Metastatic and recurrent adrenocortical cancer is not defined by its genomic landscape
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RESEARCH ARTICLE
Open Access
Metastatic and recurrent adrenocortical cancer is not defined by its genomic landscape Tito Fojo1,2, Lyn Huff3, Thomas Litman4, Kate Im5, Maureen Edgerly6, Jaydira del Rivero7, Stefania Pittaluga8, Maria Merino8, Susan E. Bates1,2* and Michael Dean5
Abstract Background: Adrenocortical 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. Methods: 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. Results: 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 > 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. Conclusions: We 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. Keywords: Adrenocortical cancer, Genomic landscape, Endocrine cancer, Adrenal cancer, Driver mutation Background Adrenocortical carcinoma (ACC) is a rare, often aggressive, and frequently fatal neoplasm of the adrenal cortex. A report describing trends in ACC in the United States found an age adjusted annual incidence of ~ 1/1,000,000 population with the incidence largely unchanged since *Correspondence: [email protected] 1 Columbia University Irving Medical Center, New York, NY 10032, USA Full list of author information is available at the end of the article
the mid 1970′s [1]. The median age was 5
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