Abstract 2976: Comprehensive Pan-Genomic characterization of adrenocortical carcinoma

Abstract

Adrenocortical carcinoma (ACC) is a rare neoplasm with a heterogeneous outcome and limited treatment options. To understand its molecular and genomic landscape as a part of The Cancer Genome Atlas (TCGA) project, we performed the genomic, transcriptomic, epigenomic and proteomic profiling of 91 ACCs. We identified potential driving alterations including amplifications (TERT, TERF2 and CDK4), deletions (ZNRF3, CDKN2A and RB1) and point mutations in genes unknown to participate in adrenal disease (RPL22) and genes known to initiate familial syndromes that occasionally include adrenocortical neoplasms (TP53, CTNNB1, PRKAR1A, MEN1). The finding of PRKAR1A expands the catalogue of pathogenic pathways underlying ACC, suggesting of the protein kinase alpha signaling pathway as a potential target for molecular interventions. Novel transcript fusions potentially leading to overactive kinases included EXOSC10-MTOR and PPP1CB-BRE. DNA copy number analysis unveiled prevalent DNA losses leading to hypodiploidy as well as whole genome doubling (WGD) in 51% of ACC. The similar penetrance of loss of heterozygosity before and after WGD suggests a sequential development from hypodiploidy to polyploidy along the doubling in a subset of ACCs, which was endorsed by the worse outcome for WGD samples relative to nonWGD ACCs. An association between TERT expression and WGD was observed, suggesting a role for telomere regulation. These findings present ACC as a model disease for studies of WGD which is a frequent event in many tumor types. Unsupervised clustering of DNA methylation, copy number, gene expression, miRNA expression and protein abundance converged into three classes with specific biological characteristics and a respective median event free survival of 8, 38 and >100 months (p-value 1.7e-13). Comparison of the subtypes suggested additional drivers such as protein kinase C (PKC) phosphorylation and upregulation of a miRNA cluster at chromosome Xq27.3, which complemented the genomic alterations identified in these subtypes. To gain more insights into this rare cancer type, we placed ACC in a broader context of cancer genomic profiles including an array of other cancer types. These analyses revealed interesting shared features, including beta-catenin activation with a subset of endometroid cancer, DNA mismatch repair gene mutational signature with gastrointestinal cancers and a smoking signature with lung cancer. These findings highlight the commonalities between ACC and other lineages of cancer. Taken together, we found Wnt signaling pathway and p53/Rb signaling pathway were the most frequently altered pathways in ACC. Meanwhile, new players surfaced from our analyses including the PKA and PKC pathways. Our results present a comprehensive genomic landscape and refined molecular classification of ACC improve our understanding of its pathogenesis, and will ultimately improve the care of patients. Citation Format: 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, Gordon A. Robertson, Matthew Meyerson, Michael J. Demeure, Felix Beuschlein, Anthony Gill, Ana C. Latronico, Maria C. Fragosa, Leslie Cope, Electron Kebebew, Mouhammed A. Habra, Timothy G. Whitsett, Kimberly J. Bussey, William E. Rainey, Sylvia Asa, Jérôme Bertherat, Martin Fassnacht, David A. Wheeler, The Cancer Genome Atlas Research Network, Gary D. Hammer, Thomas J. Giordano, Roel Verhaak. Comprehensive Pan-Genomic characterization of adrenocortical carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2976. doi:10.1158/1538-7445.AM2015-2976

Mouse models of adrenocortical tumors

“…Moreover, with specific regard to ACC, these results also suggest that release from p53-sensitive checkpoints is a critical step in the process of adrenal tumorigenesis. Recent genomic profiling of human tumors further supports this notion and has found recurrent mutations in several known cell cycle regulators, including CDKN2A , CDK4 , RB1 , and CCNE1 (Zheng et al, 2015). …”

“…Since some CC-associated tumors exhibit LOH of the locus, PRKAR1A is thought to be a tumor-suppressor gene. More recently, somatic inactivating mutations of PRKAR1A have also been identified in ACTs (Espiard et al, 2014, Zheng et al, 2015). …”

MicroRNA Expression Profiling in Adrenal Myelolipoma

“…Several studies have shown that miRNAs can be useful biomarkers in different diseases, including various neoplasms. Recent studies, including ours, have reported significant differences in tissue and circulating miRNA expression of patients with ACA and ACC (13)(14)(15)(16)(17). To our knowledge, the miRNA expression profile of adrenal myelolipoma has not been investigated.…”

Preclinical progress and first translational steps for a liposomal chemotherapy protocol against adrenocortical carcinoma

“…In recent years, genetic and molecular profiling of surgical tumor specimens has led to the identification of novel biomarkers with prognostic relevance for patients with adrenocortical carcinoma (ACC) (Assie et al 2014). However, the complex interplay of underlying pathways that relate to treatment response remains largely unknown (Zheng et al 2016). Accordingly, targeted therapies in the treatment of ACC patients have shown limited efficacy, and clinical management is mainly restricted to common cytotoxic agents , Kroiss et al 2012, Fassnacht et al 2015.…”