5.1. MEN

In 1988, the MEN1 gene was first mapped to chromosome 11q13 (Larsson, Skogseid et al. 1988) and closely linked to the PYGM locus. Screening of chromosome 11q13 using highly polymorphic markers frequently showed somatic loss of heterozygosity (LOH) in MEN1 tumors (Larsson, Skogseid et al. 1988; Friedman, Sakaguchi et al. 1989; Thakker, Bouloux et al. 1989; Bystrom, Larsson et al. 1990; Skogseid, Rastad et al. 1995). These findings are strongly suggestive of a tumor suppressor function of the MEN1 gene. Following Knudson`s two-mutational hit theory of hereditary neoplasm etiology, MEN-1 tumorigenesis results from a germline mutation followed by a second somatic chromosomal hit (Knudson, Di Ferrante et al. 1971). After progressive restriction of the MEN1 candidate region the gene causing MEN1 was finally cloned in 1997 and the gene was located approximately 70 kb telomeric of PYGM (Chandrasekharappa, Guru et al. 1997; Lemmens, Van de Ven et al. 1997). The gene of 9 kb contains 10 exons. The first exon and part of exon 10 are untranslated and a 2.8 kb transcript has been found in all human tissues. The gene encodes for a 610 aminoacid protein, menin with no homology to previously known proteins (1. 1997; Chandrasekharappa, Guru et al. 1997). Menin is a nuclear protein which translocates from the nucleus to the cytoplasma during the cell cycle (Huang, Zhuang et al. 1999)and is known to bind JunD, a member of the transcription factor family AP1, and to repress transcriptional activity in transfection assays (Agarwal, Guru et al. 1999; Gobl, Berg et al. 1999).

Close to 250 different mutations of the MEN1 gene have been described since 1997 (1. 1997; Agarwal, Kester et al. 1997; Aoki, Tsukada et al. 1997; Chandrasekharappa, Guru et al. 1997; Mayr, Apenberg et al. 1997; Basset, Forbes et al. 1998; Olufemi, Green et al. 1998). They are spread over the whole gene and not accumulated on known functional domains.

LOH on chromosome 11q13 has even been found in sporadic endocrine tumors with a frequency [page 25↓]ranging from 30-70% in tumors of the parathyroids and the endocrine pancreas whereas pituitary tumors rarely exhibited losses. Only in a subset of these tumors (30-58%), however, the re-maining MEN1 gene was mutated (Hessman, Lindberg et al. 1998; Tanaka, Kimura et al. 1998; Wang, Ebrahimi et al. 1998; Heppner, Reincke et al. 1999). LOH on chromosome 11q13 without any MEN1 gene mutation has also been detected in a number of neoplasms, e.g. adrenocortical and follicular thyroid tumors. This leads to the assumption that there might exist another tumor suppressor gene at this locus involved in endocrine tumorigenesis (Heppner, Reincke et al. 1999; Kjellman, Roshani et al. 1999; Nord, Larsson et al. 1999).

5.2. EPT

Homozygous somatic mutations of the MEN1 gene have been found in about one third of non-familial EPT (Zhuang, Vortmeyer et al. 1997; Hessman, Lindberg et al. 1998; Wang, Ebrahimi et al. 1998). Nonfamilial tumors show 3p deletions as well as allelic loss on chromosomal arms 3q, 11p, 11q, 16q and 22q. No mutations have been found for the VHL gene on 3p26 (Chung, Brown et al. 1998). In contrast, a striking association between LOH at 11q13 and 3p and malignant phenotype was found for nonfamilial tumors in another tumor deletion study (Hessman, Lindberg et al. 1999).

Chromosome 18q21 is frequently deleted in a variety of human cancers including exocrine pancreas tumors. Chromosome 18q21 harbours the putative tumor suppressor genes DCC, Smad4/DPC4 and Smad2/MADR2/JV18-1 genes(Fearon, Cho et al. 1990; Eppert, Scherer et al. 1996; Schutte, Hruban et al. 1996; Kong, Choi et al. 1997; Toliat, Berger et al. 1997).

5.3. Midgut Carcinoid Tumors

So far, only a limited number of carcinoid tumors have been investigated (Jakobovitz, Nass et al. 1996; Toliat, Berger et al. 1997; Debelenko, Emmert-Buck et al. 1997a; Ghimenti, Lonobile et al. 1999; Gortz, Roth et al. 1999; Zhao, de Krijger et al. 2000; D´Adda, Pizzi et al. 2002; Kytola, Nord et al. 2002). Sporadic foregut carcinoids frequently display allelic losses at 11q13 and somatic MEN1 mutations have been revealed in about a third of the investigated tumors (Debelenko, Emmert-Buck et al. 1997a; Hessman, Lindberg et al. 1998; Zhao, de Krijger et al. 2000). In contrast to foregut carcinoids, midgut carcinoids are not overrepresented in the MEN1 syndrome and only infrequently display LOH at 11q13. When pooling the results from all previous studies, LOH on chromosome 11 has been detected in 16 of 83 analyzed midgut carcinoids (Jakobovitz, Nass et al. 1996; Debelenko, Emmert-Buck et al. 1997a; Ghimenti, Lonobile et al. 1999; Gortz, Roth et al. 1999; Zhao, de Krijger et al. 2000) (D´Adda, Pizzi et al. 2002; Kytola, Nord et al. 2002). One somatic missense MEN1 mutation in one of sixteen midgut carcinoid tumors has been described (Toliat, Berger et al. 1997; Gortz, Roth et al. 1999). Two constitutional putative missense mutations, H50R and G12S on the SDHD (TSG) (succinate-ubiquinone oxidoreductase subunit D) gene locus were found in two midgut carcinoids, both mutations were associated with LOH of the other allele (Kytola, Nord et al. 2002). Microsatellite instability was detected in one of six analyzed midgut carcinoid tumors (Ghimenti, Lonobile et al. 1999). Only one study, using comparative genomic hybridization could find LOH on chromosome 18 so far: LOH on chromosome 18p in eight (38%) and on 18q in seven (33%) out of 21 gastro-intestinal tumors whereas in none of the bronchial carcinoids (Zhao, de Krijger et al. 2000). In a recently published X-chromosome inactivation study, the same X-chromosome had been inactivated in multiple ileal tumors from the same patient. These results suggest that the multiple lesions result from intraintestinal spread (Guo, Li et al. 2000). Both TGF-α and EGF receptors are expressed in midgut carcinoids in vitro and in vivo (Nilsson, Wangberg et al. 1995). Mostly TGF-ß2 was found in 2/3 of midgut carcinoid cells and their stroma and was lacking expression in normal small intestine tissue. TGF-ß has also been found in stromal tissue only, leading to the suggestion that TGF-ß might stimulate matrix growth and angiogenesis in the stroma surrounding the neoplastic tissue whereas the tumor cells remain unaffected (Chaudhry, Oberg et al. 1994). PDGF seems to play a role in the growth of carcinoid tumor and stroma cells and is likely to add to the fibrosis often found in carcinoid tumors (Funa, Papanicolaou et al. 1990; Chaudhry, Papanicolaou et al. 1992). Carcinoid tumor growth may furthermore be stimulated by IGF-I and IGF-I receptors (Nilsson, Wangberg et al. 1993). p53 mutations appear to play a role in the pathogenesis of a small subset classical and goblet cell carcinoids of the appendix and classical midgut carcinoids whereas K-ras mutations are absent in midgut carcinoids.

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