Abstract
BackgroundAdrenocortical carcinoma (ACC) is a rare, often-aggressive neoplasm of the adrenal cortex, with a 14–17 month median overall survival. 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.MethodsWe 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.ResultsCopy 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 > T, C > A and T > C transitions. Only cancer genes TP53 (26%) and beta-catenin (CTNNB1, 14%) were mutated in more than 10% of samples. The TCGA-identified putative cancer genes MEN1 and PRKAR1A were found in low frequency—4.7 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.ConclusionsWe conclude that the mutational and expression profiles of advanced and metastatic tumors are very similar to those from newly diagnosed patients—with 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.
Highlights
Adrenocortical carcinoma (ACC) is a rare, often-aggressive neoplasm of the adrenal cortex, with a 14–17 month median overall survival
We report a cohort of patients with advanced/metastatic adrenocortical cancer (ACC) whose tumors have undergone genomic and expression analyses
Aggregating ATRX, SETD2, the mismatch repair and homologous recombination genes, and other genes involved in DNA repair, but excluding TP53, we find 36 mutations in samples obtained from 21 (49%) of the 43 patients suggesting impaired DNA repair may be an important theme in these aggressive ACCs an observation that could explain the higher incidence of mutations
Summary
Adrenocortical carcinoma (ACC) is a rare, often-aggressive neoplasm of the adrenal cortex, with a 14–17 month median overall survival. Adrenocortical carcinoma (ACC) is a rare, often aggressive, and frequently fatal neoplasm of the adrenal cortex. Multiple strategies have been utilized to identify prognostic factors, including clinical, transcriptomic, epigenomic, and genomic. A staging system by the European Network for the Study of Adrenal Tumors (ENS@T) based on a retrospective analysis of data from 416 patients in the German ACC registry utilizes clinical data [5]. One study that examined 203 ACC tumors in a validation cohort concluded that CpG island methylation analysis was an independent prognostic marker of survival in ACC, “independent of the best established prognostic factors, including tumor stage and Ki67” [11]
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