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Deletion map of chromosome 22q in PETs. Homozygous deletion (shaded star); retention of heterozygosity (open squares); LOH (shaded squares); tumors with distant metastases (solid circles). NI, not informative; cen, centomere; tel, telomere. LOH rates are given in percentage of informative markers. The boxed area indicates the markers D22S280 and D22S283 on 22q12.3 where LOH is significantly correlated with the presence of distant metastases ð r 1⁄4 0 : 78; P , 0 : 0001 Þ :
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A variety of human tumors frequently show allelic deletions of chromosome 22q, suggesting that inactivation of one or more tumor suppressor genes in this region is important for their tumorigenesis.
In this study, 23 patients with pancreatic endocrine tumors (PETs), including gastrinomas, VIPomas and non-functioning islet cell carcinomas, were anal...
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... included twelve NNPCs, eight gastrinomas, two VIPomas and one renin-producing PET. Nineteen cases were sporadic and four patients had MEN1 ( Table 1). There were 12 males and 11 females with a mean age of 49 (range 28– 64) years at the time of surgery. The tumor size ranged from 5 mm to 350 mm in diameter (Table 1). All patients were explored, staged and underwent resection of the tumor and/or detectable metastases. At the time of surgery, six patients had localized disease, defined by the absence of any extra-pancreatic spread of the tumor. Nine patients had tumors with lymph node metastases. Three patients presented with synchronous liver metastases and one patient with a synchronous single lung metastasis. During mean follow-up of 81 (range 2 – 192) months seven patients developed liver metastases. At the conclusion of the study, eleven patients had no evidence of disease, eight patients were alive with disease and four patients were deceased due to diffuse liver metastases. The 19 markers used in this study are localized on chromosomal bands 22q11.22 to 22q13.32 and are distributed over a genomic region of about 25 Mb according to the published sequence data of chromosome 22q (10). LOH was identified in 22 of 23 (96%) PETs (Fig. 1). All 11 tumors with distant metastases revealed LOH in more than 60% of the markers (Fig. 1). Highest LOH rates were detected on 22q12.1 at markers D22S1167 and D22S1144 with 85% (17/20) and 76% (16/21) of informative tumors respectively (Fig. 2). In our material, the deletions were large in all but three cases, contributing to different markers on chromosomal bands 22q11.23 and 22q12.1 (Fig. 2). Therefore a smallest common region of overlap for LOH is hard to define. Notably, NNPC 166/98 showed a homozygous deletion on chromosomal band 22q12.3 corresponding to marker D22S280 that revealed an LOH rate of 59% (Figs. 1 and 3). After exclusion of a primer site mutation, a fine deletion mapping with seven STS markers span- ning approximately 300 kb around D22S280 was performed in all tumors at this locus. None of the other tumors revealed any homozygous deletion, whereas the homozygous deletion of tumor 166/98 spanned about 70 kb centered between markers D22S280 and STS marker G49339 (Fig. 3). We further analyzed whether chromosome 22q allelic loss correlates with clinical features of PETs. Remarkably, there was a strong positive correlation between the presence or development of distant metastases (liver, lung) and the rate of LOH ð r 1⁄4 0 : 78; 95% CI: 0.54 –0.91; P , 0 : 0001 Þ ; whereas no association between 22q loss and patient sex, age, tumor type or tumor size was identified. It was also of note that ten of eleven informative tumors with distant metastases showed LOH on chromosome band 22q12.3 compared with only three of twelve tumors without distant metastases ( P 1⁄4 0 : 0057; Table 1). After a mean follow-up of 81 months, four of thirteen patients with tumors exhibiting LOH at 22q12.3 died due to diffuse liver metastases compared with none of the patients without LOH at this locus. Survival analysis revealed strong positive correlation (log rank test P 1⁄4 0 : 032; df 1⁄4 1) between the presence of distant metastases and premature death, whereas a correlation between the presence of LOH at 22q12.3 and premature death was not quite achieved (log rank test P 1⁄4 0 : 073; df 1⁄4 1). LOH studies are a powerful tool to assess the status of particular gene loci in the development and progression of human neoplasms (11). The goal of this study was to evaluate whether chromosome 22q contains a tumor suppressor gene region associated with the development or progression of PETs. Utilizing a large number of microsatellite markers we could show, for the first time, that 22 of 23 (96%) reveal LOH on chromosome 22q with marker D22S1167 showing an LOH rate of 85% (17 of 20 informative tumors) at locus 22q12.1. This is in contrast to three previous reports that observed LOH at the long arm of chromosome 22 in only 0 –38% of PETs (12– 15). There are