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

Abstract

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.

Global DNA Methylation Analysis Identifies Two Discrete clusters of Pheochromocytoma with Distinct Genomic and Genetic Alterations

“…vascular cells, immune cells and fibroblasts) in the tumour samples. We have previously shown that tumour cell purity differs between mutational subgroups36. This may contribute to the differences noted between different subgroups by the present study and others.…”

“…One patient with von Hippel-Lindau disease had bilateral disease with both tumours included in the cohort. The tumours had been previously studied for mutations in known driver genes and using high-density SNP array (data available for 35 of the tumours)3637. Tumour purity was estimated from SNP array data using ASCAT v. 2.138 as implemented in Nexus Copy-number Variation 7.5 (Biodiscovery Inc., CA).…”

GEP- NETS UPDATE: Genetics of neuroendocrine tumors

“…Widespread genetic heterogeneity within these tumors as well as and between paired lesions has been recently shown (152). Of particular notice was the observed differences between paired primary and metastatic tumor lesions as well as indication of parallel evolution of different metastatic clones (152).…”

An Integrative Genomic Analysis of Formalin Fixed Paraffin-Embedded Archived Serous Ovarian Carcinoma Comparing Long-term and Short-term Survivors

“…As previously described, the estimation of tumor cellularity through light microscopy tended to overestimate the proportion of tumor cells. 20,21 This relatively low proportion of tumor cells is expected to reduce the sensitivity for somatic mutation detection and may explain the relatively low prevalence of TP53 mutations in high-grade tumors. Indeed, the tumor cell proportion was determined as less than 25% in 4/6 TP53 wt high-grade tumors.…”