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

Korpershoek, Esther; Stobbe, Claudia; Nederveen, Francien H. van; Krijger, Ronald R. de; Dinjens, Winand N.M.

doi:10.1677/erc-10-0072

Cited by 7 publications

(6 citation statements)

References 23 publications

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“…We proceeded with qualitative observations that identified primary tumors from patients with local metastatic recurrences as having pronounced chromosomal instability with a relatively low degree of intra-and intertumor heterogeneity. This was in contrast with primary tumors from patients with distant metastatic lesions that were characterized by a lower degree of aneuploidy but having pronounced inter-and intratumor genetic heterogeneity, in line with previous observations (39,40).…”

Section: Discussionsupporting

confidence: 90%

Spatiotemporal Heterogeneity Characterizes the Genetic Landscape of Pheochromocytoma and Defines Early Events in Tumorigenesis

Crona

Backman

Maharjan

et al. 2015

Clinical Cancer Research

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Purpose: Pheochromocytoma and paraganglioma (PPGL) patients display heterogeneity in the clinical presentation and underlying genetic cause. The degree of inter-and intratumor genetic heterogeneity has not yet been defined.Experimental Design: In PPGLs from 94 patients, we analyzed LOH, copy-number variations, and mutation status of SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, EPAS1, NF1, RET, TMEM127, MAX, and HRAS using high-density SNP array and targeted deep sequencing, respectively. Genetic heterogeneity was determined through (i) bioinformatics analysis of individual samples that estimated absolute purity and ploidy from SNP array data and (ii) comparison of paired tumor samples that allowed reconstruction of phylogenetic trees.Results: Mutations were found in 61% of the tumors and correlated with specific patterns of somatic copy-number aberrations (SCNA) and degree of nontumoral cell admixture. Intratumor genetic heterogeneity was observed in 74 of 136 samples using absolute bioinformatics estimations and in 22 of 24 patients by comparison of paired samples. In addition, a low genetic concordance was observed between paired primary tumors and distant metastases. This allowed for reconstructing the life history of individual tumors, identifying somatic mutations as well as copy-number loss of 3p and 11p (VHL subgroup), 1p (Cluster 2), and 17q (NF1 subgroup) as early events in PPGL tumorigenesis.Conclusions: Genomic landscapes of PPGL are specific to mutation subtype and characterized by genetic heterogeneity both within and between tumor lesions of the same patient.

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Section: Discussionsupporting

confidence: 90%

Spatiotemporal Heterogeneity Characterizes the Genetic Landscape of Pheochromocytoma and Defines Early Events in Tumorigenesis

Crona

Backman

Maharjan

et al. 2015

Clinical Cancer Research

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“…A possible explanation for this could be a heterogeneity of the tumors, which has recently been shown in PCCs [31]. For both SDHAF2 and SDHD, LOH was associated with a significantly (p<0.01 and p<0.05, respectively) decreased levels of mRNA expression.…”

Section: Discussionmentioning

confidence: 84%

“…Another 7 and 20 % of the PCCs showed signs of LOH/allelic imbalance at the SDHAF2 and SDHD regions, respectively, but were inconclusive because the allele ratios were [0.7 but \0.8. A possible explanation for this could be heterogeneity of the tumors, which has recently been shown in PCCs [31].…”

Section: Discussionmentioning

confidence: 97%

Role of SDHAF2 and SDHD in von Hippel–Lindau Associated Pheochromocytomas

et al. 2013

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Pheochromocytomas (PCCs) develop from the adrenal medulla and are often part of a hereditary syndrome such as von Hippel Lindau (VHL) syndrome. In VHL, only about 30% of patients with a VHL missense mutation develop PCCs. Thus, additional genetic events leading to formation of such tumors in patients with VHL syndrome are sought for. SDHAF2 (previously termed SDH5) and SDHD are both located on chromosome 11q and required for the function of mitochondrial complex II. While SDHAF2 has been shown to be mutated in patients with paragangliomas (PGLs), SDHD mutations have been found in both patients with PCCs and PGLs. Since loss of 11q is a common event in VHLassociated PCCs, we aimed to investigate whether SDHAF2 and SDHD are targets. In this study, 41 VHL-associated PCCs were screened for mutations and loss of heterozygosity (LOH) in SDHAF2 or SDHD. Promoter methylation as well as mRNA expression of SDHAF2 and SDHD was studied. In addition, immunohistochemistry (IHC) of SDHB, known to be a universal marker for loss of any part the SDH complex, was conducted. LOH was found in more than 50% of the VHL-associated PCCs, and was correlated to a significant decrease (p<0.05) in both SDHAF2 and SDHD mRNA expression, which may be suggestive of a pathogenic role. However, while SDHB protein expression as determined by IHC in a small cohort of tumors was lower in PCCs than in the surrounding adrenal cortex, there was no obvious correlation with LOH or the level of SDHAF2/SDHD mRNA expression.In addition, the lack of mutations and promoter methylation in the investigated samples indicate that other events on chromosome 11 might be involved in the development of PCCs in association with VHL syndrome.3

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“…A complication in the development of genetic biomarkers is genetic heterogeneity within and between PPGL lesions . Preliminary findings indicate that genetic divergence is considerable between clones observed within primary and metastatic lesions of the same patient (Fig.…”

Section: Future Concepts For Precision Medicinementioning

confidence: 95%

Precision medicine in pheochromocytoma and paraganglioma: current and future concepts

2016

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Pheochromocytoma and paraganglioma (PPGL) are rare diseases but are also amongst the most characterized tumour types. Hence, patients with PPGL have greatly benefited from precision medicine for more than two decades. According to current molecular biology and genetics‐based taxonomy, PPGL can be divided into three different clusters characterized by: Krebs cycle reprogramming with oncometabolite accumulation or depletion (group 1a); activation of the (pseudo)hypoxia signalling pathway with increased tumour cell proliferation, invasiveness and migration (group 1b); and aberrant kinase signalling causing a pro‐mitogenic and anti‐apoptotic state (group 2). Categorization into these clusters is highly dependent on mutation subtypes. At least 12 different syndromes with distinct genetic causes, phenotypes and outcomes have been described. Genetic screening tests have a documented benefit, as different PPGL syndromes require specific approaches for optimal diagnosis and localization of various syndrome‐related tumours. Genotype‐tailored treatment options, follow‐up and preventive care are being investigated. Future new developments in precision medicine for PPGL will mainly focus on further identification of driver mechanisms behind both disease initiation and malignant progression. Identification of novel druggable targets and prospective validation of treatment options are eagerly awaited. To achieve these goals, we predict that collaborative large‐scale studies will be needed: Pheochromocytoma may provide an example for developing precision medicine in orphan diseases that could ultimately aid in similar efforts for other rare conditions.

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

Cited by 7 publications

References 23 publications

Spatiotemporal Heterogeneity Characterizes the Genetic Landscape of Pheochromocytoma and Defines Early Events in Tumorigenesis

Spatiotemporal Heterogeneity Characterizes the Genetic Landscape of Pheochromocytoma and Defines Early Events in Tumorigenesis

Role of SDHAF2 and SDHD in von Hippel–Lindau Associated Pheochromocytomas

Precision medicine in pheochromocytoma and paraganglioma: current and future concepts

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