins RM, Park SY, Saggar S, Chandrasekharappa SC, Collins FS, Spiegel AM, Marx SJ, Burns AL
Cell. 1999 ; 96 (1) : 143-152.
PMID 9989505
Identification and characterization of JunD missense mutants that lack menin binding.
Knapp JI, Heppner C, Hickman AB, Burns AL, Chandrasekharappa SC, Collins FS, Marx SJ, Spiegel AM, Agarwal SK
Oncogene. 2000 ; 19 (41) : 4706-4712.
PMID 11032020
Menin represses JunD-activated transcription by a histone deacetylase-dependent mechanism.
Gobl AE, Berg M, Lopez-Egido JR, Oberg K, Skogseid B, Westin G
Biochimica et biophysica acta. 1999 ; 1447 (1) : 51-56.
PMID 10500243
Stable overexpression of MEN1 suppresses tumorigenicity of RAS.
Kim YS, Burns AL, Goldsmith PK, Heppner C, Park SY, Chandrasekharappa SC, Collins FS, Spiegel AM, Marx SJ
Oncogene. 1999 ; 18 (43) : 5936-5942.
PMID 10557080
Germline mutations of the MEN1 gene in familial multiple endocrine neoplasia type 1 and related states.
Agarwal SK, Kester MB, Debelenko LV, Heppner C, Emmert-Buck MR, Skarulis MC, Doppman JL, Kim YS, Lubensky IA, Zhuang Z, Green JS, Guru SC, Manickam P, Olufemi SE, Liotta LA, Chandrasekharappa SC, Collins FS, Spiegel AM, Burns AL, Marx SJ
Human molecular genetics. 1997 ; 6 (7) : 1169-1175.
PMID 9215689
Germline mutations of the MEN1 gene in Japanese kindred with multiple endocrine neoplasia type 1.
Shimizu S, Tsukada T, Futami H, Ui K, Kameya T, Kawanaka M, Uchiyama S, Aoki A, Yasuda H, Kawano S, Ito Y, Kanbe M, Obara T, Yamaguchi K
Japanese journal of cancer research : Gann. 1997 ; 88 (11) : 1029-1032.
PMID 9439676
Characterization of mutations in patients with multiple endocrine neoplasia type 1.
Bassett JH, Forbes SA, Pannett AA, Lloyd SE, Christie PT, Wooding C, Harding B, Besser GM, Edwards CR, Monson JP, Sampson J, Wass JA, Wheeler MH, Thakker RV
American journal of human genetics. 1998 ; 62 (2) : 232-244.
PMID 9463336
Germ-line mutation analysis in patients with multiple endocrine neoplasia type 1 and related disorders.
Giraud S, Zhang CX, Serova-Sinilnikova O, Wautot V, Salandre J, Buisson N, Waterlot C, Bauters C, Porchet N, Aubert JP, Emy P, Cadiot G, Delemer B, Chabre O, Niccoli P, Leprat F, Duron F, Emperauger B, Cougard P, Goudet P, Sarfati E, Riou JP, Guichard S, Rodier M, Meyrier A, Caron P, Vantyghem MC, Assayag M, Peix JL, Pugeat M, Rohmer V, Vallotton M, Lenoir G, Gaudray P, Proye C, Conte-Devolx B, Chanson P, Shugart YY, Goldgar D, Murat A, Calender A
American journal of human genetics. 1998 ; 63 (2) : 455-467.
PMID 9683585
Mutation analysis of the MEN1 gene in multiple endocrine neoplasia type 1, familial acromegaly and familial isolated hyperparathyroidism.
Teh BT, Kytölä S, Farnebo F, Bergman L, Wong FK, Weber G, Hayward N, Larsson C, Skogseid B, Beckers A, Phelan C, Edwards M, Epstein M, Alford F, Hurley D, Grimmond S, Silins G, Walters M, Stewart C, Cardinal J, Khodaei S, Parente F, Tranebjaerg L, Jorde R, Salmela P
The Journal of clinical endocrinology and metabolism. 1998 ; 83 (8) : 2621-2626.
PMID 9709921
Mutation analysis of the MEN1 gene in Belgian patients with multiple endocrine neoplasia type 1 and related diseases.
