Next-generation sequencing of adrenocortical carcinoma reveals new routes to targeted therapies.
Bottom Line: At least one GA was found in 22 (76%) ACC (mean 2.6 alterations per ACC).The most frequent GAs were in TP53 (34%), NF1 (14%), CDKN2A (14%), MEN1 (14%), CTNNB1 (10%) and ATM (10%).APC, CCND2, CDK4, DAXX, DNMT3A, KDM5C, LRP1B, MSH2 and RB1 were each altered in two cases (7%) and EGFR, ERBB4, KRAS, MDM2, NRAS, PDGFRB, PIK3CA, PTEN and PTCH1 were each altered in a single case (3%).
Affiliation: Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA Foundation Medicine, Inc., Cambridge, Massachusetts, USA.Show MeSH
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Mentions: For example in Case 13, a pleomorphic ACC derived from a 48-year-old man that had metastasized to the liver, amplifications of CDK4 and MDM2 were identified (figure 2). CDK4 encodes cyclin-dependent kinase 4, which, along with functional homologue CDK6 and family member CDK2, regulates cell cycle G1 phase progression and the G1/S transition.30 Amplification of CDK4 has been identified in multiple cancer types and in a small number of adrenal carcinomas.31 A number of drugs that target CDK4 are under investigation in phase I clinical trials.32 Similarly, therapies targeting MDM2 are under study in clinical trials.33 In another case (Case 7), a locally advanced oncocytic ACC derived from a 60-year-old man, a single alteration was identified, amplification of PDGFRB (figure 3). GAs, including amplification of PDGFRB, have not been reported in ACC in the literature until now. PDGFRB amplification has been associated with PDGFRB protein overexpression and increased kinase activity in a variety of other tumours.34 Although there are no PDGFRB inhibitors currently approved for use in ACC, several drugs that inhibit PDGFRB, including dasatinib, imatinib, sorafenib and sunitinib, have been food and drug administration (FDA) approved for use in other tumour types. Although an initial study indicated significant efficacy of sorafenib in the treatment of metastatic ACC, more recent phase II trial was unable to duplicate that result.3536 The vascular endothelial growth factor (VEGF) inhibitor axitinib has also shown limited impact on the outcome of this disease.37
Affiliation: Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA Foundation Medicine, Inc., Cambridge, Massachusetts, USA.