several possible explanations for this discrepancy of overall LOH rates. First, three of the studies (12 –14) used at most three markers that were in the main different from ours, whereas we used 12 markers enhancing the chance for detecting LOH. The study of Rigaud et al. (15) analysed seven markers on 22q in 16 non-functioning PETs, including markers D22S280, D22S283 and D22S423, and found LOH rates of 35% 42% and 35% respectively. These LOH rates are statistically not different from the LOH rates of 59%, 48% and 36% detected in the present study, given the small number of PETs analyzed and the relatively high number of non-informative cases in the study of Rigaud et al. (15). Second, the differences may relate to different tumor populations and to different amounts of con- taminating normal DNA in the tumor samples. Third, intermediate levels of allele retention could theoretic- ally also be due to a variable degree of intratumoral gene amplification of one chromosomal copy. Fourth, intratumoral genetic heterogeneity is a known feature of PETs (14, 16), that can result in complete loss of chromosomal material or varying levels of allelic retention. The present examination of a large number of microsatellite markers encompasses more than 25 Mb and about 82% of the coding regions of chromosome 22q. PETs with distant metastases revealed loss of larger portions of 22q, whereas PETs without distant metastases often showed smaller regional deletions. In previous comparative genomic hybridization (CGH) and karyotyping studies of PETs, only very few genomic losses on chromosome 22q, comprising either the ...
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... included twelve NNPCs, eight gastrinomas, two VIPomas and one renin-producing PET. Nineteen cases were sporadic and four patients had MEN1 ( Table 1). There were 12 males and 11 females with a mean age of 49 (range 28– 64) years at the time of surgery. The tumor size ranged from 5 mm to 350 mm in diameter (Table 1). All patients were explored, staged and underwent resection of the tumor and/or detectable metastases. At the time of surgery, six patients had localized disease, defined by the absence of any extra-pancreatic spread of the tumor. Nine patients had tumors with lymph node metastases. Three patients presented with synchronous liver metastases and one patient with a synchronous single lung metastasis. During mean follow-up of 81 (range 2 – 192) months seven patients developed liver metastases. At the conclusion of the study, eleven patients had no evidence of disease, eight patients were alive with disease and four patients were deceased due to diffuse liver metastases. The 19 markers used in this study are localized on chromosomal bands 22q11.22 to 22q13.32 and are distributed over a genomic region of about 25 Mb according to the published sequence data of chromosome 22q (10). LOH was identified in 22 of 23 (96%) PETs (Fig. 1). All 11 tumors with distant metastases revealed LOH in more than 60% of the markers (Fig. 1). Highest LOH rates were detected on 22q12.1 at markers D22S1167 and D22S1144 with 85% (17/20) and 76% (16/21) of informative tumors respectively (Fig. 2). In our material, the deletions were large in all but three cases, contributing to different markers on chromosomal bands 22q11.23 and 22q12.1 (Fig. 2). Therefore a smallest common region of overlap for LOH is hard to define. Notably, NNPC 166/98 showed a homozygous deletion on chromosomal band 22q12.3 corresponding to marker D22S280 that revealed an LOH rate of 59% (Figs. 1 and 3). After exclusion of a primer site mutation, a fine deletion mapping with seven STS markers span- ning approximately 300 kb around D22S280 was performed in all tumors at this locus. None of the other tumors revealed any homozygous deletion, whereas the homozygous deletion of tumor 166/98 spanned about 70 kb centered between markers D22S280 and STS marker G49339 (Fig. 3). We further analyzed whether chromosome 22q allelic loss correlates with clinical features of PETs. Remarkably, there was a strong positive correlation between the presence or development of distant metastases (liver, lung) and the rate of LOH ð r 1⁄4 0 : 78; 95% CI: 0.54 –0.91; P , 0 : 0001 Þ ; whereas no association between 22q loss and patient sex, age, tumor type or tumor size was identified. It was also of note that ten of eleven informative tumors with distant metastases showed LOH on chromosome band 22q12.3 compared with only three of twelve tumors without distant metastases ( P 1⁄4 0 : 0057; Table 1). After a mean follow-up of 81 months, four of thirteen patients with tumors exhibiting LOH at 22q12.3 died due to diffuse liver metastases compared with none of the patients without LOH at this locus. Survival analysis revealed strong positive correlation (log rank test P 1⁄4 0 : 032; df 1⁄4 1) between the presence of distant metastases and premature death, whereas a correlation between the presence of LOH at 22q12.3 and premature death was not quite achieved (log rank test