Poncin J, Abs R, Velkeniers B, Bonduelle M, Abramowicz M, Legros JJ, Verloes A, Meurisse M, Van Gaal L, Verellen C, Koulischer L, Beckers A
Human mutation. 1999 ; 13 (1) : 54-60.
PMID 9888389
Germline mutations in the multiple endocrine neoplasia type 1 gene: evidence for frequent splicing defects.
Mutch MG, Dilley WG, Sanjurjo F, DeBenedetti MK, Doherty GM, Wells SA Jr, Goodfellow PJ, Lairmore TC
Human mutation. 1999 ; 13 (3) : 175-185.
PMID 10090472
Somatic mutation of the MEN1 gene in parathyroid tumours.
Heppner C, Kester MB, Agarwal SK, Debelenko LV, Emmert-Buck MR, Guru SC, Manickam P, Olufemi SE, Skarulis MC, Doppman JL, Alexander RH, Kim YS, Saggar SK, Lubensky IA, Zhuang Z, Liotta LA, Chandrasekharappa SC, Collins FS, Spiegel AM, Burns AL, Marx SJ
Nature genetics. 1997 ; 16 (4) : 375-378.
PMID 9241276
Mutations in the MEN I gene in sporadic neuroendocrine tumours of gastroenteropancreatic system.
Toliat MR, Berger W, Ropers HH, Neuhaus P, Wiedenmann B
Lancet. 1997 ; 350 (9086) : page 1223.
PMID 9652567
Somatic mutations of the MEN1 tumor suppressor gene in sporadic gastrinomas and insulinomas.
Zhuang Z, Vortmeyer AO, Pack S, Huang S, Pham TA, Wang C, Park WS, Agarwal SK, Debelenko LV, Kester M, Guru SC, Manickam P, Olufemi SE, Yu F, Heppner C, Crabtree JS, Skarulis MC, Venzon DJ, Emmert-Buck MR, Spiegel AM, Chandrasekharappa SC, Collins FS, Burns AL, Marx SJ, Lubensky IA
Cancer research. 1997 ; 57 (21) : 4682-4686.
PMID 9354421
Identification of MEN1 gene mutations in sporadic carcinoid tumors of the lung.
Debelenko LV, Brambilla E, Agarwal SK, Swalwell JI, Kester MB, Lubensky IA, Zhuang Z, Guru SC, Manickam P, Olufemi SE, Chandrasekharappa SC, Crabtree JS, Kim YS, Heppner C, Burns AL, Spiegel AM, Marx SJ, Liotta LA, Collins FS, Travis WD, Emmert-Buck MR
Human molecular genetics. 1997 ; 6 (13) : 2285-2290.
PMID 9361035
Mutations of the MEN1 tumor suppressor gene in pituitary tumors.
Zhuang Z, Ezzat SZ, Vortmeyer AO, Weil R, Oldfield EH, Park WS, Pack S, Huang S, Agarwal SK, Guru SC, Manickam P, Debelenko LV, Kester MB, Olufemi SE, Heppner C, Crabtree JS, Burns AL, Spiegel AM, Marx SJ, Chandrasekharappa SC, Collins FS, Emmert-Buck MR, Liotta LA, Asa SL, Lubensky IA
Cancer research. 1997 ; 57 (24) : 5446-5451.
PMID 9407947
Molecular characterization of the men1 tumor suppressor gene in sporadic pituitary tumors.
Prezant TR, Levine J, Melmed S
The Journal of clinical endocrinology and metabolism. 1998 ; 83 (4) : 1388-1391.
PMID 9543172
MEN1 gene mutation analysis of sporadic adrenocortical lesions.
Görtz B, Roth J, Speel EJ, Krähenmann A, De Krijger RR, Matias-Guiu X, Muletta-Feurer S, Rütmann K, Saremaslani P, Heitz PU, Komminoth P
International journal of cancer. Journal international du cancer. 1999 ; 80 (3) : 373-379.
PMID 9935177
Genotyping of adrenocortical tumors: very frequent deletions of the MEN1 locus in 11q13 and of a 1-centimorgan region in 2p16.
Kjellman M, Roshani L, Teh BT, Kallioniemi OP, Höög A, Gray S, Farnebo LO, Holst M, Bäckdahl M, Larsson C
The Journal of clinical endocrinology and metabolism. 1999 ; 84 (2) : 730-735.
PMID 10022445
The MEN-1 gene is rarely down-regulated in pituitary adenomas.
