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We asked whether tumors from patients with advanced or metastatic ACC would offer clues as to putative genes that might have critical roles in disease progression or in more aggressive disease biology.\n<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Methods<\/jats:title>\n<jats:p>We conducted comprehensive genomic and expression analyses of ACCs from 43 patients, 30 female, and 42 from metastatic sites, including deep sequencing, copy number analysis, mRNA expression and microRNA arrays.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Results<\/jats:title>\n<jats:p>Copy number gains and losses were similar to that previously reported for ACC. We identified a median mutation rate of 3.38 per megabase (Mb). The mutational signature was characterized by a predominance of C\u2009&gt;\u2009T, C\u2009&gt;\u2009A and T\u2009&gt;\u2009C transitions. Only cancer genes <jats:italic>TP53<\/jats:italic> (26%) and beta-catenin (<jats:italic>CTNNB1<\/jats:italic>, 14%) were mutated in more than 10% of samples. The TCGA-identified putative cancer genes <jats:italic>MEN1<\/jats:italic> and <jats:italic>PRKAR1A<\/jats:italic> were found in low frequency\u20144.7 and 2.3%, respectively. The majority of the mutations were in genes not implicated in the etiology or maintenance of cancer. Specifically, amongst the 38 genes that were mutated in more than 9% of samples, only four were represented in Tier 1 of the 576 COSMIC Cancer Gene Census (CCGC). Thus, 82% of genes found to have mutations likely have no role in the etiology or biology of ACC; while the role of the other 18%, if any, remains to be proven. Finally, the transcript length for the 38 most frequently mutated genes in ACC is statistically longer than the average of all coding genes, raising the question of whether transcript length in part determined mutation probability.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Conclusions<\/jats:title>\n<jats:p>We conclude that the mutational and expression profiles of advanced and metastatic tumors are very similar to those from newly diagnosed patients\u2014with very little in the way of genomic aberration to explain differences in biology. With relatively low mutation rates, few major oncogenic drivers, and loss of function mutations in several epigenetic regulators, an epigenetic basis for ACC may be postulated and serve as the basis for future studies.<\/jats:p>\n<\/jats:sec>","DOI":"10.1186\/s12920-020-00809-7","type":"journal-article","created":{"date-parts":[[2020,11,4]],"date-time":"2020-11-04T09:08:39Z","timestamp":1604480919000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Metastatic and recurrent adrenocortical cancer is not defined by its genomic landscape"],"prefix":"10.1186","volume":"13","author":[{"given":"Tito","family":"Fojo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lyn","family":"Huff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Litman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kate","family":"Im","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maureen","family":"Edgerly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaydira","family":"del Rivero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Pittaluga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Merino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6708-0330","authenticated-orcid":false,"given":"Susan E.","family":"Bates","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Dean","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,11,4]]},"reference":[{"key":"809_CR1","doi-asserted-by":"publisher","first-page":"636","DOI":"10.14740\/jocmr3503w","volume":"10","author":"E Sharma","year":"2018","unstructured":"Sharma E, Dahal S, Sharma P, Bhandari A, Gupta V, Amgai B, et al. 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All patients were enrolled on IRB-approved protocols and provided written informed consent to allow their tumor to be analyzed. Additionally, all patients who had germline testing were enrolled on a separate IRB-approved protocol and provided written informed consent for this analysis. No administrative permissions and\/or licenses were required to access the clinical\/personal patient data used in this study.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable\u2014no individually identifiable information included.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests. None of the authors havefinancial or non-financial competing interests with this work.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"165"}}