Sex chromosome anomalies in pancreatic endocrine tumors

Missiaglia, Edoardo; Moore, Patrick S.; Williamson, Jon; Lemoine, Nicholas R.; Falconi, Massimo; Zamboni, Giuseppe; Scarpa, Aldo

doi:10.1002/ijc.10223

Cited by 52 publications

(37 citation statements)

References 34 publications

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“…Future studies will determine if these genes are involved in insulinoma oncogenesis. Deletions of other chromosomal regions that were reported to be associated with malignant behavior of EPTs, such as 1p, 3p, 3q, 11q, 17p, 22q and X (Chung et al 1997, Beghelli et al 1998, Ebrahimi et al 1999, Hessman et al 1999, Barghorn et al 2001a, b, Guo et al 2002, Missiaglia et al 2002, Wild et al 2002, were only occasionally observed in this CGH study on insulinomas. Losses of chromosome 3p and 3q were identified significantly more frequently in the malignant insulinomas, but only at low frequencies of 17 and 33% respectively.…”

Section: Discussionmentioning

confidence: 52%

“…The few malignant insulinomas that have been genetically analyzed by molecular allelotyping and CGH were mainly part of larger studies on EPTs, including different functioning and non-functioning subtypes (Chung et al 1998, Speel et al 1999, Stumpf et al 2000. Several markers for malignant or metastatic progression in EPTs have been indicated, in particular loss of chromosomes 1 (Ebrahimi et al 1999), 3p (Chung et al 1997, Hessman et al 1999, Barghorn et al 2001a, 3q (Chung et al 1998, Guo et al 2002), 6q22-24 (Barghorn et al 2001b, 11q13 (Hessman et al 1999), 17p (Beghelli et al 1998), 22q (Chung et al 1998, Wild et al 2002 and X (Missiaglia et al 2002). These do, however, require further validation in larger series of individual EPT subtypes, including insulinomas.…”

Section: Introductionmentioning

confidence: 99%

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Chromosomal instability predicts metastatic disease in patients with insulinomas

Jonkers

Claessen²,

Perren³

et al. 2005

Endocrine Related Cancer

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Endocrine pancreatic tumors (EPTs) comprise a highly heterogeneous group of tumors with different clinical behavior and genetic makeup. Insulinomas represent the predominant syndromic subtype of EPTs. The metastatic potential of insulinomas can frequently not be predicted using histopathological criteria, and also molecular markers indicating malignant progression are unreliable because of the small number of cases per subtype studied so far. For the identification of reliable indicators of metastatic disease, we investigated 62 sporadic insulinomas (44 benign and 18 tumors with metastases) by means of comparative genomic hybridization (CGH). In addition, the role of MEN1 (multiple endocrine neoplasia type 1) gene mutations was determined to assess specific chromosomal alterations associated with dysfunction of this endocrine tumor-related tumor suppressor gene. Only one case with a somatic MEN1 mutation was identified (1527del7bp), indicating that the MEN1 gene plays a minor pathogenic role in sporadic insulinomas. CGH analysis revealed that the total number of aberrations per tumor differs strongly between the benign and the malignant group (4.2 vs 14.1; P<0.0001). Furthermore, chromosome 9q gain was found to be the most frequent aberration in both benign and malignant insulinomas, whereas chromosome 6q losses and 12q, 14q and 17pq gains are strongly associated with metastatic disease. Our study shows that chromosomal instability, as defined by ‡5 gains together with ‡5 losses, or total number of gains and losses ‡8, rather than parameters such as tumor size and proliferation index, is the most powerful indicator for the development of metastatic disease in patients with sporadic insulinoma.

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Section: Discussionmentioning

confidence: 52%

Section: Introductionmentioning

confidence: 99%

Chromosomal instability predicts metastatic disease in patients with insulinomas

Jonkers

Claessen²,

Perren³

et al. 2005

Endocrine Related Cancer

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“…In another study, loss of chromosome X was described in 40% of cases of PETs from females, while loss of chromosome Y was present in 36% of cases of PETs from males. In the same study, sex chromosome alterations were associated with the presence of metastases, higher proliferation index and worse prognosis (Missiaglia et al 2002).…”

Section: Loss Of Heterozygositymentioning

confidence: 69%

Molecular pathology and genetics of pancreatic endocrine tumours

Capurso¹,

Festa²,

Valente³

et al. 2012

Journal of Molecular Endocrinology

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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.

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“…Indeed, the association between X chromosome allelic losses and malignancy has been clearly documented in endocrine tumors of the stomach 7 and pancreas. 6,28 Moreover, X chromosome LOH has recently been found to correlate with aggressive post operative tumor X chromosome in lung endocrine tumors T D'Adda et al growth in pancreatic gastrinomas. 29 In contrast, endocrine tumors of midgut and hindgut origin, even if malignant, did not present a significant occurrence of X chromosome losses.…”

Section: Discussionmentioning

confidence: 99%

Malignancy-associated X chromosome allelic losses in foregut endocrine neoplasms: further evidence from lung tumors

et al. 2005

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Association of X chromosome allelic losses with tumor malignancy has been identified in foregut but not in midgut endocrine neoplasms. The aim of this study was to investigate the association of deletions on X chromosome with malignancy in lung neuroendocrine tumors, another family of foregut neoplasms comprising four categories with increased malignancy: typical and atypical carcinoids, large cell neuroendocrine and small cell lung carcinomas. To evaluate loss of heterozygosity, DNA extracted from nine typical carcinoids, 17 atypical carcinoids, six large cell neuroendocrine carcinomas and five small cell lung carcinomas was PCRamplified for 18 microsatellite markers spanning the whole X chromosome. All tissue samples were formalinfixed and paraffin-embedded. X chromosome losses were absent in typical carcinoids, whereas they were found in nine out of 17 atypical carcinoids and in five out of six large cell neuroendocrine carcinomas (involving 28 and 70% of informative loci, respectively). On the contrary, deletions on X chromosome were an extremely rare event in small cell lung carcinomas. In atypical carcinoids, the presence of losses was associated with larger tumor size, higher pT status and advanced stage. No death occurred in atypical carcinoid patients without deletions on X chromosome, whereas all atypical carcinoid patients who had died from disease showed allelic losses. In conclusion, X chromosome allelic losses, absent in benign 'typical' carcinoids, progressively increased in frequency from intermediate-grade 'atypical' carcinoids to high-grade large cell neuroendocrine carcinomas. These results extend the association of deletions on X chromosome with malignancy, already demonstrated in other foregut endocrine neoplasms, to lung neuroendocrine tumors. The absence of X chromosome allelic losses in small cell lung carcinomas underlines a striking difference from large cell neuroendocrine carcinomas, possibly linked to different pathogenetic mechanisms of these two highly aggressive neuroendocrine lung tumors.

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Sex chromosome anomalies in pancreatic endocrine tumors

Cited by 52 publications

References 34 publications

Chromosomal instability predicts metastatic disease in patients with insulinomas

Chromosomal instability predicts metastatic disease in patients with insulinomas

Molecular pathology and genetics of pancreatic endocrine tumours

Malignancy-associated X chromosome allelic losses in foregut endocrine neoplasms: further evidence from lung tumors

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