P 1⁄4 0 : 073; df 1⁄4 1). LOH studies are a powerful tool to assess the status of particular gene loci in the development and progression of human neoplasms (11). The goal of this study was to evaluate whether chromosome 22q contains a tumor suppressor gene region associated with the development or progression of PETs. Utilizing a large number of microsatellite markers we could show, for the first time, that 22 of 23 (96%) reveal LOH on chromosome 22q with marker D22S1167 showing an LOH rate of 85% (17 of 20 informative tumors) at locus 22q12.1. This is in contrast to three previous reports that observed LOH at the long arm of chromosome 22 in only 0 –38% of PETs (12– 15). There are several possible explanations for this discrepancy of overall LOH rates. First, three of the studies (12 –14) used at most three markers that were in the main different from ours, whereas we used 12 markers enhancing the chance for detecting LOH. The study of Rigaud et al. (15) analysed seven markers on 22q in 16 non-functioning PETs, including markers D22S280, D22S283 and D22S423, and found LOH rates of 35% 42% and 35% respectively. These LOH rates are statistically not different from the LOH rates of 59%, 48% and 36% detected in the present study, given the small number of PETs analyzed and the relatively high number of non-informative cases in the study of Rigaud et al. (15). Second, the differences may relate to different tumor populations and to different amounts of con- taminating normal DNA in the tumor samples. Third, intermediate levels of allele retention could theoretic- ally also be due to a variable degree of intratumoral gene amplification of one chromosomal copy. Fourth, intratumoral genetic heterogeneity is a known feature of PETs (14, 16), that can result in complete loss of chromosomal material or varying levels of allelic retention. The present examination of a large number of microsatellite markers encompasses more than 25 Mb and about 82% of the coding regions of chromosome 22q. PETs with distant metastases revealed loss of larger portions of 22q, whereas PETs without distant metastases often showed smaller regional deletions. In previous comparative genomic hybridization (CGH) and karyotyping studies of PETs, only very few genomic losses on chromosome 22q, comprising either the ...
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... eight gastrinomas, two VIPomas and one renin-producing PET, were obtained from the tumor bank of the Department of Surgery, Philipps-University of Marburg. The diagnosis of Zollinger– Ellison syndrome was established by clinical symptoms, an ele- vated fasting serum gastrin level ( . 125 pg/ml) in the presence of acid in the stomach, a positive secretin stimulation test defined as increase to a serum gastrin concentration of . 200 pg/ml, and positive immuno- histochemistry for gastrin in the tumor. The diagnosis of VIPoma was confirmed by secretory diarrhea ( . 6 liters/day) and a fasting vasoactive intestinal polypeptide VIP concentration . 130pg/ml. Characteristics of the renin-producing PET have been described pre- viously (9). Tumors were considered as non-functioning if clinically no symptoms of hormonal excess were present and plasma hormone levels were within normal limits. Malignancy was determined based on the strict criteria of infiltrating growth, lymph node or distant metastases. Twenty-one tumors were malignant and two gastrinomas appeared to be benign ( Table 1). Clinical follow-up was obtained through the patient’s personal physician or at outpatient attend- ance. Survival was calculated from the time of surgical resection to either death or most recent contact. Informed consent was obtained from all patients. All investigations and all patients’ material in this study were assessed under a research protocol approved by the Philipps-University of Marburg Ethic Committee. The tumor samples used for DNA isolation had a neo- plastic cellularity between 85% and 100% after cryo- stat microdissection, whereas constitutional normal DNA was derived from blood lymphocytes. Genomic DNA from fresh-frozen tissue and whole blood samples was isolated using the QIAamp DNA kit (Qiagen, Hilden, Germany) according to the manufacturer’s protocol. Eleven highly polymorphic microsatellite markers D22S345, D22S1174, D22S351, D22S1167, D22S1144, D22S929, D22S280, D22S283, D22S423, D22S1140, D22S1169, and one expressed sequence tag (EST) marker A006E25 have been chosen for deletion mapping. Their location as shown in Fig. 1 and genomic sequences were confirmed by the published National Center for Biotechnology Infor- mation or Sanger Centre chromosome 22q sequences. PCR amplification was performed with fluorescence- labeled oligonucleotides on a MWG Primus 25 PCR cycler (MWG Biotech, Ebersberg, Germany) with a standard protocol. PCR product analysis was performed on a 310 Genetic Analyzer (ABI Applied Biosystems, Foster City, CA, USA) as described by the manufacturer. LOH was defined as a reduction in intensity of 50% ...
