Integrated genomic characterization of adrenocortical carcinoma

Abstract

Adrenocortical carcinomas (ACCs) are aggressive cancers originating in the cortex of the adrenal gland. Despite overall poor prognosis, ACC outcome is heterogeneous. We performed exome sequencing and SNP array analysis of 45 ACCs and identified recurrent alterations in known driver genes (CTNNB1, TP53, CDKN2A, RB1 and MEN1) and in genes not previously reported in ACC (ZNRF3, DAXX, TERT and MED12), which we validated in an independent cohort of 77 ACCs. ZNRF3, encoding a cell surface E3 ubiquitin ligase, was the most frequently altered gene (21%) and is a potential new tumor suppressor gene related to the β-catenin pathway. Our integrated genomic analyses further identified two distinct molecular subgroups with opposite outcome. The C1A group of ACCs with poor outcome displayed numerous mutations and DNA methylation alterations, whereas the C1B group of ACCs with good prognosis displayed specific deregulation of two microRNA clusters. Thus, aggressive and indolent ACCs correspond to two distinct molecular entities driven by different oncogenic alterations.

Nuclear β-Catenin Expression is Frequent in Sinonasal Hemangiopericytoma and Its Mimics

“…CTNNB1 alterations in sinonasal HPC have been consistently reported in exon 3, with missense mutations [4,5]; mutations affecting positions 32-45 of the amino-terminal region disrupt phosphorylation-dependent degradation of b-catenin [6]. Numerous other tumor types harbor CTNNB1 mutations, most frequently desmoid-type fibromatosis [7,8] as well as salivary basal cell adenoma [9], pilomatricoma and pilomatrix carcinoma [10], hepatocellular carcinoma [11], colorectal carcinoma [12], medulloblastoma [13], endometrial adenocarcinoma [14], Wilms tumor [15], and adrenocortical carcinoma [16]. Sinonasal HPC shares the features of a uniform spindle and ovoid cell population and HPC-like vessels with SFT, Fig.…”

Immunohistochemical Validation of Overexpressed Genes Identified by Global Expression Microarrays in Adrenocortical Carcinoma Reveals Potential Predictive and Prognostic Biomarkers

“…These have paved the way for further studies attempting to correlate these profiles with clinical outcomes [17,35,36]. Notably, more recent integrated genomic analyses involving exome sequencing, DNA methylation analysis, mRNA expression arrays, and miRNA sequencing have suggested that aggressive and indolent ACCs belong to two distinct molecular entities, each spearheaded by separate oncogenic mutations [16]. Despite these advances in knowledge of the underlying molecular pathology of ACCs, there has been a paucity of data on immunohistologically validated markers.…”

Chronic lymphocytic leukemia: Time to go past genomics?

“…Missense mutations of MED12 are associated with X-linked genetic syndromes [103][104][105]. Somatic mutations have been described in many solid tumors, including, hormone-associated cancers (prostate and adrenocortical carcinoma) [106,107], breast [108], uterine tumors [109]. The mutations are essentially missense mutations but fall in different parts of the protein, depending on the tumors.…”