Mutations of the DPC4/Smad4 gene in neuroendocrine pancreatic tumors

Bartsch, Detlef K.; Hahn, Stephan A.; Danichevski, Kirill D; Ramaswamy, Annette; Daniel, Bastian; Galehdari, Hamid; Barth, Peter; Schmiegel, Wolff; Simon, Babette; Rothmund, M.

doi:10.1038/sj.onc.1202585

Cited by 115 publications

(61 citation statements)

References 15 publications

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“…Only exons 8 -11 were sequenced since the majority of previously described mutations have been found in this region. 15 The results revealed no mutations, and immunohistochemical staining showed expression of the Smad4/ DPC4 protein in the 7 analyzed tumors (data not shown). Tumor 5216 was not analyzed by immunohistochemical staining due to a shortage of tissue material.…”

Section: Resultsmentioning

confidence: 89%

Chromosome 18 deletions are common events in classical midgut carcinoid tumors

et al. 2001

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Classical midgut carcinoids are rare intestinal neuroendocrine tumors that often present with metastases at diagnosis. In contrast to foregut carcinoids, midgut carcinoids are not related to the multiple endocrine neoplasia type 1 syndrome, and the mechanisms involved in their tumorigenesis are unknown. Eight classical midgut carcinoids were analyzed by genome-wide screening for loss of heterozygosity. Deletions on chromosome 18 were found in 88% of the tumors. DNA sequencing and immunohistochemical staining for Smad4/ DPC4, which often is homozygously mutated in pancreatic and colon carcinomas, revealed no aberrations. In 1 tumor, a region telomeric to the Smad4/DPC4/DCC genes at 18q21 was deleted. Other chromosomes were affected in 3 lesions only. The high frequency of chromosome 18 deletions strongly indicates a genetic alteration of importance in classical midgut carcinoid tumorigenesis, apparently not involving the Smad4/DPC4 gene.

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Section: Resultsmentioning

confidence: 89%

Chromosome 18 deletions are common events in classical midgut carcinoid tumors

et al. 2001

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“…Chromosome 18 harbors several candidate tumor suppressor genes, including DCC, SMAD4, and SMAD2. Interestingly, 55% of nonfunctioning pancreatic endocrine carcinomas had point mutations or deletion of SMAD4 gene (Bartsch et al, 1999), but no SMAD4 mutations were identified in classical midgut WDNTs (Lö llgen et al, 2001) and goblet cell carcinoids of the vermiform appendix (Stancu et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Allelic alterations in well‐differentiated neuroendocrine tumors (carcinoid tumors) identified by genome‐wide single nucleotide polymorphism analysis and comparison with pancreatic endocrine tumors

Kim

Nagano

Choi

et al. 2007

Genes Chromosomes & Cancer

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Well-differentiated neuroendocrine tumors (WDNT, carcinoid tumors) are uncommon indolent neoplasms. The genetic alterations of these tumors are not well characterized. We used genome-wide high-density single nucleotide polymorphism (SNP) array analysis to detect copy number alterations in 29 WDNTs, including seven lung, seven nonileal gastrointestinal, and 15 ileal tumors, and compared with allelic imbalances in 15 pancreatic endocrine tumors (PETs). Most frequent allelic imbalances in WDNTs were losses of chromosome 18 in 10 tumors (34%), chromosome 21 or 21q in six (21%), chromosome 13 or 13q in five (17%) and chromosome 16 or 16q in four (14%) tumors, and amplification of chromosome 20 or 20p in seven (24%) tumors. We also found one tumor with loss of heterozygosity of chromosomes 10 and 15 without copy number loss. These allelic imbalances were associated with primary site of tumor: loss of chromosome 18 was present exclusively in ileal WDNTs (P 5 0.001), and loss of chromosome 21 or 21q was more frequent in nonileal gastrointestinal WDNTs (P 5 0.02). The tumors with loss of chromosome 21 were larger compared to tumors without loss (P 5 0.03). Chromosomal aberrations were less common in WDNTs from lung and gastrointestinal tract compared to PETs (P 5 0.001). Our study shows that genome-wide allelotyping using SNP array is a powerful new tool for the analysis of allelic imbalances in WDNTs, and some of these alterations are tumor site-dependent and are different than in PETs. V V C 2007 Wiley-Liss, Inc.

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“…The majority of SMAD4 gene mutations in human cancer occur at the MH2 domain (17). In pancreatic cancer, somatic mutational events occur with high frequency (2,18,19). In total, approximately 55% of pancreatic cancers show inactivation of the SMAD4 gene (17).…”

Section: -------------------------------------------------Size Of Primentioning

confidence: 99%

Alteration of SMAD4 does not participate in tumorigenesis of adenoid cystic carcinoma of the salivary gland

Daa¹

2008

Mol Med Rep

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Abstract. SMAD4, also known as DPC4 (deleted in pancreatic carcinoma 4) was initially identified as a tumor-suppressor gene. It is located on 18q21, a region frequently deleted in pancreatic carcinoma. Functionally inactivating mutation of the gene also occurs in many cases of pancreatic cancer. Functional loss of SMAD4 is frequently detected not only in pancreatic carcinoma but also in colorectal carcinoma. However, in other human cancers, SMAD4 aberrations are seen only occasionally. The purpose of this study was to elucidate the role of SMAD4 in adenoid cystic carcinoma of the salivary glands. We examined 34 cases of adenoid cystic carcinoma for loss of heterozygosity (LOH) of the SMAD4 locus and for the existence of mutations of the gene. LOH was detected in 2/14 informative cases. No mutations were detected in any of the 34 cases. In conclusion, the infrequent LOH of the SMAD4 gene locus and lack of SMAD4 mutations indicate that SMAD4 does not play a role in the tumorigenesis of adenoid cystic carcinoma of the salivary gland.

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Mutations of the DPC4/Smad4 gene in neuroendocrine pancreatic tumors

Cited by 115 publications

References 15 publications

Chromosome 18 deletions are common events in classical midgut carcinoid tumors

Chromosome 18 deletions are common events in classical midgut carcinoid tumors

Allelic alterations in well‐differentiated neuroendocrine tumors (carcinoid tumors) identified by genome‐wide single nucleotide polymorphism analysis and comparison with pancreatic endocrine tumors

Alteration of SMAD4 does not participate in tumorigenesis of adenoid cystic carcinoma of the salivary gland

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