{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T06:51:23Z","timestamp":1784616683010,"version":"3.55.0"},"reference-count":52,"publisher":"Oxford University Press (OUP)","issue":"22","license":[{"start":{"date-parts":[[2020,11,15]],"date-time":"2020-11-15T00:00:00Z","timestamp":1605398400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"VeloSano Pilot Program"},{"name":"Ambrose Monell Foundation Cancer Genomic Medicine Fellow"},{"name":"Cleveland Clinic Genomic Medicine Institute"},{"name":"Cleveland Clinic and an American Cancer Society Clinical Research Professor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,1,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Adrenocortical Carcinoma (ACC) is a rare endocrine tumor with poor overall prognosis and 1.5-fold overrepresentation in females. In children, ACC is associated with inherited cancer syndromes with 50\u201380% of childhood-ACC associated with TP53 germline variants. ACC in adolescents and young adults (AYA) is rarely due to germline TP53, IGF2, PRKAR1A and MEN1 variants. We analyzed exome sequencing data from 21 children (&amp;lt;15y), 32 AYA (15-39y), and 60 adults (&amp;gt;39y) with ACC, and retained all pathogenic, likely pathogenic, and highly prioritized variants of uncertain significance. We engineered a stable lentiviral-mutant ACC cell line, harboring an EGFR variant (p.Asp1080Asn) from a 21-year-old female without germline-TP53-variant and with aggressive ACC. We found that 4.8% of the children (P = 0.004) and 6.2% of AYA (P &amp;lt;\u20090.0001), all-female participants, harbored germline EGFR variants, compared to only 0.3% of the control group. Expanding our analysis to the RTK-RAS-MAPK pathway, we found that the RTK genes have the highest number of highly prioritized germline variants in these individuals amongst all three arms of this pathway. We showed EGFR mutant cells migrate faster and are characterized by a stem-like phenotype compared to wild type cells. While EGFR inhibitors did not affect the stemness of mutant cells, Sunitinib, a multireceptor tyrosine kinase inhibitor, significantly reduced their stem-like behavior. Our data suggest that EGFR could be a novel underlying germline predisposition factor for ACC, especially in the Childhood-AYA (C-AYA) population. Further clinical validation can improve precision oncology management of this disease, which is known to have limited therapeutic options.<\/jats:p>","DOI":"10.1093\/hmg\/ddaa268","type":"journal-article","created":{"date-parts":[[2020,12,10]],"date-time":"2020-12-10T21:22:19Z","timestamp":1607635339000},"page":"3679-3690","source":"Crossref","is-referenced-by-count":9,"title":["Germline <i>EGFR<\/i> variants are over-represented in adolescents and young adults (AYA) with adrenocortical carcinoma"],"prefix":"10.1093","volume":"29","author":[{"given":"Sara","family":"Akhavanfard","sequence":"first","affiliation":[{"name":"Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA"},{"name":"Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lamis","family":"Yehia","sequence":"additional","affiliation":[{"name":"Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roshan","family":"Padmanabhan","sequence":"additional","affiliation":[{"name":"Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordan P","family":"Reynolds","sequence":"additional","affiliation":[{"name":"Department of Pathology, Cleveland Clinic, Cleveland, OH 44195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Ni","sequence":"additional","affiliation":[{"name":"Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA"},{"name":"Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH 44195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charis","family":"Eng","sequence":"additional","affiliation":[{"name":"Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA"},{"name":"Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA"},{"name":"Center for Personalized Genetic Healthcare, Cleveland Clinic Community Care and Population Health, Cleveland, OH 44195, USA"},{"name":"Germline High-Risk Cancer Focus Group, Cancer Prevention, Control & Population Research Program, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA"},{"name":"Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,12,16]]},"reference":[{"key":"2021012301294940200_ref1","doi-asserted-by":"crossref","first-page":"3130","DOI":"10.1002\/cncr.23886","article-title":"Adrenocortical carcinoma in the United States: treatment utilization and prognostic factors","volume":"113","author":"Bilimoria","year":"2008","journal-title":"Cancer"},{"key":"2021012301294940200_ref2","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. 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