{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T03:28:38Z","timestamp":1787801318442,"version":"build-2784847793"},"reference-count":22,"publisher":"The Endocrine Society","issue":"10","license":[{"start":{"date-parts":[[2022,8,5]],"date-time":"2022-08-05T00:00:00Z","timestamp":1659657600000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005972","name":"Deutsche Krebshilfe","doi-asserted-by":"publisher","award":["70113526"],"award-info":[{"award-number":["70113526"]}],"id":[{"id":"10.13039\/501100005972","id-type":"DOI","asserted-by":"publisher"}]},{"name":"AMEND"},{"name":"European Reference Network on Rare Endocrine Conditions"},{"DOI":"10.13039\/501100018952","name":"NIHR Birmingham Biomedical Research Centre","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100018952","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013963","name":"University Hospitals Birmingham NHS Foundation Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100013963","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,9,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Context<\/jats:title>\n                  <jats:p>Adrenocortical carcinoma (ACC) is a rare aggressive disease with heterogeneous prognoses. Previous studies identified hypermethylation in the promoter region of specific genes to be associated with poor clinical outcome.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>Comparative analysis of promising hypermethylated genes as prognostic markers and evaluation of their added value to established clinical prognostic tools.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Design<\/jats:title>\n                  <jats:p>We included 237 patients with ACCs. Tumor DNA was isolated from formalin-fixed paraffin-embedded (FFPE) samples. Targeted pyrosequencing was used to detect promoter region methylation in 5 preselected genes (PAX5, GSTP1, PYCARD, PAX6, G0S2). The prognostic role of hypermethylation pattern was compared with the Stage, Grade, Resection status, Age, Symptoms (S-GRAS) score. Primary endpoints were progression-free (PFS) and overall survival (OS), with disease-free (DFS) as secondary endpoint.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>A total of 27.9%, 13.9%, 49%, 49%, and 25.3% of cases showed hypermethylation in PAX5, GSTP1, PYCARD, PAX6, and G0S2, respectively. Hypermethylation in all individual genes\u2014except GSTP1\u2014was significantly associated with both PFS and OS\u2014with hazard ratios (HR) between 1.4 and 2.3. However, only hypermethylation of PAX5 remained significantly associated with OS (P\u2005=\u20050.013; HR\u2005=\u20051.95, 95% CI, 1.2-3.3) in multivariable analysis. A model for risk stratification was developed, combining PAX5 methylation status and S-GRAS groups, showing improved prognostic performance compared to S-GRAS alone (Harrell\u2019s C index: OS\u2005=\u20050.751, PFS\u2005=\u20050.711, DFS\u2005=\u20050.688).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>This study demonstrated that hypermethylation in PAX5 is associated with worst clinical outcome in ACC, even after accounting for S-GRAS score. Assessing methylation in FFPE material is straightforward in the clinical setting and could be used to improve accuracy of prognostic classification, enabling the direction of personalized management.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1210\/clinem\/dgac470","type":"journal-article","created":{"date-parts":[[2022,8,5]],"date-time":"2022-08-05T12:23:57Z","timestamp":1659702237000},"page":"2892-2899","source":"Crossref","is-referenced-by-count":18,"title":["Prognostic Role of Targeted Methylation Analysis in Paraffin-embedded Samples of Adrenocortical Carcinoma"],"prefix":"10.1210","volume":"107","author":[{"given":"Juliane","family":"Lippert","sequence":"first","affiliation":[{"name":"Division of Endocrinology and Diabetes, University Hospital of Wuerzburg , 97080 Wuerzburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Altieri","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Diabetes, University Hospital of Wuerzburg , 97080 Wuerzburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Breanna","family":"Morrison","sequence":"additional","affiliation":[{"name":"Institute of Applied Health Research, University of Birmingham , B152TT Birmingham , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonja","family":"Steinhauer","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Diabetes, University Hospital of Wuerzburg, 97080 Wuerzburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabrielle","family":"Smith","sequence":"additional","affiliation":[{"name":"Institute of Metabolism and System Research, University of Birmingham , B152TT Birmingham , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonia","family":"Lorey","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Diabetes, University Hospital of Wuerzburg , 97080 Wuerzburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna","family":"Urlaub","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Diabetes, University Hospital of Wuerzburg , 97080 Wuerzburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Kircher","sequence":"additional","affiliation":[{"name":"Institute for Pathology, University of Wuerzburg , 97080 Wuerzburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Sitch","sequence":"additional","affiliation":[{"name":"Institute of Applied Health Research, University of Birmingham , B152TT Birmingham , UK"},{"name":"NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust and University of Birmingham, B152TH Birmingham , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6170-6398","authenticated-orcid":false,"given":"Martin","family":"Fassnacht","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Diabetes, University Hospital of Wuerzburg , 97080 Wuerzburg , Germany"},{"name":"Comprehensive Cancer Centre Mainfranken (CCCM), University of Wuerzburg , 97080 Wuerzburg , Germany"},{"name":"Central Labor, University Hospital of Wuerzburg , 97080 Wuerzburg , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5020-2071","authenticated-orcid":false,"given":"Cristina L","family":"Ronchi","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Diabetes, University Hospital of Wuerzburg , 97080 Wuerzburg , Germany"},{"name":"Institute of Metabolism and System Research, University of Birmingham , B152TT Birmingham , UK"},{"name":"Centre for Endocrinology, Diabetes and Metabolism (CEDAM), Birmingham Health Partners, B152TT , Birmingham , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2022,8,4]]},"reference":[{"issue":"2","key":"2022092808394155800_CIT0001","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1002\/cncr.24030","article-title":"Limited prognostic value of the 2004 International Union Against Cancer staging classification for adrenocortical carcinoma: proposal for a Revised TNM Classification","volume":"115","author":"Fassnacht","year":"2009","journal-title":"Cancer."},{"issue":"2","key":"2022092808394155800_CIT0002","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1210\/er.2013-1029","article-title":"Adrenocortical carcinoma","volume":"35","author":"Else","year":"2014","journal-title":"Endocr Rev."},{"issue":"4","key":"2022092808394155800_CIT0003","doi-asserted-by":"crossref","first-page":"G1","DOI":"10.1530\/EJE-18-0608","article-title":"European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors","volume":"179","author":"Fassnacht","year":"2018","journal-title":"Eur J Endocrinol."},{"issue":"10","key":"2022092808394155800_CIT0004","doi-asserted-by":"crossref","first-page":"2119","DOI":"10.1093\/annonc\/mdv329","article-title":"Prognostic factors in stage III-IV adrenocortical carcinomas (ACC): an European Network for the Study of Adrenal Tumor (ENSAT) study","volume":"26","author":"Libe","year":"2015","journal-title":"Ann Oncol."},{"issue":"12","key":"2022092808394155800_CIT0005","doi-asserted-by":"crossref","first-page":"4511","DOI":"10.1210\/jc.2018-01348","article-title":"Targeted molecular analysis in adrenocortical carcinomas: a strategy toward improved personalized prognostication","volume":"103","author":"Lippert","year":"2018","journal-title":"J Clin Endocrinol Metab."},{"issue":"1","key":"2022092808394155800_CIT0006","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1530\/EJE-21-0510","article-title":"S-GRAS score for prognostic classification of adrenocortical carcinoma: an international, multicenter ENSAT study","volume":"186","author":"Elhassan","year":"2021","journal-title":"Eur J Endocrinol."},{"issue":"6","key":"2022092808394155800_CIT0007","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1038\/ng.2953","article-title":"Integrated genomic characterization of adrenocortical carcinoma","volume":"46","author":"Assie","year":"2014","journal-title":"Nat Genet."},{"issue":"2","key":"2022092808394155800_CIT0008","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1016\/j.ccell.2016.07.013","article-title":"Comprehensive pan-genomic characterization of adrenocortical carcinoma","volume":"30","author":"Zheng","year":"2016","journal-title":"Cancer Cell."},{"issue":"3","key":"2022092808394155800_CIT0009","first-page":"923","article-title":"DNA methylation is an independent prognostic marker of survival in adrenocortical cancer","volume":"102","author":"Jouinot","year":"2017","journal-title":"J Clin Endocrinol Metab."},{"issue":"11","key":"2022092808394155800_CIT0010","doi-asserted-by":"crossref","first-page":"3276","DOI":"10.1158\/1078-0432.CCR-18-2693","article-title":"Targeted assessment of G0S2 methylation identifies a rapidly recurrent, routinely fatal molecular subtype of adrenocortical carcinoma","volume":"25","author":"Mohan","year":"2019","journal-title":"Clin Cancer Res."