Citations
... The analysis of the FaPaCa data led to the identification of a novel candidate region for mutation analysis in FPC families on chromosome 22q13.33. The long arm of chromosome 22 has long been suspected to harbor genetic loci involved in the etiology of PDAC [111] and endocrine pancreatic tumors [112] using loss of heterozygosity mapping; however, the precise genetic loci involved in the etiology of pancreatic cancer on 22q are still unknown. Our newly discovered region encompasses the locus of the proto-oncogene PIM3, a serine/threonine-protein kinase showing enhanced expression in human pancreatic cancer cells [113], and the cytokine receptor IL17REL, which was found to be associated with inflammatory bowel disease [114] being a potential risk factor for PDAC [115]. ...
Introduction: Joint linkage and association (JLA) analysis combines two disease gene mapping strategies: linkage information contained in families and association information contained in populations. Such a JLA analysis can increase mapping power, especially when the evidence for both linkage and association is low to moderate. Similarly, an association analysis based on haplotypes instead of single markers can increase mapping power when the association pattern is complex. Methods: In this paper, we present an extension to the GENEHUNTER-MODSCORE software package that enables a JLA analysis based on haplotypes and uses information from arbitrary pedigree types and unrelated individuals. Our new JLA method is an extension of the MOD score approach for linkage analysis, which allows the estimation of trait-model and linkage disequilibrium (LD) parameters, i.e., penetrance, disease-allele frequency, and haplotype frequencies. LD is modelled between alleles at a single diallelic disease locus and up to three diallelic test markers. Linkage information is contributed by additional multi-allelic flanking markers. We investigated the statistical properties of our JLA implementation using extensive simulations, and we compared our approach to another commonly used single-marker JLA test. To demonstrate the applicability of our new method in practice, we analyzed pedigree data from the German National Case Collection for Familial Pancreatic Cancer (FaPaCa). Results: Based on the simulated data, we demonstrated the validity of our JLA MOD score analysis implementation and identified scenarios in which haplotype-based tests outperformed the single-marker test. The estimated trait-model and LD parameters were in good accordance with the simulated values. Our method outperformed another commonly used JLA single-marker test when the LD pattern was complex. The exploratory analysis of the FaPaCa families led to the identification of a promising genetic region on chromosome 22q13.33, which can serve as a starting point for future mutation analysis and molecular research in pancreatic cancer. Conclusion: Our newly proposed JLA MOD score method proves to be a valuable gene mapping and characterization tool, especially when either linkage or association information alone provide insufficient power to identify the disease-causing genetic variants.
... 79 Loss of heterozygosity of TIMP-3 has been involved in several cancer types. [80][81][82] Frequency of TIMP-3 loss by LOH and/or promoter hypermethylation is higher in HPV-16/18 infected NSCLC than HPV-16/18 negative NSCLC. 63 Loss of TIMP-3 potentiates malignant behaviors and poor survival of HPV-infected NSCLC by elevating IL-6 production via the tumor necrosis factor a/ nuclear factor κB axis. ...
Lung cancer is the most common cause of cancer death worldwide. Tobacco smoking is the most predominant etiology for lung cancer. However, only a small percentage of heavy smokers develop lung cancer, which suggests that other cofactors are required for lung carcinogenesis. Viruses have been central to modern cancer research and provide profound insights into cancer causes. Nevertheless, the role of virus in lung cancer is still unclear. In this article, we reviewed the possible oncogenic viruses associated with lung cancer.
