Replication error-positive samples found in pheochromocytomas (original) (raw)
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The American Journal of Pathology, 2000
Despite several loss of heterozygosity studies, a comprehensive genomic survey of pheochromocytomas is still lacking. To identify DNA copy number changes which might be important in tumor development and progression and which may have diagnostic utility, we evaluated genetic aberrations in 29 sporadic adrenal and extra-adrenal pheochromocytomas (19 clinically benign tumors and 10 malignant lesions). Comparative genomic hybridization was performed using directly fluorochrome-conjugated DNA extracted from frozen (16) and paraffin-embedded (13) tumor tissues. The most frequently observed changes were losses of chromosomes 1p11-p32 (86%), 3q (52%), 6q (34%), 3p, 17p (31% each), 11q (28%), and gains of chromosomes 9q (38%) and 17q (31%). No amplification was identified and no difference between adrenal and extra-adrenal tumors was detected. Progression to malignant tumors was strongly associated with deletions of chromosome 6q (60% versus 21% in clinically benign lesions, P ؍ 0.0368) and 17p (50% versus 21%). Fluorescence in situ hybridization confirmed the comparative genomic hybridization data of chromosomes 1p, 3q, and 6q, and revealed aneuploidy in some tumors. Our results suggest that the development of pheochromocytomas is associated with specific genomic aberrations, such as losses of 1p, 3q, and 6q and gains of 9q and 17q. In particular, tumor suppressor genes on chromosomes 1p and 3q may be involved in early tumorigenesis, and deletions of chromosomes 6q and 17p in progression to malignancy.
Endocrine Related Cancer, 2010
Pheochromocytomas and abdominal paragangliomas are adrenal and extra-adrenal catecholamine-producing tumours. They arise due to heritable cancer syndromes, or more frequently occur sporadically due to an unknown genetic cause. The majority of cases are benign, but malignant tumours are observed. Previous comparative genomic hybridization (CGH) and loss of heterozygosity studies have shown frequent deletions of chromosome arms 1p, 3q and 22q in pheochromocytomas. We applied high-resolution whole-genome array CGH on 53 benign and malignant pheochromocytomas and paragangliomas to narrow down candidate regions as well as to identify chromosomal alterations more specific to malignant tumours. Minimal overlapping regions (MORs) were identified on 16 chromosomes, with the most frequent MORs of deletion (R32%) occurring on chromosome arms 1p, 3q, 11p/q, 17p and 22q, while the chromosome arms 1q, 7p, 12q and 19p harboured the most common MORs of gain (R14%). The most frequent MORs (61-75%) in the pheochromocytomas were identified at 1p, and the four regions of common losses encompassed 1p36, 1p32-31, 1p22-21 and 1p13. Tumours that did not show 1p loss generally demonstrated aberrations on chromosome 11. Gain of chromosomal material was significantly more frequent among the malignant cases. Moreover, gain at 19q, trisomy 12 and loss at 11q were positively associated with malignant pheochromocytomas, while 1q gain was commonly observed in the malignant paragangliomas. Our study revealed novel and narrow recurrent chromosomal regions of loss and gain at several autosomes, a prerequisite for identifying candidate tumour suppressor genes and oncogenes involved in the development of adrenal and extra-adrenal catecholamine-producing tumours.
The Journal of Pathology
Background: Adrenal pheochromocytomas have been extensively studied at the molecular level, but no information is available on their molecular profile by topographic compartments Methods: Microdissected samples from the peripheral and internal zones of 73 pheochromocytomas (49 sporadic, 24 associated to MEN9A) were selected for loss of heterozygosity (LOH) and single nucleotide polymorphism (SNP) analyses. Five polymorphic DNA regions from TP53, R67, WTI, and NF7 were systematically studied by polymerase chain reaction-denaturing gradient gel electrophoresis. Statistical differences between tumor compartments were evaluated using Fisher's exact test. Pheochromocytomas were classified malignant (8 sporadic tumors with distant metastases), locally invasive (15 sporadic tumors showing retroperitoneal infiltration only), and benign (all remaining tumors). Results: LOH/SNP involved TP53 in 20167 informative cases (29.9%), RBI in 11/53 informative cases (20.8%), WT1 in 16/60 informative cases (26.7%), and NF7 in 16/40 informative cases (40.0%). Peripheral compartment revealed more genetic alterations in 17 pheochromocytomas (23.3%): 6 benign, 5 locally invasive (NF7 locus, p<O.OOOOl), and 6 malignant (TP53 locus, p=0.00933). MEN-PA pheochromocytomas revealed higher proportion of NF1 locus abnormalities. Conclusions: We conclude that convergent selection at the peripheral compartment of pheochromocytomas determines the accumulation of microsatellite lesions and intratumor heterogeneity (TP53 and NF 7 loci) that eventually results in multistep tumorigenesis.
An Update on the Histology of Pheochromocytomas: How Does it Relate to Genetics?
Hormone and Metabolic Research
Pheochromocytomas are rare neuroendocrine tumors of the adrenal gland, whereas any extra-adrenal tumor with similar histology is designated as paraganglioma. These tumors have a very high rate of germline mutations in a large number of genes, up to 35% to 40%, frequently predisposing for other tumors as well. Therefore, they represent a phenomenal challenge for treating physicians. This review focuses on pheochromocytomas only, with special attention to gross and microscopic clues to the diagnosis of genetic syndromes, including the role of succinate dehydrogenase subunit A and subunit B immunohistochemistry as surrogate markers for genetic analysis in the field of succinate dehydrogenase subunit gene mutations.
