Abstract
Molecular characterization of adrenocortical carcinomas (ACC) by The Cancer Genome Atlas (TCGA) has highlighted a high prevalence of TERT alterations, which are associated with disease progression. Herein, 78 ACC were profiled using a combination of next generation sequencing (n = 76) and FISH (n = 9) to assess for TERT alterations. This data was combined with TCGA dataset (n = 91). A subset of borderline adrenocortical tumors (n = 5) and adrenocortical adenomas (n = 7) were also evaluated. The most common alteration involving the TERT gene involved gains/amplifications, seen in 22.2% (37/167) of cases. In contrast, “hotspot” promoter mutations (C > T promoter mutation at position -124, 7/167 cases, 4.2%) and promoter rearrangements (2/165, 1.2%) were rare. Recurrent co-alterations included 22q copy number losses seen in 24% (9/38) of cases. Although no significant differences were identified in cases with and without TERT alterations pertaining to age at presentation, tumor size, weight, laterality, mitotic index and Ki67 labeling, cases with TERT alterations showed worse outcomes. Metastatic behavior was seen in 70% (28/40) of cases with TERT alterations compared to 51.2% (65/127, p = 0.04) of cases that lacked these alterations. Two (of 5) borderline tumors showed amplifications and no TERT alterations were identified in 7 adenomas. In the borderline group, 0 (of 4) patients with available follow up had adverse outcomes. We found that TERT alterations in ACC predominantly involve gene amplifications, with a smaller subset harboring “hotspot” promoter mutations and rearrangements, and 70% of TERT-altered tumors are associated with metastases. Prospective studies are needed to validate the prognostic impact of these findings.
Highlights
Programmed loss of telomeric DNA in somatic cells leads to the activation of DNA damage responses and subsequent cell cycle arrest and senescence [1]
Whole genome doubling associated with decreased telomere length and increased TERT expression has been associated with disease progression in adrenocortical carcinomas in The Cancer Genome Atlas (TCGA) datasets [12]
Using a combination of next generation sequencing (NGS) (n = 76) and fluorescence in situ hybridization (FISH) (n = 9), 78 cases of adrenocortical carcinomas were evaluated for copy number alterations (Table 1)
Summary
Programmed loss of telomeric DNA (telomere shortening) in somatic cells leads to the activation of DNA damage responses and subsequent cell cycle arrest and senescence [1]. Telomerase reverse transcriptase, which is encoded by the TERT gene, forms an important component of the telomerase complex and TERT mediated de novo telomeric DNA synthesis in rapidly proliferating cancer cells prevents chromosomal ends from being recognized as sites of DNA damage [1]. This prevents the initiation of repair pathways and allows neoplastic cells to escape telomere crisis [1]. Alterations of the TERT gene such as “hotspot” promoter mutations, amplifications and promoter rearrangements have been associated with increased TERT expression and these. Due to an association between whole genome doubling and TERT expression in a prior TCGA study, it has been suggested that TERT is required in a subset of adrenocortical carcinomas for telomere maintenance [12]
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