... Furthermore, in insulinomas, metastatic tumours tend to display far greater extents of chromosomal aberrations than non-metastatic tumours, which may have relevance for clinical outcomes (Jonkers et al. 2005). Specific chromosomal losses in metastatic pancreatic NET may include 6q, 3p, 11pq and 22q or gains of 17q, 4p and 41 (Wild et al. 2002, Floridia et al. 2005, Pea et al. 2016. ...
Neuroendocrine neoplasms (NEN) are a class of tumours heterogeneous in terms of their anatomical sites of origin and clinical behaviour. Outdated perspectives of indolence have been superseded by appreciation for their myriad clinical challenges, such as the high rates of regional and distant metastases at initial diagnosis, lack of clarity on optimal treatment strategies/sequencing, and incompletely elucidated genetic/other pathophysiological drivers. The first randomised controlled trials in this arena were published approximately a decade ago – since then, increased understanding of the genetic drivers and signalling pathway perturbations in these tumours have suggested promise for precision therapy influenced by an individual tumour’s molecular sub-type, but this is yet to be realised for manifold reasons. In this article, the authors review the genetic landscapes as currently understood for selected forms of NEN and discuss the current and developing evidence to support the use of genetic information to influence therapy. They provide a critical assessment of the potential limitations of using such approaches, and also posit avenues for future developments in this arena.
... TIMP-3 gene function may also be reduced through loss of heterozygosity on chromosome 22q. It has been hypothesised that chromosome region 22q contains a number of tumour suppressor genes, as loss of heterozygosity in this region is common in a number of tumour types [45][46][47][48]. ...
TIMP-3 is one of four tissue inhibitors of matrix metalloproteinases, the endogenous inhibitors of the matrix metalloproteinase enzymes. These enzymes have an important role in metastasis, in the invasion of cancer cells through the basement membrane and extracellular matrix. TIMP-1, -2 and -4 both promote and inhibit tumour development, in a context-dependent manner, however TIMP-3 is consistently anti-tumourigenic. TIMP-3 is also the only insoluble member of the family, being either bound to the extracellular matrix or the low density lipoprotein-related protein-1, through which it can be endocytosed. Levels of TIMP-3 have also been shown to be regulated by micro RNAs and promoter hypermethylation, resulting in frequent silencing in many tumour types, to the extent that its expression has been suggested as a prognostic marker in some tumours, being associated with lower levels of metastasis, or better response to treatment. TIMP-3 has been shown to have anti-metastatic effects, both through inhibition of matrix metalloproteinases and ADAM family members and downregulation of angiogenesis. This occurs via interactions with receptors including VEGF, via modulation of signaling pathways and due to protease inhibition. TIMP-3 has also been shown to reduce tumour growth rate, most often by inducing apoptosis by stabilisation of death receptors. A number of successful mechanisms of delivery of TIMP-3 to tumour or inflammatory sites have been investigated in vitro or in animal studies. It may therefore be worthwhile further exploring the use of TIMP-3 as a potential anti-metastatic or anti-tumorigenic therapy for many tumour types.
... where hSNF5/INI1 gene is located but no alteration was identified by single strand conformational polymorphism analysis, direct DNA sequencing, or RNA expression analysis [57]. The same group (Wild 2002), described LOH on chromosome 22q in 22 of 23 PETs (including Non-Functioning tumors, gastrinomas and Vipomas) showing a LOH rate of 85% at locus 22q12.1, with LOH strongly correlated with the presence or the development of distant metastases [58]. Moreover, LOH on 22q12.3 was significantly associated with distant metastases, an area where two putative candidate gene are located, that is, synapsin3 (SYN3) and tissue inhibitor of metalloproteinase-3 (TIMP-3). ...
... where hSNF5/INI1 gene is located but no alteration was identified by single strand conformational polymorphism analysis, direct DNA sequencing, or RNA expression analysis [57]. The same group (Wild 2002), described LOH on chromosome 22q in 22 of 23 PETs (including Non-Functioning tumors, gastrinomas and Vipomas) showing a LOH rate of 85% at locus 22q12.1, with LOH strongly correlated with the presence or the development of distant metastases [58]. Moreover, LOH on 22q12.3 was significantly associated with distant metastases, an area where two putative candidate gene are located, that is, synapsin3 (SYN3) and tissue inhibitor of metalloproteinase-3 (TIMP-3). ...
