PURPOSE: Pediatric adrenocortical carcinomas (ACCs) are aggressive; the overall survival of patients with ACCs is 40%-50%. Appropriate staging and histologic classification are crucial because children with incomplete resections, metastases, or relapsed disease have a dismal prognosis. The clinical course of pediatric adrenocortical tumors (ACTs) is difficult to predict using the current classification schemas, which rely on subjective microscopic and gross macroscopic variables. Recent advances in adult ACT studies have revealed distinct DNA methylation patterns with prognostic significance that have not been systematically interrogated in the pediatric population. PATIENTS AND METHODS: We performed DNA methylation analyses on 48 newly diagnosed ACTs from the International Pediatric Adrenocortical Tumor Registry and 12 pediatric adrenal controls to evaluate for distinct methylation groups. Pediatric methylation data were also compared systematically with the adult ACC cohort from The Cancer Genome Atlas (TCGA). RESULTS: Two pediatric ACT methylation groups were identified and showed differences in selected clinicopathologic and outcome characteristics. The A1 group was enriched for CTNNB1 variants and unfavorable outcome. The A2 group was enriched for TP53 germline variants, younger age at onset, and favorable outcome. Pediatric ACT methylation groups were maintained when International Pediatric Adrenocortical Tumor Registry cohort data were combined with TCGA cohort data. The CpG-island hypermethylator phenotype characterizing the TCGA cohort was not identified in the pediatric patients. When methylome findings were combined with independent histopathologic review using the Wieneke criteria, a high-risk population was identified with uniform fatal outcome. CONCLUSION: Our results indicate DNA methylation analysis can enhance current diagnostic algorithms. A combination of methylation and histologic classification produced the strongest prediction model and may prove useful in future risk-adapted therapeutic trials.
PURPOSE: Pediatric adrenocortical carcinomas (ACCs) are aggressive; the overall survival of patients with ACCs is 40%-50%. Appropriate staging and histologic classification are crucial because children with incomplete resections, metastases, or relapsed disease have a dismal prognosis. The clinical course of pediatric adrenocortical tumors (ACTs) is difficult to predict using the current classification schemas, which rely on subjective microscopic and gross macroscopic variables. Recent advances in adult ACT studies have revealed distinct DNA methylation patterns with prognostic significance that have not been systematically interrogated in the pediatric population. PATIENTS AND METHODS: We performed DNA methylation analyses on 48 newly diagnosed ACTs from the International Pediatric Adrenocortical Tumor Registry and 12 pediatric adrenal controls to evaluate for distinct methylation groups. Pediatric methylation data were also compared systematically with the adult ACC cohort from The Cancer Genome Atlas (TCGA). RESULTS: Two pediatric ACT methylation groups were identified and showed differences in selected clinicopathologic and outcome characteristics. The A1 group was enriched for CTNNB1 variants and unfavorable outcome. The A2 group was enriched for TP53 germline variants, younger age at onset, and favorable outcome. Pediatric ACT methylation groups were maintained when International Pediatric Adrenocortical Tumor Registry cohort data were combined with TCGA cohort data. The CpG-island hypermethylator phenotype characterizing the TCGA cohort was not identified in the pediatric patients. When methylome findings were combined with independent histopathologic review using the Wieneke criteria, a high-risk population was identified with uniform fatal outcome. CONCLUSION: Our results indicate DNA methylation analysis can enhance current diagnostic algorithms. A combination of methylation and histologic classification produced the strongest prediction model and may prove useful in future risk-adapted therapeutic trials.
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: 2016-08-08 Impact factor: 31.743
Authors: Susanne N Gröbner; Barbara C Worst; Joachim Weischenfeldt; Ivo Buchhalter; Kortine Kleinheinz; Vasilisa A Rudneva; Pascal D Johann; Gnana Prakash Balasubramanian; Maia Segura-Wang; Sebastian Brabetz; Sebastian Bender; Barbara Hutter; Dominik Sturm; Elke Pfaff; Daniel Hübschmann; Gideon Zipprich; Michael Heinold; Jürgen Eils; Christian Lawerenz; Serap Erkek; Sander Lambo; Sebastian Waszak; Claudia Blattmann; Arndt Borkhardt; Michaela Kuhlen; Angelika Eggert; Simone Fulda; Manfred Gessler; Jenny Wegert; Roland Kappler; Daniel Baumhoer; Stefan Burdach; Renate Kirschner-Schwabe; Udo Kontny; Andreas E Kulozik; Dietmar Lohmann; Simone Hettmer; Cornelia Eckert; Stefan Bielack; Michaela Nathrath; Charlotte Niemeyer; Günther H Richter; Johannes Schulte; Reiner Siebert; Frank Westermann; Jan J Molenaar; Gilles Vassal; Hendrik Witt; Birgit Burkhardt; Christian P Kratz; Olaf Witt; Cornelis M van Tilburg; Christof M Kramm; Gudrun Fleischhack; Uta Dirksen; Stefan Rutkowski; Michael Frühwald; Katja von Hoff; Stephan Wolf; Thomas Klingebiel; Ewa Koscielniak; Pablo Landgraf; Jan Koster; Adam C Resnick; Jinghui Zhang; Yanling Liu; Xin Zhou; Angela J Waanders; Danny A Zwijnenburg; Pichai Raman; Benedikt Brors; Ursula D Weber; Paul A Northcott; Kristian W Pajtler; Marcel Kool; Rosario M Piro; Jan O Korbel; Matthias Schlesner; Roland Eils; David T W Jones; Peter Lichter; Lukas Chavez; Marc Zapatka; Stefan M Pfister Journal: Nature Date: 2018-02-28 Impact factor: 49.962
Authors: Carlos Rodriguez-Galindo; Mark D Krailo; Emilia M Pinto; Farzana Pashankar; Christopher B Weldon; Li Huang; Eliana M Caran; John Hicks; M Beth McCarville; David Malkin; Jonathan D Wasserman; Antonio G de Oliveira Filho; Michael P LaQuaglia; Deborah A Ward; Gerard Zambetti; Maria J Mastellaro; Alberto S Pappo; Raul C Ribeiro Journal: J Clin Oncol Date: 2021-04-06 Impact factor: 50.717