Asa SL, Somers K, Ezzat S
The Journal of clinical endocrinology and metabolism. 1998 ; 83 (9) : 3210-3212.
PMID 9745428
UMD (Universal mutation database): a generic software to build and analyze locus-specific databases.
Béroud C, Collod-Béroud G, Boileau C, Soussi T, Junien C
Human mutation. 2000 ; 15 (1) : 86-94.
PMID 10612827
Germline mutations in the MEN1 gene: creation of a new splice acceptor site and insertion of 7 intron nucleotides into the mRNA.
Engelbach M, Forst T, Hankeln T, Tratzky M, Heerdt S, Pfützner A, Kann P, Kunt T, Schneider S, Schmidt ER, Beyer J
International journal of molecular medicine. 1999 ; 4 (5) : 483-485.
PMID 10534569
Internally shortened menin protein as a consequence of alternative RNA splicing due to a germline deletion in the multiple endocrine neoplasia type 1 gene.
Roijers JF, Apel T, Neumann HP, Arnim UV, Lips CJ, Hoppener JW
International journal of molecular medicine. 2000 ; 5 (6) : 611-614.
PMID 10812010
Characterization of the mouse Men1 gene and its expression during development.
Stewart C, Parente F, Piehl F, Farnebo F, Quincey D, Silins G, Bergman L, Carle GF, Lemmens I, Grimmond S, Xian CZ, Khodei S, Teh BT, Lagercrantz J, Siggers P, Calender A, Van de Vem V, Kas K, Weber G, Hayward N, Gaudray P, Larsson C
Oncogene. 1998 ; 17 (19) : 2485-2493.
PMID 9824159
Studies of the murine homolog of the multiple endocrine neoplasia type 1 (MEN1) gene, men1.
Bassett JH, Rashbass P, Harding B, Forbes SA, Pannett AA, Thakker RV
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 1999 ; 14 (1) : 3-10.
PMID 9893060
Primary structure, gene expression and chromosomal mapping of rodent homologs of the MEN1 tumor suppressor gene.
Karges W, Maier S, Wissmann A, Dralle H, Dosch HM, Boehm BO
Biochimica et biophysica acta. 1999 ; 1446 (3) : 286-294.
PMID 10524203
Structure and distribution of rat menin mRNA.
Maruyama K, Tsukada T, Hosono T, Ohkura N, Kishi M, Honda M, Nara-Ashizawa N, Nagasaki K, Yamaguchi K
Molecular and cellular endocrinology. 1999 ; 156 (1-2) : 25-33.
PMID 10612420
Regulation of AP1 (Jun/Fos) factor expression and activation in ovarian granulosa cells. Relation of JunD and Fra2 to terminal differentiation.
Sharma SC, Richards JS
The Journal of biological chemistry. 2000 ; 275 (43) : 33718-33728.
PMID 10934195
Characterization of the MEN1 ortholog in zebrafish.
Khodaei S, O'Brien KP, Dumanski J, Wong FK, Weber G
Biochemical and biophysical research communications. 1999 ; 264 (2) : 404-408.
PMID 10529376
Complementary DNA structure and genomic organization of Drosophila menin.
Maruyama K, Tsukada T, Honda M, Nara-Ashizawa N, Noguchi K, Cheng J, Ohkura N, Sasaki K, Yamaguchi K
Molecular and cellular endocrinology. 2000 ; 168 (1-2) : 135-140.
PMID 11064160
Localization of the MEN1 gene to a small region within chromosome 11q13 by deletion mapping in tumors.
Byström C, Larsson C, Blomberg C, Sandelin K, Falkmer U, Skogseid B, Oberg K, Werner S, Nordenskjöld M
Proceedings of the National Academy of Sciences of the United States of America. 1990 ; 87 (5) : 1968-1972.
PMID 1968641
Mutation and cancer: statistical study of retinoblastoma.
Knudson AG Jr
Proceedings of the National Academy of Sciences of the United States of America. 1971 ; 68 (4) : 820-823.
PMID 5279523
A mouse model of multiple endocrine neoplasia, type 1, develops multiple endocrine tumors.
Crabtree JS, Scacheri PC, Ward JM, Garrett-Beal L, Emmert-Buck MR, Edgemon KA, Lorang D, Libutti SK, Chandrasekharappa SC, Marx SJ, Spiegel AM, Collins FS
Proceedings of the National Academy of Sciences of the United States of America. 2001 ; 98 (3) : 1118-1123.
