Telomerase Activation and ATRX Mutations Are Independent Risk Factors for Metastatic Pheochromocytoma and Paraganglioma

Abstract

Purpose: Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors. Whereas most PPGLs are benign, up to 20% may become metastatic with SDHB-and FH-mutated tumors showing the higher risk. We aimed at determining the contribution of immortalization mechanisms to metastatic progression.Experimental Design: Immortalization mechanisms were investigated in 200 tumors. To identify telomerase (þ) tumors, we analyzed genomic alterations leading to transcriptional activation of TERT comprising promoter mutations, hypermethylation and gain copy number. To identify tumors that activated the alternative lengthening of telomere (ALT) mechanism, we combined analyses of telomere length by slot blot, telomere heterogeneity by telomere FISH, and ATRX mutations by next-generation sequencing. Univariate/ multivariate and metastasis-free survival (MFS) and overall survival (OS) analyses were carried out for assessment of risk factors and clinical outcomes.Results: Only 37 of 200 (18.5%) tumors achieved immortalization. Telomerase activation occurred in 12 metastatic tumors and was prevalent in SDHB-mutated paragangliomas (P ¼ 2.42eÀ09). ALT features were present in 25 tumors, mostly pheochromocytomas, regardless of metastatic status or molecular group (P ¼ 0.169), yet ATRX mutations were found preferentially in SDHB/FH-mutated metastatic tumors (P ¼ 0.0014). Telomerase activation and ATRX mutations were independent factors of poor prognosis: MFS (hazard ratio, 48.2 and 33.1; P ¼ 6.50EÀ07 and 1.90EÀ07, respectively); OS (hazard ratio, 97.4 and 44.1; P ¼ 4.30EÀ03 and 2.00EÀ03, respectively) and were associated with worse MFS and OS (log-rank tests P < 0.0001).Conclusions: Assessment of telomerase activation and ATRX mutations could be used to identify metastatic PPGLs, particularly in tumors at high risk of progression.

Long intergenic noncoding RNA profiles of pheochromocytoma and paraganglioma: A novel prognostic biomarker

“…Until now, the most relevant molecular markers for aggressive or metastatic PCPG have been the SDHB and ATRX mutations . We wondered whether lincRNA expression levels could also be markers of aggressive and/or metastatic PCPG.…”

“…The pathways associated with the lincRNA clusters specific to the aggressive ( SDHx ‐mutated pseudohypoxia) or less aggressive subtypes (non‐ SDHx ‐mutated pseudohypoxia, kinase‐signaling) are reported to play certain roles in tumor progression . The pathways associated with the 18 lincRNAs related to aggressive/metastatic PCPGs or metastasis‐free survival in the different subtypes (univariate analysis) included known tumorigenic processes in PCPGs, such as the TCA cycle, glycolysis, VEGF signaling pathway and telomere maintenance (Supporting Information Fig. S8).…”

“…Until now, the most relevant molecular markers for aggressive or metastatic PCPG have been the SDHB and ATRX mutations. 13,14,[16][17][18] We wondered whether lincRNA expression levels could also be markers of aggressive and/or metastatic PCPG. LincRNA expression profiles in tumors from TCGA cohort with an aggressive and/or metastatic phenotype were compared to patient samples lacking these features (annotation for clinically aggressive and/or metastatic tumors were collected from the supplementary clinical information in the publication by Fishbein et al), and 13 out of 106 lincRNAs were differentially expressed between these two groups (two-sided t-test, p < 0.05) ( Table 1).…”

“…In contrast, kinase‐signaling PCPGs rarely develop metastasis, while the Wnt‐altered subtype and non‐ SDHx ‐mutated pseudohypoxia displays an intermediate phenotype in terms of metastatic/recurrent disease . Other factors reported to be associated with metastasis in PCPG are somatic mutations in ATRX or telomerase activation, which generally co‐occur with SDHB mutation . Since there are very few currently known markers for metastatic PCPGs that do not account for all cases, new markers are urgently needed.…”

“…6,15,16 Other factors reported to be associated with metastasis in PCPG are somatic mutations in ATRX or telomerase activation, which generally cooccur with SDHB mutation. 17,18 Since there are very few currently known markers for metastatic PCPGs that do not account for all cases, new markers are urgently needed.…”