TERT Copy Number Alterations, Promoter Mutations and Rearrangements in Adrenocortical Carcinomas

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.

DNA cytosine deamination is associated with recurrent Somatic Copy Number Alterations in stomach adenocarcinoma

“…The distribution of SCNAs has been extensively studied and found to be associated with various abnormal conditions, including autism spectrum disorder and Adrenocortical Carcinomas (Girirajan et al, 2013;Gupta et al, 2022). However, the relationship between the prognosis of STAD patients and hotspots of SCNAs remained unclear.…”

The regulations of telomerase reverse transcriptase (TERT) in cancer

“…Alteration in the TERT gene includes genomic gains/amplifications, promoter rearrangements, and "hotspot" promoter mutations at a position relative to the transcription start site [39]. These alterations have been reported in multiple cancer types, especially TERT promoter mutations, which are associated with increased TERT expression [20,21,[40][41][42].…”