PMID 11158604
Sporadic primary hyperparathyroidism in the setting of multiple endocrine neoplasia type 1.
Teh BT, McArdle J, Parameswaran V, David R, Larsson C, Shepherd J
Archives of surgery (Chicago, Ill. : 1960). 1996 ; 131 (11) : 1230-1232.
PMID 8911266
A kindred with a variant of multiple endocrine neoplasia type 1 demonstrating frequent expression of pituitary tumors but not linked to the multiple endocrine neoplasia type 1 locus at chromosome region 11q13.
Stock JL, Warth MR, Teh BT, Coderre JA, Overdorf JH, Baumann G, Hintz RL, Hartman ML, Seizinger BR, Larsson C, Aronin N
The Journal of clinical endocrinology and metabolism. 1997 ; 82 (2) : 486-492.
PMID 9024241
Heterogeneity at the 5'-end of MEN1 transcripts.
Khodaei-O'Brien S, Zablewska B, Fromaget M, Bylund L, Weber G, Gaudray P
Biochemical and biophysical research communications. 2000 ; 276 (2) : 508-514.
PMID 11027505
A large germline deletion of the MEN1 gene in a family with multiple endocrine neoplasia type 1.
Kishi M, Tsukada T, Shimizu S, Futami H, Ito Y, Kanbe M, Obara T, Yamaguchi K
Japanese journal of cancer research : Gann. 1998 ; 89 (1) : 1-5.
PMID 9510467
Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC.
Donis-Keller H, Dou S, Chi D, Carlson KM, Toshima K, Lairmore TC, Howe JR, Moley JF, Goodfellow P, Wells SA Jr
Human molecular genetics. 1993 ; 2 (7) : 851-856.
PMID 8103403
Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A.
Mulligan LM, Kwok JB, Healey CS, Elsdon MJ, Eng C, Gardner E, Love DR, Mole SE, Moore JK, Papi L
Nature. 1993 ; 363 (6428) : 458-460.
PMID 8099202
Familial medullary thyroid carcinoma without associated endocrinopathies: a distinct clinical entity.
Farndon JR, Leight GS, Dilley WG, Baylin SB, Smallridge RC, Harrison TS, Wells SA Jr
The British journal of surgery. 1986 ; 73 (4) : 278-281.
PMID 3697657
Familial medullary thyroid carcinoma: not a distinct entity? Genotype-phenotype correlation in a large family.
Moers AM, Landsvater RM, Schaap C, Jansen-Schillhorn van Veen JM, de Valk IA, Blijham GH, Höppener JW, Vroom TM, van Amstel HK, Lips CJ
The American journal of medicine. 1996 ; 101 (6) : 635-641.
PMID 9003111
Cloning and expression of the ret proto-oncogene encoding a tyrosine kinase with two potential transmembrane domains.
Takahashi M, Buma Y, Iwamoto T, Inaguma Y, Ikeda H, Hiai H
Oncogene. 1988 ; 3 (5) : 571-578.
PMID 3078962
GDNF family neurotrophic factor signaling: four masters, one servant?
Airaksinen MS, Titievsky A, Saarma M
Molecular and cellular neurosciences. 1999 ; 13 (5) : 313-325.
PMID 10356294
Signalling by the RET receptor tyrosine kinase and its role in the development of the mammalian enteric nervous system.
Taraviras S, Marcos-Gutierrez CV, Durbec P, Jani H, Grigoriou M, Sukumaran M, Wang LC, Hynes M, Raisman G, Pachnis V
Development (Cambridge, England). 1999 ; 126 (12) : 2785-2797.
PMID 10331988
Characterization of Ret-Shc-Grb2 complex induced by GDNF, MEN 2A, and MEN 2B mutations.
Ohiwa M, Murakami H, Iwashita T, Asai N, Iwata Y, Imai T, Funahashi H, Takagi H, Takahashi M
Biochemical and biophysical research communications. 1997 ; 237 (3) : 747-751.
PMID 9299438
Transforming ability of MEN2A-RET requires activation of the phosphatidylinositol 3-kinase/AKT signaling pathway.
Segouffin-Cariou C, Billaud M
The Journal of biological chemistry. 2000 ; 275 (5) : 3568-3576.
