| Title: |
Genotype and Tumor Locus Determine Expression Profile of Pseudohypoxic Pheochromocytomas and Paragangliomas |
| Authors: |
Shankavaram, U; Fliedner, SMJ; Elkahloun, AG; Barb, JJ; Munson, PJ; Huynh, TT; Matro, JC; Turkova, H; Linehan, WM; Timmers, HJ; Tischler, AS; Powers, JF; de Krijger, Ronald; Baysal, BE; Takacova, M; Pastorekova, S; Gius, D; Lehnert, H; Camphausen, K; Pacak, K |
| Source: |
Shankavaram, U, Fliedner, SMJ, Elkahloun, AG, Barb, JJ, Munson, PJ, Huynh, TT, Matro, JC, Turkova, H, Linehan, WM, Timmers, HJ, Tischler, AS, Powers, JF, de Krijger, R, Baysal, BE, Takacova, M, Pastorekova, S, Gius, D, Lehnert, H, Camphausen, K & Pacak, K 2013, 'Genotype and Tumor Locus Determine Expression Profile of Pseudohypoxic Pheochromocytomas and Paragangliomas', Neoplasia, vol. 15, no. 4, pp. 435-+. https://doi.org/10.1593/neo.122132 |
| Publication Year: |
2013 |
| Subject Terms: |
/dk/atira/pure/keywords/researchprograms/AFL001000/EMCMM032401; name=EMC MM-03-24-01 |
| Description: |
Pheochromocytomas (PHEOs) and paragangliomas (PGLs) related to mutations in the mitochondrial succinate dehydrogenase (SDH) subunits A, B, C, and D, SDH complex assembly factor 2, and the von Hippel-Lindau (VHL) genes share a pseudohypoxic expression profile. However, genotype-specific differences in expression have been emerging. Development of effective new therapies for distinctive manifestations, e. g., a high rate of malignancy in SDHB- or predisposition to multifocal PGLs in SDHD patients, mandates improved stratification. To identify mutation/location-related characteristics among pseudohypoxic PHEOs/PGLs, we used comprehensive microarray profiling (SDHB: n = 18, SDHD-abdominal/thoracic (AT): n = 6, SDHD-head/neck (HN): n = 8, VHL: n = 13). To avoid location-specific bias, typical adrenal medulla genes were derived from matched normal medullas and cortices (n = 8) for data normalization. Unsupervised analysis identified two dominant clusters, separating SDHB and SDHD-AT PHEOs/PGLs (cluster A) from VHL PHEOs and SDHD-HN PGLs (cluster B). Supervised analysis yielded 6937 highly predictive genes (misclassification error rate of 0.175). Enrichment analysis revealed that energy metabolism and inflammation/fibrosis-related genes were most pronouncedly changed in clusters A and B, respectively. A minimum subset of 40 classifiers was validated by quantitative real-time polymerase chain reaction (quantitative real-time polymerase chain reaction vs. microarray: r = 0.87). Expression of several individual classifiers was identified as characteristic for VHL and SDHD-HN PHEOs and PGLs. In the present study, we show for the first time that SDHD-HN PGLs share more features with VHL PHEOs than with SDHD-AT PGLs. The presented data suggest novel subclassification of pseudohypoxic PHEOs/PGLs and implies cluster-specific pathogenic mechanisms and treatment strategies. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
unknown |
| ISSN: |
1522-8002; 1476-5586 |
| Relation: |
info:eu-repo/semantics/altIdentifier/pmid/23555188; info:eu-repo/semantics/altIdentifier/pissn/1522-8002; info:eu-repo/semantics/altIdentifier/eissn/1476-5586 |
| DOI: |
10.1593/neo.122132 |
| Availability: |
https://pure.eur.nl/en/publications/6fc21216-8c8d-448c-ab8a-95009b1f68f9; https://doi.org/10.1593/neo.122132; https://pure.eur.nl/ws/files/47509636/REPUB_39878-OA.pdf |
| Rights: |
info:eu-repo/semantics/openAccess |
| Accession Number: |
edsbas.ED58874B |
| Database: |
BASE |