PhD, Translational Research Laboratory and Biobank, Institut Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif Cedex, France.
J Clin Endocrinol Metab. 2013 Oct;98(10):4080-8. doi: 10.1210/jc.2013-2165. Epub 2013 Aug 26.
Adrenocortical cancer (ACC) is a rare cancer with poor prognosis and scant treatment options. In ACC, no personalized approach has emerged but no extensive molecular screening has been performed to date.
The objective of the study was to evaluate the presence of a large number of potentially targetable molecular events in a large cohort of advanced ACC.
DESIGN, SETTING, AND PARTICIPANTS: We used hot spot gene sequencing (Ion Torrent, 40 patients) and comparative genomic hybridization (CGH; 28 patients; a subset of the entire cohort) in adult stage III-IV ACC samples to screen for mutations and copy number abnormalities of potential interest for therapeutic use in 46 and 130 genes, respectively.
At least one copy number alteration or mutation was found in 19 patients (47.5%). The most frequent mutations were detected on TP53, ATM, and CTNNB1 [6 of 40 (15%), 5 of 40 (12.5%), and 4 of 40 (10%), respectively]. The most frequent copy number alterations identified were: amplification of the CDK4 oncogene (5 of 28; 17.9%) and deletion of the CDKN2A (4 of 28; 14.3%) and CDKN2B (3 of 28; 10.7%) tumor suppressor genes. Amplifications of FGFR1, FGF9, or FRS2 were discovered in three subjects (10.7%). Associated alterations were: deletions of CDKN2A, CDKN2B with ATM mutations, and TP53 mutations with CTNNB1 mutations.
No simple targetable molecular event emerged. Drugs targeting the cell cycle could be the most relevant new therapeutic approach for patients with advanced ACC. Inhibitors of the fibroblast growth factor receptor pathway could also be a therapeutic option in a subset of patients, whereas other targeted therapies should be considered on a case-by-case basis.
肾上腺皮质癌（ACC）是一种预后不良且治疗选择有限的罕见癌症。在 ACC 中，尚未出现个性化治疗方法，但迄今为止尚未进行广泛的分子筛选。
本研究旨在评估大量晚期 ACC 患者中存在的大量潜在靶向分子事件。
设计、地点和参与者：我们使用热点基因测序（Ion Torrent，40 例患者）和比较基因组杂交（CGH；28 例患者；整个队列的一个子集），分别筛选 46 个和 130 个基因中与治疗相关的潜在靶点的基因突变和拷贝数异常。
在 19 名患者（47.5%）中发现至少存在一个拷贝数改变或突变。最常见的突变发生在 TP53、ATM 和 CTNNB1 上[分别为 6 例（15%）、5 例（12.5%）和 4 例（10%）]。最常见的拷贝数改变包括：CDK4 癌基因扩增（28 例中有 5 例；17.9%）和 CDKN2A（28 例中有 4 例；14.3%）和 CDKN2B（28 例中有 3 例；10.7%）肿瘤抑制基因缺失。在 3 名患者（10.7%）中发现 FGFR1、FGF9 或 FRS2 的扩增。相关改变包括：CDKN2A、CDKN2B 的缺失与 ATM 突变，以及 TP53 突变与 CTNNB1 突变。
未发现简单的可靶向分子事件。针对细胞周期的药物可能是晚期 ACC 患者最相关的新治疗方法。成纤维细胞生长因子受体通路抑制剂也可能成为一部分患者的治疗选择，而其他靶向治疗则应根据具体情况考虑。