PMID 10652352
Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret.
Schuchardt A, D'Agati V, Larsson-Blomberg L, Costantini F, Pachnis V
Nature. 1994 ; 367 (6461) : 380-383.
PMID 8114940
Renal agenesis and the absence of enteric neurons in mice lacking GDNF.
S´nchez MP, Silos-Santiago I, Frisén J, He B, Lira SA, Barbacid M
Nature. 1996 ; 382 (6586) : 70-73.
PMID 8657306
GFR alpha1-deficient mice have deficits in the enteric nervous system and kidneys.
Enomoto H, Araki T, Jackman A, Heuckeroth RO, Snider WD, Johnson EM Jr, Milbrandt J
Neuron. 1998 ; 21 (2) : 317-324.
PMID 9728913
Expression of the ret proto-oncogene product in human normal and neoplastic tissues of neural crest origin.
Nakamura T, Ishizaka Y, Nagao M, Hara M, Ishikawa T
The Journal of pathology. 1994 ; 172 (3) : 255-260.
PMID 8195928
Developmental expression of the RET protooncogene.
Avantaggiato V, Dathan NA, Grieco M, Fabien N, Lazzaro D, Fusco A, Simeone A, Santoro M
Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research. 1994 ; 5 (3) : 305-311.
PMID 8018563
Tyrosine 1062 of RET-MEN2A mediates activation of Akt (protein kinase B) and mitogen-activated protein kinase pathways leading to PC12 cell survival.
De Vita G, Melillo RM, Carlomagno F, Visconti R, Castellone MD, Bellacosa A, Billaud M, Fusco A, Tsichlis PN, Santoro M
Cancer research. 2000 ; 60 (14) : 3727-3731.
PMID 10919641
RET mutations in human disease.
Pasini B, Ceccherini I, Romeo G
Trends in genetics : TIG. 1996 ; 12 (4) : 138-144.
PMID 8901418
The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis.
Eng C, Clayton D, Schuffenecker I, Lenoir G, Cote G, Gagel RF, van Amstel HK, Lips CJ, Nishisho I, Takai SI, Marsh DJ, Robinson BG, Frank-Raue K, Raue F, Xue F, Noll WW, Romei C, Pacini F, Fink M, Niederle B, Zedenius J, Nordenskjöld M, Komminoth P, Hendy GN, Mulligan LM
JAMA : the journal of the American Medical Association. 1996 ; 276 (19) : 1575-1579.
PMID 8918855
Development of medullary thyroid carcinoma in transgenic mice expressing the RET protooncogene altered by a multiple endocrine neoplasia type 2A mutation.
Michiels FM, Chappuis S, Caillou B, Pasini A, Talbot M, Monier R, Lenoir GM, Feunteun J, Billaud M
Proceedings of the National Academy of Sciences of the United States of America. 1997 ; 94 (7) : 3330-3335.
PMID 9096393
Tissue-specific carcinogenesis in transgenic mice expressing the RET proto-oncogene with a multiple endocrine neoplasia type 2A mutation.
Kawai K, Iwashita T, Murakami H, Hiraiwa N, Yoshiki A, Kusakabe M, Ono K, Iida K, Nakayama A, Takahashi M
Cancer research. 2000 ; 60 (18) : 5254-5260.
PMID 11016655
Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B.
Santoro M, Carlomagno F, Romano A, Bottaro DP, Dathan NA, Grieco M, Fusco A, Vecchio G, Matoskova B, Kraus MH
Science (New York, N.Y.). 1995 ; 267 (5196) : 381-383.
PMID 7824936
Distinct biological properties of two RET isoforms activated by MEN 2A and MEN 2B mutations.
Rossel M, Pasini A, Chappuis S, Geneste O, Fournier L, Schuffenecker I, Takahashi M, van Grunsven LA, Urdiales JL, Rudkin BB, Lenoir GM, Billaud M
Oncogene. 1997 ; 14 (3) : 265-275.
PMID 9018112
Biological and biochemical properties of Ret with kinase domain mutations identified in multiple endocrine neoplasia type 2B and familial medullary thyroid carcinoma.
Iwashita T, Kato M, Murakami H, Asai N, Ishiguro Y, Ito S, Iwata Y, Kawai K, Asai M, Kurokawa K, Kajita H, Takahashi M
Oncogene. 1999 ; 18 (26) : 3919-3922.
