Genetic Differences in Endocrine Pancreatic Tumor Subtypes Detected by Comparative Genomic Hybridization

Abstract

The molecular pathogenesis as well as histogenesis of endocrine pancreatic tumors (EPTs) is not well understood , and the clinical behavior of EPTs is difficult to predict using current morphological criteria. Thus, more accurate markers of risk and better understanding of tumor initiation and progression are needed to allow a precise classification of EPTs. We have studied 44 benign and malignant EPTs by comparative genomic hybridization to correlate the overall number of genetic alterations with clinical and histopathological parameters and to identify chromosomal regions which might harbor genes involved in EPT pathogenesis and progression. Aberrations were found in 36 EPTs , and chromosomal losses (mean, 5.3) were slightly more frequent than gains (mean, 4.6). The most frequent losses involved Y (45% of male EPTs) , 6q (39%) , 11q (36%) , 3p , 3q , 11p (each 30%) , 6p (27%) , and 10q and Xq (each 25%) , whereas most common gains included 7q (43%) , 17q (41%), 5q and 14q (each 32%) , 7p , 9q , 17p , 20q (each 27%), and 12q and Xp (each 25%). A correlation was found between the total number of genetic changes per tumor and both tumor size and disease stage. In particular , losses of 3p and 6 and gains of 14q and Xq were found to be associated with metastatic disease. Furthermore , characteristic patterns of genetic changes were found in the various EPT subtypes , eg , 6q loss in malignant insulinomas , indicating that these groups might evolve along genetically different pathways. The highlighted genetic aberrations , including the newly found involvement of 6q losses and sex chromosome alterations , should stimulate the further analysis of these chromosomal regions, which may lead to the discovery of novel genes important in the tumorigenesis and evolution of EPTs. (Am J Pathol 1999, 155:1787-1794)

Defining molecular classifications and targets in gastroenteropancreatic neuroendocrine tumors through DNA microarray analysis

“…In addition, genes on chromosomes 11 and 17 were overrepresented in PNETs. This is consistent with published comparative genomic hybridization (CGH) literature, which has shown that genomic gains are common on chromosome 17 (Terris et al 1998, Speel et al 1999, Stumpf et al 2000 and frequently associated with malignant behavior (Speel et al 2001).…”

Absence of somatic SDHD mutations in sporadic neuroendocrine tumors and detection of two germline variants in paraganglioma patients

“…The disease phenotype of familial PGL1 caused by SDHD mutations is inherited as an autosomal dominant trait with incomplete penetrance when transmitted through fathers whereas no disease phenotype occurs when transmitted maternally. This inheritance pattern is consistent with genomic imprinting of the maternal allele of the SDHD gene (van der Mey et al, 1989). However, allelic expression analysis in fetal brain and lymphomatoid cell lines revealed biallelic expression (Malik et al, 2000).…”

“…In addition, it participates in electron transport and interacts with quinones (Scheffler, 1998). Indirect evidence is in favor for a tumor suppressor function of SDHD in endocrine tumors: It is responsible for familial PGA type 1 (PGL1, OMIM 168000); it is mutated in 10% of apparently sporadic PCC (Gimm et al, 2000) and it seems to be selectively imprinted in some neuroendocrine tissues (van der Mey et al, 1989).…”

MEN1 in pancreatic endocrine tumors: analysis of gene and protein status in 169 sporadic neoplasms reveals alterations in the vast majority of cases

“…The most common anomaly also encountered in sporadic PETs is MEN1 gene inactivation due to mutation of one allele and loss of the second allele (Capelli et al 2009). Indeed, allelic losses at chromosome 11q13, which includes the locus of MEN1 gene (Larsson et al 1988), are found in 46% of sporadic PETs (Speel et al 1999, Rigaud et al 2001, while the reported frequency of MEN1 mutations is lower, thus suggesting that additional oncosuppressor genes lie on this chromosomal arm (Eubanks et al 1994, Chakrabarti et al 1998, Gortz et al 1999, Jonkers et al 2006. MEN1 gene encodes for menin, a 610 amino acid protein (Chandrasekharappa et al 1997, Lemmens et al 1997 that is ubiquitously expressed in adult tissues (Chandrasekharappa et al 1997) and located prevalently in the nucleus via three nuclear localization signals (NLS1, NLS2, and NLSa) in its C-terminal fragment (Guru et al 1998, La et al 2006.…”