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6.  AIMS OF THE INVESTIGATION

A genome-wide search for molecular alterations using fluorescent technique has been performed on eight sporadic midgut carcinoid tumors in order to find a commonly deleted chromosomal region. Deletions of genomic regions containing candidate tumor suppressor genes may play an important role in the initiation and progression of some neoplasms. However, there is a lack of knowledge about the sequence of events leading to tumorigenesis in midgut carcinoid tumors and whether the MEN-1 gene is involved in the tumor development. The molecular basis of the neoplastic transformation of neuroendocrine cells is still not well understood (DeLellis 1995), it is not known if a carcinoid tumor evolves from a precancerous lesion or if various molecular alterations found in a tumor occur in a specific order or at random. Growth factors such as TGF alpha, EGF and NGF might induce malignant progression of midgut carcinoids as this has been shown to hold true for endocrine cell lines (Bold, Ishizuka et al. 1995; Nilsson, Wangberg et al. 1995). Furthermore, chromosomal instability and apoptotic mediators might influence the neogenetic process. In order to gain insight into this process it is necessary to accumulate data on genetic alterations in midgut carcinoids.

In sharp contrast to the scarce findings of p53 mutations and the absence of K-ras mutations in midgut carcinoids are frequent findings of such alterations in half or more of examined adenocarcinomas of the gastrointestinal tract, both K-ras and p53 mutations as well as mismatch repair deficiency have been described (Bos, Fearon et al. 1987; Weckstrom, Hedrum et al. 1996; Arber, Neugut et al. 1997; Younes, Fulton et al. 1997; Ramnani, Wistuba et al. 1999). Thus, small bowel carcinomas, which originate from the same organ and occur with approximately the same frequency, seem to have a different genetic background.

The availability of a series of tumor samples in which deletions are molecularly detected on a genome-wide basis could help make progress on these questions.


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