PMID 10445857
Mutation of the RET protooncogene in sporadic medullary thyroid carcinoma.
Eng C, Mulligan LM, Smith DP, Healey CS, Frilling A, Raue F, Neumann HP, Pfragner R, Behmel A, Lorenzo MJ
Genes, chromosomes & cancer. 1995 ; 12 (3) : 209-212.
PMID 7536460
Relevance of RET proto-oncogene mutations in sporadic medullary thyroid carcinoma.
Wohllk N, Cote GJ, Bugalho MM, Ordonez N, Evans DB, Goepfert H, Khorana S, Schultz P, Richards CS, Gagel RF
The Journal of clinical endocrinology and metabolism. 1996 ; 81 (10) : 3740-3745.
PMID 8855832
Prophylactic thyroidectomy for medullary thyroid carcinoma in gene carriers of MEN2 syndrome.
Lallier M, St-Vil D, Giroux M, Huot C, Gaboury L, Oligny L, Desjardins JG
Journal of pediatric surgery. 1998 ; 33 (6) : 846-848.
PMID 9660211
Pancreatic involvement in von Hippel-Lindau disease. The Groupe Francophone d'Etude de la Maladie de von Hippel-Lindau.
Hammel PR, Vilgrain V, Terris B, Penfornis A, Sauvanet A, Correas JM, Chauveau D, Balian A, Beigelman C, O'Toole D, Bernades P, Ruszniewski P, Richard S
Gastroenterology. 2000 ; 119 (4) : 1087-1095.
PMID 11040195
[Von Hippel-Lindau disease: recent genetic progress and patient management. Francophone Study Group of von Hippel-Lindau Disease (GEFVH)]
Richard S, Giraud S, Beroud C, Caron J, Penfornis F, Baudin E, Niccoli-Sire P, Murat A, Schlumberger M, Plouin PF, Conte-Devolx B
Annales d'endocrinologie. 1998 ; 59 (6) : 452-458.
PMID 10189987
von Hippel-Lindau disease.
Couch V, Lindor NM, Karnes PS, Michels VV
Mayo Clinic proceedings. Mayo Clinic. 2000 ; 75 (3) : 265-272.
PMID 10725953
Identification of the von Hippel-Lindau disease tumor suppressor gene.
Latif F, Tory K, Gnarra J, Yao M, Duh FM, Orcutt ML, Stackhouse T, Kuzmin I, Modi W, Geil L
Science (New York, N.Y.). 1993 ; 260 (5112) : 1317-1320.
PMID 8493574
Elongin (SIII): a multisubunit regulator of elongation by RNA polymerase II.
Aso T, Lane WS, Conaway JW, Conaway RC
Science (New York, N.Y.). 1995 ; 269 (5229) : 1439-1443.
PMID 7660129
Binding of the von Hippel-Lindau tumor suppressor protein to Elongin B and C.
Kibel A, Iliopoulos O, DeCaprio JA, Kaelin WG Jr
Science (New York, N.Y.). 1995 ; 269 (5229) : 1444-1446.
PMID 7660130
The von Hippel-Lindau tumor suppressor gene product interacts with Sp1 to repress vascular endothelial growth factor promoter activity.
Mukhopadhyay D, Knebelmann B, Cohen HT, Ananth S, Sukhatme VP
Molecular and cellular biology. 1997 ; 17 (9) : 5629-5639.
PMID 9271438
The von Hippel-Lindau tumor suppressor protein is required for proper assembly of an extracellular fibronectin matrix.
Ohh M, Yauch RL, Lonergan KM, Whaley JM, Stemmer-Rachamimov AO, Louis DN, Gavin BJ, Kley N, Kaelin WG Jr, Iliopoulos O
Molecular cell. 1998 ; 1 (7) : 959-968.
PMID 9651579
Identification of the von Hippel-lindau tumor-suppressor protein as part of an active E3 ubiquitin ligase complex.
Iwai K, Yamanaka K, Kamura T, Minato N, Conaway RC, Conaway JW, Klausner RD, Pause A
Proceedings of the National Academy of Sciences of the United States of America. 1999 ; 96 (22) : 12436-12441.
PMID 10535940
Role of exon 2-encoded beta -domain of the von Hippel-Lindau tumor suppressor protein.
