SDHD gene mutations in patients presenting with apparently sporadic adrenal pheochromocytoma are rare. We recommend SDHD mutation screening for patients presenting with a family history of pheochromocytoma or PGL, multiple tumors, isolated adrenal or extra-adrenal pheochromocytomas, and age = 35 years. Analysis of SDHD can also help to distinguish synchronous primary tumors from abdominal metastases.
The Von Hippel-Lindau (VHL) gene product has a wide spectrum of tissue-specific functions, and specific germline mutations are associated with clinical phenotypes in VHL disease. In particular, missense mutations are correlated with the susceptibility to pheochromocytomas. An association between VHL aberrations and prognosis has been suggested in renal clear cell carcinoma but has not been studied in pheochromocytomas. We studied the frequency and spectrum of VHL alterations in apparently sporadic pheochromocytomas in relation to the clinical behavior in 72 patients, including 48 patients with clinically benign and 24 patients with malignant pheochromocytomas. Single-strand conformation polymorphism (SSCP) analysis followed by DNA sequencing, loss of heterozygosity analysis of the VHL locus and immunohistochemistry for VHL protein expression were used to investigate somatic VHL gene alterations. In 2 patients, 1 with a malignant tumor, germline mutations were identified in the stop codon. Tumor-specific intragenic VHL mutations and accompanying loss of heterozygosity were identified in 2 (4.3%) of 47 sporadic benign pheochromocyto- Key words: Von Hippel-Lindau; pheochromocytoma; mutation; loss of heterozygosityVon Hippel-Lindau (VHL) disease is characterized by the development of multiple highly vascularized tumors in mesenchymal and neural crest-derived tissues of several organ systems. These concern mostly the central nervous system (hemangioblastoma), eye (retinal angioma), kidney (renal clear cell carcinoma), adrenal medulla (pheochromocytoma), inner ear (endolymphatic sac tumor) and endocrine pancreas (islet cell tumors). 1 In nearly all VHL patients, germline mutations or deletions in the VHL gene can be identified. 2,3 The VHL gene codes for a 213-amino acid protein (pVHL), which is involved in regulation of angiogenesis, extracellular matrix formation and plays a role in the cell cycle. 4 -9 As a recessive tumor suppressor gene, VHL demonstrates some important additional features, such as allelic heterogeneity resulting in genotypephenotype correlations and epigenetic effects. 10 -12 A correlation has been found between the nature and localization of inactivating mutations and the clinical consequences in patients afflicted by VHL disease. In particular, the development of pheochromocytoma (PCC) in VHL disease (type II VHL disease) is strongly correlated with missense mutations. These are found in 96% of these families, frequently in the exon 3-encoded ␣-domain of pVHL. 10 -13 PCC may even be the only tumor arising in some individuals with VHL type II disease. It is hypothesized that some retention of pVHL function is necessary in the development of PCC, arising from a dominant-negative effect of mutated pVHL and based on its involvement in the VHL-Elongin C-Elongin B complex. 14 The majority of PCCs occur sporadically, and the genetic mechanisms underlying their tumorigenesis and progression towards malignancy are poorly understood. At present, one cannot predict which patient will experience progres...
Up to 60% of gastro-oesophageal junction (GEJ) adenocarcinomas show nuclear β-catenin expression, pointing to activated T-cell factor (TCF)/β-catenin-driven gene transcription. We demonstrate in five human GEJ adenocarcinoma cell lines that nuclear β-catenin expression indeed correlates with enhanced TCF-mediated transcription of a reporter gene. In several tumour types, TCF/β-catenin activation is caused by mutations in either adenomatous polyposis coli (APC), β-catenin exon 3, AXIN1, AXIN2 or β-transducin repeat-containing protein (β-TrCP). In GEJ adenocarcinomas, very few APC and β-catenin mutations have been found. Therefore, the mechanism of Wnt pathway activation remains unclear. In the present study, we did not find AXIN1 gene mutations in 17 GEJ tumours with nuclear β-catenin expression (without β-catenin exon 3 mutations). Six intragenic single nucleotide polymorphisms (SNPs) were identified. One of these, the AXIN1 gene T1942C SNP, has a frequency of 21% but is only very recently described despite numerous AXIN1 gene mutational studies. We provide evidence why this SNP was missed in single strand conformation polymorphism analyses. The AXIN1 gene G2063A variation was previously described as a gene mutation but we demonstrate that this is a polymorphism. With these six SNPs loss of heterozygosity (LOH) was found in 11 of 15 (73%) informative tumours. To investigate a possible AXIN1 gene dosage effect in GEJ tumours expressing nuclear β-catenin, AXIN1 locus LOH was determined in 20 tumours expressing membranous and no nuclear β-catenin. LOH was found in 10 of 13 (77%) informative cases. AXIN1 protein immunohistochemistry revealed cytoplasmic expression in all tumours irrespective of the presence of AXIN1 locus LOH. These data indicate that nuclear β-catenin expression is indicative for activated Wnt signalling and that neither AXIN1 gene mutations nor AXIN1 locus LOH are involved in Wnt pathway activation in GEJ adenocarcinomas.
In response to DNA damage, the cell cycle checkpoint kinase 2 (CHEK2) may phosphorylate p53, Cdc25A and Cdc25C, and regulate BRCA1 function, leading to cell cycle arrest and DNA repair. The truncating germline mutation CHEK2*1100delC abrogates kinase activity and confers low-penetrance susceptibility to breast cancer. We found CHEK2*1100delC in 0.5% of 190 oesophageal squamous cell carcinomas and in 1.5% of 196 oesophageal adenocarcinomas. In addition, we observed the mutation in 3.0% of 99 Barrett's metaplasias and 1.5% of 66 dysplastic Barrett's epithelia, both known precursor lesions of oesophageal adenocarcinoma. Since CHEK2*1100delC mutation frequencies did not significantly differ among oesophageal squamous cell carcinomas, adenocarcinomas and (dysplastic) Barrett's epithelia, as compared to healthy individuals, we conclude that the CHEK2*1100delC mutation has no major contribution in oesophageal carcinogenesis.
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