Pheochromocytomas (PCCs) and paragangliomas (PGLs) are chromaffin-cell tumors that arise from the adrenal medulla and extra-adrenal paraganglia, respectively. The dysfunction of genes involved in the cellular response to hypoxia, such as VHL, EGL nine homolog 1, and the succinate dehydrogenase (SDH) genes, leads to a direct abrogation of hypoxia inducible factor (HIF) degradation, resulting in a pseudo-hypoxic state implicated in PCC/PGL development. Recently, somatic post-zygotic mutations in EPAS1 (HIF2A) have been found in patients with multiple PGLs and congenital erythrocytosis. We assessed 41 PCCs/PGLs for mutations in EPAS1 and herein describe the clinical, molecular and genetic characteristics of the 7 patients found to carry somatic EPAS1 mutations; 4 presented with multiple PGLs (3 of them also had congenital erythrocytosis), whereas 3 were single sporadic PCC/PGL cases. Gene expression analysis of EPAS1-mutated tumors revealed similar mRNA EPAS1 levels to those found in SDH-gene- and VHL-mutated cases and a significant up-regulation of two hypoxia-induced genes (PCSK6 and GNA14). Interestingly, single nucleotide polymorphism array analysis revealed an exclusive gain of chromosome 2p in three EPAS1-mutated tumors. Furthermore, multiplex-PCR screening for small rearrangements detected a specific EPAS1 gain in another EPAS1-mutated tumor and in three non-EPAS1-mutated cases. The finding that EPAS1 is involved in the sporadic presentation of the disease not only increases the percentage of PCCs/PGLs with known driver mutations, but also highlights the relevance of studying other hypoxia-related genes in apparently sporadic tumors. Finally, the detection of a specific copy number alteration affecting chromosome 2p in EPAS1-mutated tumors may guide the genetic diagnosis of patients with this disease.
Key words: HLA; 2m; antigen processing machinery; bladder carcinoma; tumor escape Downregulation of HLA class I molecules is a frequent event observed in human tumors, and it is believed to be related with tumor immune escape. Several types of HLA class I downregulation have been described including total, locus, allele and haplotype loss. 1 Total HLA class I loss is a relatively frequent phenotype (9 -52%) detected in tumors derived from different tissues such as melanoma, head-neck, colorectal, prostate and breast cancer. 2 Molecular mechanisms that have been shown to be responsible for this phenotype include the following. 1) 2-microglobulin (2-m) gene mutations, which play an important role in assembly of the HLA complex (HLA heavy chain, 2-m and peptide). 2-microglobulin gene mutations result in failure to assemble the class I molecules for cell surface expression and are therefore responsible for total HLA class I loss. Frequent 2-m mutations have been described in colorectal and gastric cancers of the microsatellite mutator phenotype (MMP), 3,4 which exhibit a type of genetic instability characterized by the accumulation of somatic mutations in repeated sequences. 5 The 2-m gene contains several repeat sequences and so is a mutational target for mismatch repair deficiency. The frequency of 2-m mutations in other tumor types that infrequently display MMP (breast cancer and melanoma) is lower than in colorectal carcinomas. 3 2) Downregulation of proteins involved in the antigen processing pathway is responsible for total HLA class I loss due to a deficiency in peptide formation, loading of MHC molecules and transport. MHC class I presentation of peptides is a multistep process involving several molecules: catalytic  subunits of the proteasome (LMP2, LMP7 and LMP10), transporter associated with antigen processing (TAP-1 and TAP-2) and various endoplasmic reticulum chaperones. Numerous studies have demonstrated deficiencies in the expression of antigen-processing genes in tumor cell lines. 6 -10 Most of the deficits described are combined deficiencies comprising multiple components, 6,9,10 though selective deficiencies have also been described. 7,10 Most of these alterations are corrected by cytokine treatment, particularly by IFNgamma. In contrast, structural defects in antigen-processing genes are very uncommon and only 2 point mutations in TAP-1 gene have been described. 11,12 3) Finally, hypermethylation of HLA class I promotor genes can also repress HLA class I expression, as has been demonstrated in melanoma cell lines. 13 Although HLA class I total loss can be found in histologically different tumor types, carcinogenesis in each tissue present particular characteristics. In despite of the great advances in our knowledge of molecular lesions that produce HLA class I total loss in tumor cell lines, in some particular human tumor tissues the underlying mechanisms remain to be established.Bladder cancer is one of the most common malignancies worldwide, with transitional cell carcinoma (TCC) being ...
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