The molecular biology of pancreatic neuroendocrine tumors (pNETs) carcinogenesis is poorly understood and is generally different from that of exocrine pancreatic neoplasms. pNETs represent a rare group of neoplasms with heterogeneous clinicopathological features. They are generally sporadic but can also arise within very rare hereditary syndromes, such as multiple endocrine neoplasia type I (MEN-I), von Hippel-Lindau disease (VHL), neurofibromatosis type 1 (NF1), and tuberous sclerosis complex (TSC). In these syndromes although a specific genotype/phenotype association with pNETs has been described, exact mechanisms leading to tumors development are still debated. Some clinical and biological features of pNETs associated with hereditary syndromes are similar in sporadic cases. The presence of germline mutations has been indeed recently proved also in a high proportion of sporadic pNETs (17%) by whole genoming sequencing. These mutations include (beyond the well-known MEN1 and VHL) also other genes (such as BRCA2, or other of the mTOR pathway). Overall, main genomic changes involve gain of 17q, 7q, 20q, 9p, 7p, 9q and loss of 11q, 6q, 11p, 3p, 1p, 10q, 1q that identify the region of putative candidate oncogenes or tumor suppressor genes (TSGs) respectively. For some of them a possible relevant prognostic role has been described. "Classical" oncogenes involved in exocrine neoplasms (k-Ras, c-Jun, c-Fos) are of limited relevance in pNETs; on the contrary, overexpression of Src-like kinases and cyclin DI oncogene (CCNDI) has been described. As for TSGs, p53, DPC4/Smad, and Rb are not implicated in pNETs tumorigenesis, while for p16INK4a, TIMP-3, RASSF1A, and hMLH1 more data are available, with data suggesting a role for methylation as silencing mechanism. Different molecular pathways and the role of tyrosine kinase receptors have also been investigated in pNETs (EGF, c-KIT) with interesting findings especially for VEGF and m-TOR, which encourage clinical development. Microarray analysis of expression profiles has recently been employed to investigate pNETs, with a number of different strategies, even if these studies suffer from a number of limitations, mainly related with the poor repeatability and the poor concordance between different studies. However, apart from methodological limits, molecular biology studies are needed to better know this group of neoplasms, aiming at identifying novel markers and targets for therapy also highlighting relations with clinical outcome. Besides biomarkers recent studies are currently focusing on the role of the immune system in tumor pathogenesis of pNETs, paving the way to a new therapeutic approach also in these rare tumors: the immunotherapy. © Springer Science+Business Media, LLC, part of Springer Nature 2018.
... where hSNF5/INI1 gene is located but no alteration was identified by single strand conformational polymorphism analysis, direct DNA sequencing, or RNA expression analysis [57]. The same group (Wild 2002), described LOH on chromosome 22q in 22 of 23 PETs (including Non-Functioning tumors, gastrinomas and Vipomas) showing a LOH rate of 85% at locus 22q12.1, with LOH strongly correlated with the presence or the development of distant metastases [58]. Moreover, LOH on 22q12.3 was significantly associated with distant metastases, an area where two putative candidate gene are located, that is, synapsin3 (SYN3) and tissue inhibitor of metalloproteinase-3 (TIMP-3). ...
... where hSNF5/INI1 gene is located but no alteration was identified by single strand conformational polymorphism analysis, direct DNA sequencing, or RNA expression analysis [57]. The same group (Wild 2002), described LOH on chromosome 22q in 22 of 23 PETs (including Non-Functioning tumors, gastrinomas and Vipomas) showing a LOH rate of 85% at locus 22q12.1, with LOH strongly correlated with the presence or the development of distant metastases [58]. Moreover, LOH on 22q12.3 was significantly associated with distant metastases, an area where two putative candidate gene are located, that is, synapsin3 (SYN3) and tissue inhibitor of metalloproteinase-3 (TIMP-3). ...