},{"issue":"8","key":"2022092808394155800_CIT0011","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1038\/ncponc0252","article-title":"REporting recommendations for tumor MARKer prognostic studies (REMARK)","volume":"2","author":"McShane","year":"2005","journal-title":"Nat Clin Pract Urol."},{"key":"2022092808394155800_CIT0012","author":"Lippert","year":"2022"},{"issue":"18","key":"2022092808394155800_CIT0013","doi-asserted-by":"crossref","first-page":"2543","DOI":"10.1001\/jama.1982.03320430047030","article-title":"Evaluating the yield of medical tests","volume":"247","author":"Harrell","year":"1982","journal-title":"JAMA."},{"key":"2022092808394155800_CIT0014","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0065-230X(08)60678-8","article-title":"5-methylcytosine, gene regulation, and cancer","volume":"40","author":"Riggs","year":"1983","journal-title":"Adv Cancer Res."},{"issue":"6","key":"2022092808394155800_CIT0015","first-page":"1444","article-title":"Rearrangements at the 11p15 locus and overexpression of insulin-like growth factor-II gene in sporadic adrenocortical tumors","volume":"78","author":"Gicquel","year":"1994","journal-title":"J Clin Endocrinol Metab."},{"issue":"1","key":"2022092808394155800_CIT0016","doi-asserted-by":"crossref","first-page":"E174","DOI":"10.1210\/jc.2012-2993","article-title":"Identification of a CpG island methylator phenotype in adrenocortical carcinomas","volume":"98","author":"Barreau","year":"2013","journal-title":"J Clin Endocrinol Metab."},{"issue":"7","key":"2022092808394155800_CIT0017","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1530\/EC-20-0228","article-title":"Intratumor heterogeneity of prognostic DNA-based molecular markers in adrenocortical carcinoma","volume":"9","author":"Jouinot","year":"2020","journal-title":"Endocr Connect."},{"issue":"10","key":"2022092808394155800_CIT0018","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1038\/nrg.2016.93","article-title":"Targeting the cancer epigenome for therapy","volume":"17","author":"Jones","year":"2016","journal-title":"Nat Rev Genet."},{"issue":"2","key":"2022092808394155800_CIT0019","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1038\/s41571-019-0267-4","article-title":"Combining epigenetic drugs with other therapies for solid tumours - past lessons and future promise","volume":"17","author":"Morel","year":"2020","journal-title":"Nat Rev Clin Oncol."},{"issue":"7","key":"2022092808394155800_CIT0020","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.1200\/JCO.2008.18.5678","article-title":"Gene expression profiling reveals a new classification of adrenocortical tumors and identifies molecular predictors of malignancy and survival","volume":"27","author":"de Reynies","year":"2009","journal-title":"J Clin Oncol."},{"issue":"1","key":"2022092808394155800_CIT0021","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1530\/EJE-11-0806","article-title":"Combined expression of BUB1B, DLGAP5, and PINK1 as predictors of poor outcome in adrenocortical tumors: validation in a Brazilian cohort of adult and pediatric patients","volume":"166","author":"Fragoso","year":"2012","journal-title":"Eur J Endocrinol."},{"issue":"3","key":"2022092808394155800_CIT0022","doi-asserted-by":"crossref","first-page":"E493","DOI":"10.1210\/jc.2014-3282","article-title":"Whole-exome sequencing characterizes the landscape of somatic mutations and copy number alterations in adrenocortical carcinoma","volume":"100","author":"Juhlin","year":"2015","journal-title":"J Clin Endocrinol Metab."}],"container-title":["The Journal of Clinical Endocrinology &amp; Metabolism"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jcem\/advance-article-pdf\/doi\/10.1210\/clinem\/dgac470\/45564006\/dgac470.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jcem\/article-pdf\/107\/10\/2892\/46112343\/dgac470.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jcem\/article-pdf\/107\/10\/2892\/46112343\/dgac470.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,9,28]],"date-time":"2022-09-28T08:43:13Z","timestamp":1664354593000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jcem\/article\/107\/10\/2892\/6655871"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,4]]},"references-count":22,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2022,8,4]]},"published-print":{"date-parts":[[2022,9,28]]}},"URL":"https:\/\/doi.org\/10.1210\/clinem\/dgac470","relation":{},"ISSN":["0021-972X","1945-7197"],"issn-type":[{"value":"0021-972X","type":"print"},{"value":"1945-7197","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,10,1]]},"published":{"date-parts":[[2022,8,4]]}}}