Tobias Else1, Thomas J Giordano, Gary D Hammer. 1. Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan 48109-2200, USA.
Abstract
CONTEXT: Adrenocortical cancer (ACC) is a rare disease with an often fatal outcome. The clinical and pathological diagnosis of a malignant vs. benign adrenocortical tumor is sometimes challenging. Telomere maintenance mechanisms (TMMs) are critical for the persistence of the malignant phenotype, but little is known about these mechanisms or their diagnostic value in adrenocortical lesions. OBJECTIVE: Tissue samples of diagnostically known adrenocortical neoplasms were evaluated for parameters of known TMMs, telomerase activity (TA), and alternative telomere lengthening (ALT). DESIGN: The study analyzed retrospectively collected frozen adrenocortical tissue samples from the University of Michigan Health System. PATIENT SAMPLES: Samples included 24 ACCs, 11 adrenocortical adenomas (ACAs), and three normal adrenal tissues. MAIN OUTCOME MEASURES: Telomerase activity (telomerase activity protocol assay), alternative telomere lengthening (telomere restriction fragment analysis, telomere associated promyelocyte leukemia bodies) were measured. RESULTS: A total of 22 of 24 ACCs (92%) could be definitively assigned to a TMM. The TMM classification was: 19 of 24 TA (79%), two of which displayed very long telomeres, one of 24 ALT (4%) and two of 24 (8%) TA and ALT. Results of two of 24 (8%) were inconclusive (one negative for TA and positive in one ALT assay, one negative in all assays). None of the normal adrenal tissues (none of three) or ACA (none of 11) samples had signs of an active TMM. CONCLUSIONS: TA is the main TMM in the majority of ACCs, but subsets of ACCs additionally or exclusively exhibit signs of ALT. Determination of telomere maintenance mechanisms in diagnostically challenging adrenocortical tumors might be of additional diagnostic value in the pathological diagnosis of malignant vs. benign lesions.
CONTEXT: Adrenocortical cancer (ACC) is a rare disease with an often fatal outcome. The clinical and pathological diagnosis of a malignant vs. benign adrenocortical tumor is sometimes challenging. Telomere maintenance mechanisms (TMMs) are critical for the persistence of the malignant phenotype, but little is known about these mechanisms or their diagnostic value in adrenocortical lesions. OBJECTIVE: Tissue samples of diagnostically known adrenocortical neoplasms were evaluated for parameters of known TMMs, telomerase activity (TA), and alternative telomere lengthening (ALT). DESIGN: The study analyzed retrospectively collected frozen adrenocortical tissue samples from the University of Michigan Health System. PATIENT SAMPLES: Samples included 24 ACCs, 11 adrenocortical adenomas (ACAs), and three normal adrenal tissues. MAIN OUTCOME MEASURES: Telomerase activity (telomerase activity protocol assay), alternative telomere lengthening (telomere restriction fragment analysis, telomere associated promyelocyte leukemia bodies) were measured. RESULTS: A total of 22 of 24 ACCs (92%) could be definitively assigned to a TMM. The TMM classification was: 19 of 24 TA (79%), two of which displayed very long telomeres, one of 24 ALT (4%) and two of 24 (8%) TA and ALT. Results of two of 24 (8%) were inconclusive (one negative for TA and positive in one ALT assay, one negative in all assays). None of the normal adrenal tissues (none of three) or ACA (none of 11) samples had signs of an active TMM. CONCLUSIONS: TA is the main TMM in the majority of ACCs, but subsets of ACCs additionally or exclusively exhibit signs of ALT. Determination of telomere maintenance mechanisms in diagnostically challenging adrenocortical tumors might be of additional diagnostic value in the pathological diagnosis of malignant vs. benign lesions.
Authors: Siyuan Zheng; Andrew D Cherniack; Ninad Dewal; Richard A Moffitt; Ludmila Danilova; Bradley A Murray; Antonio M Lerario; Tobias Else; Theo A Knijnenburg; Giovanni Ciriello; Seungchan Kim; Guillaume Assie; Olena Morozova; Rehan Akbani; Juliann Shih; Katherine A Hoadley; Toni K Choueiri; Jens Waldmann; Ozgur Mete; A Gordon Robertson; Hsin-Ta Wu; Benjamin J Raphael; Lina Shao; Matthew Meyerson; Michael J Demeure; Felix Beuschlein; Anthony J Gill; Stan B Sidhu; Madson Q Almeida; Maria C B V Fragoso; Leslie M Cope; Electron Kebebew; Mouhammed A Habra; Timothy G Whitsett; Kimberly J Bussey; William E Rainey; Sylvia L Asa; Jérôme Bertherat; Martin Fassnacht; David A Wheeler; Gary D Hammer; Thomas J Giordano; Roel G W Verhaak Journal: Cancer Cell Date: 2016-05-09 Impact factor: 31.743
Authors: Thomas J Giordano; Rork Kuick; Tobias Else; Paul G Gauger; Michelle Vinco; Juliane Bauersfeld; Donita Sanders; Dafydd G Thomas; Gerard Doherty; Gary Hammer Journal: Clin Cancer Res Date: 2009-01-15 Impact factor: 12.531
Authors: Alex C Kim; Ferdous M Barlaskar; Joanne H Heaton; Tobias Else; Victoria R Kelly; Kenneth T Krill; Joshua O Scheys; Derek P Simon; Alessia Trovato; Wei-Hsiung Yang; Gary D Hammer Journal: Endocr Rev Date: 2009-04-29 Impact factor: 19.871