title: Spatiotemporal Heterogeneity Characterizes the Genetic Landscape of Pheochromocytoma and Defines Early Events in Tumorigenesis.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Department of Surgical Sciences, Uppsala University, Uppsala, Sweden. joakim.crona@surgsci.uu.se.
authors.forename: Joakim
authors.initials: J
authors.lastname: Crona
authors.affiliation: Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Samuel
authors.initials: S
authors.lastname: Backman
authors.affiliation: Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Rajani
authors.initials: R
authors.lastname: Maharjan
authors.affiliation: Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Markus
authors.initials: M
authors.lastname: Mayrhofer
authors.affiliation: Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Stålberg
authors.affiliation: Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Isaksson
authors.affiliation: Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Hellman
authors.affiliation: Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Peyman
authors.initials: P
authors.lastname: Björklund
mesh_terms: D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D060965:Clonal Evolution / Q000235:genetics; D016000:Cluster Analysis; D005260:Female; D020869:Gene Expression Profiling; D018740:Genetic Heterogeneity; D042822:Genomic Instability; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D009154:Mutation; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D010673:Pheochromocytoma / Q000235:genetics* / Q000473:pathology*; D010802:Phylogeny; D011003:Ploidies; D020641:Polymorphism, Single Nucleotide