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DOI-10.1002_path.1711930102 - J. Pathol. 193-12A.pdf (121.54 kB)

GENETIC HETEROGENEITY BY TOPOGRAPHIC COMPARTMENTS IN PHEOCHROMOCYTOMAS SUGGEST A CONVERGENT CELL SELECTION IN THE PERIPHERAL AREA

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posted on 2012-11-22, 23:50 authored by Salvador J. Diaz-CanoSalvador J. Diaz-Cano, A Blanes, M de Miguel, R Tashjian, H Galera, HJ Wolfe

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 MEN2A) were selected for loss of heterozygosity (LOH) and single nucleotide polymorphism (SNP) analyses. Five polymorphic DNA regions from TP53, RB1, WT1, and NF1 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 20/67 informative cases (29.9%), RB1 in 11/53 informative cases (20.8%), WT1 in 16/60 informative cases (26.7%), and NF1 in 16/40 informative cases (40.0%). Peripheral compartment revealed more genetic alterations in 17 pheochromocytomas (23.3%): 6 benign, 5 locally invasive (NF1 locus, p<0.00001), and 6 malignant (TP53 locus, p=0.00933). MEN-2A 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 NF1 loci) that eventually results in multistep tumorigenesis.

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