The molecular biology of pancreatic neuroendocrine tumors (pNETs) carcinogenesis is poorly understood and is generally different from that of exocrine pancreatic neoplasms. pNETs represent a rare group of neoplasms with heterogeneous clinicopathological features. They are generally sporadic but can also arise within very rare hereditary syndromes, such as multiple endocrine neoplasia type I (MEN-I), von Hippel-Lindau disease (VHL), neurofibromatosis type 1 (NF1), and tuberous sclerosis complex (TSC). In these syndromes although a specific genotype/phenotype association with pNETs has been described, exact mechanisms leading to tumors development are still debated. Some clinical and biological features of pNETs associated with hereditary syndromes are similar in sporadic cases. The presence of germline mutations has been indeed recently proved also in a high proportion of sporadic pNETs (17%) by whole genoming sequencing. These mutations include (beyond the well-known MEN1 and VHL) also other genes (such as BRCA2, or other of the mTOR pathway). Overall, main genomic changes involve gain of 17q, 7q, 20q, 9p, 7p, 9q and loss of 11q, 6q, 11p, 3p, 1p, 10q, 1q that identify the region of putative candidate oncogenes or tumor suppressor genes (TSGs) respectively. For some of them a possible relevant prognostic role has been described. “Classical” oncogenes involved in exocrine neoplasms (k-Ras, c-Jun, c-Fos) are of limited relevance in pNETs; on the contrary, overexpression of Src-like kinases and cyclin DI oncogene (CCNDI) has been described. As for TSGs, p53, DPC4/Smad, and Rb are not implicated in pNETs tumorigenesis, while for p16INK4a, TIMP-3, RASSF1A, and hMLH1 more data are available, with data suggesting a role for methylation as silencing mechanism. Different molecular pathways and the role of tyrosine kinase receptors have also been investigated in pNETs (EGF, c-KIT) with interesting findings especially for VEGF and m-TOR, which encourage clinical development. Microarray analysis of expression profiles has recently been employed to investigate pNETs, with a number of different strategies, even if these studies suffer from a number of limitations, mainly related with the poor repeatability and the poor concordance between different studies. However, apart from methodological limits, molecular biology studies are needed to better know this group of neoplasms, aiming at identifying novel markers and targets for therapy also highlighting relations with clinical outcome. Besides biomarkers recent studies are currently focusing on the role of the immune system in tumor pathogenesis of pNETs, paving the way to a new therapeutic approach also in these rare tumors: the immunotherapy.
... Those changes associated with more advanced disease states may represent late events in tumor progression, perhaps involved in driving more aggressive biologic behavior, such as metastasis. Examples of these changes include losses of 1p and 1q (Ebrahimi et al., 1999;Chen et al., 2003;Yang et al., 2005;Guo et al., 2002b), 3p (Hessman et al., 1999;Speel et al., 1999;Chung et al., 1997;Barghorn et al., 2001a), 3q Guo et al., 2002b;Chung et al., 1998), 6q22 (exclusively found in malignant PanNET) Jonkers et al., 2005;Barghorn et al., 2001b), 11q13 (Hessman et al., 1999), 14q , 17p13 (Beghelli et al., 1998), 22q (Chung et al., 1998;Wild et al., 2002), X and Xq Missiaglia et al., 2002;Pizzi et al., 2002;Frenkel et al., 2002;Azzoni et al., 2006), and gains of 4 , 7 and 7q Jonkers et al., 2005), 12q (Jonkers et al., 2005), 14q (Jonkers et al., 2005), and 17p and 17q gains (Jonkers et al., 2005). ...
... As shown for other tumour types, malignant progression of PETs is driven by progressive accumulation of multiple genetic changes (Speel et al. 1999, Jonkers et al. 2005, and accumulating evidence suggests that PETs from patients with advanced disease harbour more genetic aberrations than tumours from patients with localised disease. Several LOH studies using microsatellite markers demonstrated that LOH at long arm of chromosome 1 (Ebrahimi et al. 1999, Guo et al. 2002a, Chen et al. 2003, Yang et al. 2005, at short arm of chromosome 3 (Nikiforova et al. 1999, Barghorn et al. 2001, Guo et al. 2002b, Amato et al. 2011 and at long arm of chromosome 22 (Wild et al. 2001(Wild et al. , 2002) is a common event among different PET subtypes and is significantly associated with the presence of hepatic metastases regardless of tumour type (Table 2). ...