Novel Pheochromocytoma Susceptibility Loci Identified by Integrative Genomics
Cancer Research, 2005
Pheochromocytomas are catecholamine-secreting tumors that result from mutations of at least six different genes as components of distinct autosomal dominant disorders. However, there remain familial occurrences of pheochromocytoma without a known genetic defect. We describe here a familial pheochromocytoma syndrome consistent with digenic inheritance identified through a combination of global genomics strategies. Multipoint parametric linkage analysis revealed identical LOD scores of 2.97 for chromosome 2cen and 16p13 loci. A two-locus parametric linkage analysis produced maximum LOD score of 5.16 under a double recessive multiplicative model, suggesting that both loci are required to develop the disease. Allele-specific loss of heterozygosity (LOH) was detected only at the chromosome 2 locus in all tumors from this family, consistent with a tumor suppressor gene. Four additional pheochromocytomas with a similar genetic pattern were identified through transcription profiling and helped refine the chromosome 2 locus. High-density LOH mapping with single nucleotide polymorphism-based array identified a total of 18 of 62 pheochromocytomas with LOH within the chromosome 2 region, which further narrowed down the locus to <2 cM. This finding provides evidence for two novel susceptibility loci for pheochromocytoma and adds a recessive digenic trait to the increasingly broad genetic heterogeneity of these tumors. Similarly, complex traits may also be involved in other familial cancer syndromes. (Cancer Res 2005; 65(21): 9651-8)
Germ-Line Mutations in Nonsyndromic Pheochromocytoma
New England Journal of Medicine, 2002
The group of susceptibility genes for pheochromocytoma that included the proto-oncogene RET (associated with multiple endocrine neoplasia type 2 ) and the tumor-suppressor gene VHL (associated with von Hippel-Lindau disease) now also encompasses the newly identified genes for succinate dehydrogenase subunit D ( SDHD ) and succinate dehydrogenase subunit B ( SDHB ), which predispose carriers to pheochromocytomas and glomus tumors. We used molecular tools to classify a large cohort of patients with pheochromocytoma with respect to the presence or absence of mutations of one of these four genes and to investigate the relevance of genetic analyses to clinical practice.
Journal of Clinical Investigation, 1991
Loss of heterozygosity (LOH) at specific loci may help localize tumor suppressor genes involved in the formation of various familial and sporadic tumors. In addition, the genetic loci for a number offamilial tumor syndromes have been mapped by linkage analysis. To explore the possible role of tumor suppressor genes in endocrine tumors, we tested 41 pheochromocytomas (34 sporadic and 7 familial) and 11 medullary thyroid cancers (MTC) (10 sporadic and 1 familial) for LOH near a variety of potentially important genetic loci: (a) the multiple endocrine neoplasia type 2A (MEN 2A) locus on chromosome 10; (b) the von Hippel-Lindau locus on 3p; and (c) the p53 and neurofibromatosis 1 loci on 17. We also examined chromosomes ip and 22q because previous studies in a small number of pheochromocytomas and MTCs suggested LOH in these regions. Background rates for LOH were assessed using several "random" probes. Finally, we examined a number of clinical and histologic characteristics of these tumors for possible correlations with specific genetic alterations. LOH in the region of the MEN 2A locus was uncommon (0% for MTCs, 5% for pheochromocytomas). However, we found significant allelic losses in pheochromocytomas on chromosomes ip (42%), 3p (16%), 17p (24%), and 22q (31%). We also noted a correlation between LOH on ip and urinary excretion of metanephrine by these patients (P = 0.02). LOH on ip, 3p, and 17p also appeared to be associated with increased tumor volume. Analysis of the smaller number of MTCs demonstrated allelic losses on chromosomes lp and 22q. Our results suggest that tumor formation and/or progression in pheochromocytomas and MTCs involves multiple genes, analogous with the model proposed for colon carcinoma.
The genomic landscape of phaeochromocytoma
The Journal of Pathology, 2014
Phaeochromocytomas (PCC) and paragangliomas (PGL) are rare neural crest derived tumours originating from adrenal chomaffin cells or extra-adrenal sympathetic and parasympathetic tissues. More than a third of PCC/PGL cases are associated with heritable syndromes involving thirteen or more known genes. These genes have been broadly partitioned into two groups based on pseudo-hypoxic and receptor tyrosine kinase (RTK) signaling pathways. Many of these genes can also become somatically mutated, although up to one third of sporadic cases have no known genetic driver.
Recent Advances in the Genetics of Pheochromocytomas and Paragangliomas
2016
Paragangliomas and pheochromocytomas are rare neuroendocrine tumors, which secrete catecholamines, with the same embryological origin from the neural crest cells. Pheochromocytomas develop from the adrenal medulla, while paragangliomas are extraadrenal tumors, evolving from the autonomic sympathetic and parasympathetic nervous chains. In the last 10 years, molecular medicine has discovered novelties in the understanding of genetics of these tumors. Although the majority of these tumors occur sporadically, recent medical discoveries have indicated that approximately 30-40% of these tumors are associated with an inherited mutation. In addition to this, developments in molecular pathology of pheochromocytomas and paragangliomas will provide the key to target specifi c cellular markers, assuring a personalised therapy. In this article we have reviewed the current medical literature, in order to summarise the most important aspects of genetics and clinical features of pheochromocytomas a...