A novel candidate region linked to development of both pheochromocytoma and head/neck paraganglioma

Abstract

Although the histologic distinction between pheochromocytomas and head and neck paragangliomas is clear, little is known about the genetic differences between them. To date, various sets of genes have been found to be involved in inherited susceptibility to developing both tumor types, but the genes involved in sporadic pathogenesis are still unknown. To define new candidate regions, we performed CGH analysis on 29 pheochromocytomas and on 24 paragangliomas mainly of head and neck origin (20 of 24), which allowed us to differentiate between the two tumor types. Loss of 3q was significantly more frequent in pheochromocytomas, and loss of 1q appeared only in paragangliomas. We also found gain of 11q13 to be a significantly frequent alteration in malignant cases of both types. In addition, recurrent loss of 8p22-23 was found in 62% of pheochromocytomas (including all malignant cases) versus in 33% of paragangliomas, suggesting that this region contains candidate genes involved in the pathogenesis of this abnormality. Using FISH analysis on tissue microarrays, we confirmed genomic deletion of this region in 55% of pheochromocytomas compared to 12% of paragangliomas. Loss of 8p22-23 appears to be an important event in the sporadic development of these tumors, and additional molecular studies are necessary to identify candidate genes in this chromosomal region.

Intra-tumoral molecular heterogeneity in benign and malignant pheochromocytomas and extra-adrenal sympathetic paragangliomas

“…Genomic aberrations of metastases in association with the primary tumor have been investigated (Edstrom et al 2000, Jarbo et al 2005). Loss of chromosome 1p is an early event in the pathogenesis of malignant (sporadic) PCC (Dannenberg et al 2000, Cascon et al 2005. Our results show LOH of chromosome 1p13 in 75% of malignant tumors, half of those revealing heterogeneity.…”

“…In a previous study, we have shown loss of chromosome 6 in 34% of sporadic PCC (Dannenberg et al 2000), while this relatively high percentage was not found in other studies (Edstrom et al 2000, Cascon et al 2005. In addition, Cascon et al (2005) reported loss of chromosome 8p in 62% of PCC, whereas this high percentage was not observed in other studies (Dannenberg et al 2000, Edstrom et al 2000). These discrepancies could be due to geographical variations and hereditary background of the patients, differences in methods, but can also be the effect of intra-tumoral molecular heterogeneity.…”

“…While loss of chromosome 1p is the most common genetic aberration reported in sporadic PCC (Dannenberg et al 2000, Edstrom et al 2000, Cascon et al 2005), particular genetic alterations have been demonstrated in syndrome-related PCC (Edstrom et al 2000, Lui et al 2002, Jarbo et al 2005. Generally, MEN 2-related PCCs show loss of chromosomes 1p and 3q (Edstrom et al 2000, Jarbo et al 2005, SDHD-related PCCs and PGLs display loss of chromosome 11 (Hensen et al 2004), and in NF1-related tumors, frequent loss of 1p and 17q is found (Edstrom et al 2000, Bausch et al 2007.…”

“…Few studies have demonstrated that sporadic PCCs have similar genetic aberrations as those found in syndrome-related tumors, such as loss of chromosomes 1p, 3p, 3q, 11p, and 11q (Dannenberg et al 2000, Edstrom et al 2000, Cascon et al 2005). Although the results at large of these studies are in agreement with each other, there are also differences.…”

Overexpression and activation of EGFR and VEGFR2 in medullary thyroid carcinomas is related to metastasis

“…TMA construction was carried out as previously described with 2-3 cores of each tumor placed at different positions in the TMA and including, whenever possible, surrounding normal tissue (Cascon et al 2005). Three TMAs contained most of the tumor samples (109), and the remaining samples (44) were analyzed using whole tumor sections.…”