Bonicalzi ME, Groulx I, de Paulsen N, Lee S
The Journal of biological chemistry. 2001 ; 276 (2) : 1407-1416.
PMID 11024059
Clinical and genetic analysis of patients with pancreatic neuroendocrine tumors associated with von Hippel-Lindau disease.
Libutti SK, Choyke PL, Alexander HR, Glenn G, Bartlett DL, Zbar B, Lubensky I, McKee SA, Maher ER, Linehan WM, Walther MM
Surgery. 2000 ; 128 (6) : 1022-1027.
PMID 11114638
[Neuro-endocrine tumors and von Hippel-Lindau disease. 3 cases]
Aubert-Petit G, Baudin E, Cailleux AF, Pellegriti G, Elias D, Travagli JP, Giraud S, Richard S, Schlumberger M
Presse medicale (Paris, France : 1983). 1999 ; 28 (23) : 1231-1234.
PMID 10420887
Molecular diagnosis of von Hippel-Lindau disease in a kindred with a predominance of familial phaeochromocytoma.
Garcia A, Matias-Guiu X, Cabezas R, Chico A, Prat J, Baiget M, De Leiva A
Clinical endocrinology. 1997 ; 46 (3) : 359-363.
PMID 9156047
The complex of myxomas, spotty pigmentation, and endocrine overactivity.
Carney JA, Gordon H, Carpenter PC, Shenoy BV, Go VL
Medicine. 1985 ; 64 (4) : 270-283.
PMID 4010501
Carney complex, a familial multiple neoplasia and lentiginosis syndrome. Analysis of 11 kindreds and linkage to the short arm of chromosome 2.
Stratakis CA, Carney JA, Lin JP, Papanicolaou DA, Karl M, Kastner DL, Pras E, Chrousos GP
The Journal of clinical investigation. 1996 ; 97 (3) : 699-705.
PMID 8609225
Identification of a novel genetic locus for familial cardiac myxomas and Carney complex.
Casey M, Mah C, Merliss AD, Kirschner LS, Taymans SE, Denio AE, Korf B, Irvine AD, Hughes A, Carney JA, Stratakis CA, Basson CT
Circulation. 1998 ; 98 (23) : 2560-2566.
PMID 9843463
Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex.
Kirschner LS, Carney JA, Pack SD, Taymans SE, Giatzakis C, Cho YS, Cho-Chung YS, Stratakis CA
Nature genetics. 2000 ; 26 (1) : 89-92.
PMID 10973256
Mutations in the protein kinase A R1alpha regulatory subunit cause familial cardiac myxomas and Carney complex.
Casey M, Vaughan CJ, He J, Hatcher CJ, Winter JM, Weremowicz S, Montgomery K, Kucherlapati R, Morton CC, Basson CT
The Journal of clinical investigation. 2000 ; 106 (5) : R31-R38.
PMID 10974026
Cyclic AMP, PKA, and the physiological regulation of adiposity.
McKnight GS, Cummings DE, Amieux PS, Sikorski MA, Brandon EP, Planas JV, Motamed K, Idzerda RL
Recent progress in hormone research. 1998 ; 53 : 139-159.
PMID 9769707
Ampullary carcinoid and neurofibromatosis: case report and review of the literature.
van Basten JP, van Hoek B, de Bruïne A, Arends JW, Stockbrügger RW
The Netherlands journal of medicine. 1994 ; 44 (6) : 202-206.
PMID 8052343
The association between tuberous sclerosis and insulinoma.
Kim H, Kerr A, Morehouse H
AJNR. American journal of neuroradiology. 1995 ; 16 (7) : 1543-1544.
PMID 7484652
Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34.
van Slegtenhorst M, de Hoogt R, Hermans C, Nellist M, Janssen B, Verhoef S, Lindhout D, van den Ouweland A, Halley D, Young J, Burley M, Jeremiah S, Woodward K, Nahmias J, Fox M, Ekong R, Osborne J, Wolfe J, Povey S, Snell RG, Cheadle JP, Jones AC, Tachataki M, Ravine D, Sampson JR, Reeve MP, Richardson P, Wilmer F, Munro C, Hawkins TL, Sepp T, Ali JB, Ward S, Green AJ, Yates JR, Kwiatkowska J, Henske EP, Short MP, Haines JH, Jozwiak S, Kwiatkowski DJ
Science (New York, N.Y.). 1997 ; 277 (5327) : 805-808.