Pancreatic neuroendocrine tumours (PETs) are the second most frequent pancreatic neoplasms. Their poor chemosensitivity, high rate of metastatic disease and relatively long survival make PETs an ideal field to be explored for novel therapies based on specific molecular changes. PETs are generally sporadic but can also arise within hereditary syndromes, such as multiple endocrine neoplasia type 1, von Hippel-Lindau, neurofibromatosis type 1 and tuberous sclerosis complex, which represent a model for sporadic cases too. Among allelic imbalances, main genomic changes involve gain of 17q, 7q and 20q and loss of 11q, 6q and 11p, which identify regions of putative candidate oncogenes or tumour suppressor genes (TSGs), respectively, sometime with potential prognostic significance. Overexpression of Src-like kinases and cyclin D1 (CCND1) oncogene has been described. As for TSGs, P53 (TP53), DPC4/SMAD4 and RB (RB1) are not implicated in PET tumorigenesis, while for p16INK4a (CDKN2A), TIMP3, RASSF1A and hMLH1, more data are available, suggesting a role for methylation as a silencing mechanism. In the last decade, gene expression profile studies, analysis of microRNAs and, more recently, large-scale mutational analysis have highlighted commonly altered molecular pathways in the pathology of PETs. The roles of the mammalian target of rapamycin pathway, and its connection with Src kinases, and the activity of a number of tyrosine kinase receptors seem to be pivotal, as confirmed by the results of recent clinical trials with targeted agents. Mutations of DAXX and ATRX are common and related to altered telomeres but not to prognosis.
... Several studies have suggested that EP300 may func-tion as a tumor suppressor. This gene is located on chromosome 22q; a region known for its frequent loss of heterozygosity in different cancers, including pancreatic cancer [106][107][108][109] . Mees et al [80] have classified 16 human PDAC cell lines into three hierarchical groups according to their metastatic potential, and have profiled their mRNA and miRNA expression. ...
Ductal adenocarcinoma of the pancreas is a lethal cancer for which the only chance of long-term survival belongs to the patient with localized disease in whom a potentially curative resection can be done. Therefore, biomarkers for early detection and new therapeutic strategies are urgently needed. miRNAs are a recently discovered class of small endogenous non-coding RNAs of about 22 nucleotides that have gained attention for their role in downregulation of mRNA expression at the post-transcriptional level. miRNAs regulate proteins involved in critical cellular processes such as differentiation, proliferation, and apoptosis. Evidence suggests that deregulated miRNA expression is involved in carcinogenesis at many sites, including the pancreas. Aberrant expression of miRNAs may upregulate the expression of oncogenes or downregulate the expression of tumor suppressor genes, as well as play a role in other mechanisms of carcinogenesis. The purpose of this review is to summarize our knowledge of deregulated miRNA expression in pancreatic cancer and discuss the implication for potential translation of this knowledge into clinical practice.
... LOH at CBX7 locus. In some types of cancers, LOH of tumor suppressor genes at region 22q is believed to be a key step in carcinogenesis (27,28). We therefore used several SNP markers to evaluate LOH at the CBX7 locus on chromosome 22q13.1 in 77 cases of thyroid carcinomas of different histotypes. ...
Using gene expression profiling, we found that the CBX7 gene was drastically down-regulated in six thyroid carcinoma cell lines versus control cells. The aims of this study were to determine whether CBX7 is related to the thyroid cancer phenotype and to try to identify new tools for the diagnosis and prognosis of thyroid cancer. We thus evaluated CBX7 expression in various snap-frozen and paraffin-embedded thyroid carcinoma tissues of different degrees of malignancy by quantitative reverse transcription-PCR and immunohistochemistry, respectively. CBX7 expression progressively decreased with malignancy grade and neoplasia stage. Indeed, it decreased in an increasing percentage of cases going from benign adenomas to papillary (PTC), follicular, and anaplastic (ATC) thyroid carcinomas. This finding coincides with results obtained in rat and mouse models of thyroid carcinogenesis. CBX7 loss of heterozygosity occurred in 36.8% of PTC and in 68.7% of ATC. Restoration of CBX7 expression in thyroid cancer cells reduced growth rate, with a retention in the G(1) phase of the cell cycle, suggesting that CBX7 can contribute to the proliferation of the transformed thyroid cells. In conclusion, loss of CBX7 expression correlates with a highly malignant phenotype in thyroid cancer patients.
