Abstract
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.
Overview
- The study aims to identify mutation/location-related characteristics among pseudohypoxic PHEOs/PGLs using comprehensive microarray profiling and supervised analysis. The study includes 18 SDHB, 6 SDHD-abdominal/thoracic (AT), 8 SDHD-head/neck (HN), and 13 VHL PHEOs/PGLs. To avoid location-specific bias, typical adrenal medulla genes were derived from matched normal medullas and cortices. 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 with a 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. The study shows for the first time that SDHD-HN PGLs share more features with VHL PHEOs than with SDHD-AT PGLs, suggesting novel subclassification of pseudohypoxic PHEOs/PGLs and implying cluster-specific pathogenic mechanisms and treatment strategies.
Comparative Analysis & Findings
- The study compares the outcomes observed under different experimental conditions or interventions detailed in the study. The results show that SDHB and SDHD-AT PHEOs/PGLs (cluster A) are distinct from VHL PHEOs and SDHD-HN PGLs (cluster B) in terms of gene expression patterns. The study identifies 6937 highly predictive genes with a misclassification error rate of 0.175. Enrichment analysis reveals that energy metabolism and inflammation/fibrosis-related genes are 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. The study shows for the first time that SDHD-HN PGLs share more features with VHL PHEOs than with SDHD-AT PGLs, suggesting novel subclassification of pseudohypoxic PHEOs/PGLs and implying cluster-specific pathogenic mechanisms and treatment strategies.
Implications and Future Directions
- The study's findings have significant implications for the field of research or clinical practice. The study identifies mutation/location-related characteristics among pseudohypoxic PHEOs/PGLs, which can inform effective new therapies for distinctive manifestations. The study also identifies key genes that are differentially expressed in pseudohypoxic PHEOs/PGLs, which can inform the development of targeted therapies. The study suggests novel subclassification of pseudohypoxic PHEOs/PGLs, which can inform personalized treatment strategies. The study identifies cluster-specific pathogenic mechanisms and treatment strategies, which can inform the development of new therapies. The study's limitations include the small sample size and the need for further validation of the results. Future research directions include validating the results in a larger sample size, exploring the clinical implications of the findings, and developing targeted therapies based on the identified genes and pathways.