PMID 9242607
The tuberous sclerosis 2 gene product, tuberin, functions as a Rab5 GTPase activating protein (GAP) in modulating endocytosis.
Xiao GH, Shoarinejad F, Jin F, Golemis EA, Yeung RS
The Journal of biological chemistry. 1997 ; 272 (10) : 6097-6100.
PMID 9045618
Prognostic markers in patients with typical bronchial carcinoid tumors.
Granberg D, Wilander E, Oberg K, Skogseid B
The Journal of clinical endocrinology and metabolism. 2000 ; 85 (9) : 3425-3430.
PMID 10999844
Expression of a potential metastasis suppressor gene (nm23) in thyroid neoplasms.
Farley DR, Eberhardt NL, Grant CS, Schaid DJ, van Heerden JA, Hay ID, Khosla S
World journal of surgery. 1993 ; 17 (5) : 615-620.
PMID 8273382
Natural history, clinicopathologic classification and prognosis of gastric ECL cell tumors.
Solcia E, Rindi G, Paolotti D, Luinetti O, Klersy C, Zangrandi A, La Rosa S, Capella C
The Yale journal of biology and medicine. 1998 ; 71 (3-4) : 285-290.
PMID 10461359
Deletion of chromosome 1 predicts prognosis in pancreatic endocrine tumors.
Ebrahimi SA, Wang EH, Wu A, Schreck RR, Passaro E Jr, Sawicki MP
Cancer research. 1999 ; 59 (2) : 311-315.
PMID 9927038
A novel pancreatic endocrine tumor suppressor gene locus on chromosome 3p with clinical prognostic implications.
Chung DC, Smith AP, Louis DN, Graeme-Cook F, Warshaw AL, Arnold A
The Journal of clinical investigation. 1997 ; 100 (2) : 404-410.
PMID 9218518
Deletion mapping of endocrine tumors localizes a second tumor suppressor gene on chromosome band 11q13.
Chakrabarti R, Srivatsan ES, Wood TF, Eubanks PJ, Ebrahimi SA, Gatti RA, Passaro E Jr, Sawicki MP
Genes, chromosomes & cancer. 1998 ; 22 (2) : 130-137.
PMID 9598800
Genetic alterations on 3p, 11q13, and 18q in nonfamilial and MEN 1-associated pancreatic endocrine tumors.
Hessman O, Lindberg D, Einarsson A, Lillhager P, Carling T, Grimelius L, Eriksson B, Akerström G, Westin G, Skogseid B
Genes, chromosomes & cancer. 1999 ; 26 (3) : 258-264.
PMID 10502325
Expression of transforming growth factor alpha and its receptor in human neuroendocrine tumours.
Nilsson O, Wängberg B, Kölby L, Schultz GS, Ahlman H
International journal of cancer. Journal international du cancer. 1995 ; 60 (5) : 645-651.
PMID 7860139
Nerve growth factor as a mitogen for a pancreatic carcinoid cell line.
Bold RJ, Ishizuka J, Rajaraman S, Perez-Polo JR, Townsend CM Jr, Thompson JC
Journal of neurochemistry. 1995 ; 64 (6) : 2622-2628.
PMID 7760042
Cloning and characterization of a novel human gene related to vascular endothelial growth factor.
Grimmond S, Lagercrantz J, Drinkwater C, Silins G, Townson S, Pollock P, Gotley D, Carson E, Rakar S, Nordenskjöld M, Ward L, Hayward N, Weber G
Genome research. 1996 ; 6 (2) : 124-131.
PMID 8919691
Melanoma cell lines express VEGF receptor KDR and respond to exogenously added VEGF.
Liu B, Earl HM, Baban D, Shoaibi M, Fabra A, Kerr DJ, Seymour LW
Biochemical and biophysical research communications. 1995 ; 217 (3) : 721-727.
PMID 8554590
Written2001-12Alain Calender
de genetique moleculaire et medicale, hopital Edouard-Herriot, batiment B7, 5, place d'Arsonval, 69437 Lyon 03, France


This paper should be referenced as such :
Calender, A
Deregulation of genetic pathways in neuroendocrine tumors
Atlas Genet Cytogenet Oncol Haematol. 2002;6(2):147-157.
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