Transcriptomes define distinct subgroups of salivary gland adenoid cystic carcinoma with different driver mutations and outcomes.
Transcriptomes define distinct subgroups of salivary gland adenoid cystic carcinoma with different driver mutations and outcomes.
复制标题
DOI：
10.18632/oncotarget.23641
复制
发表时间：
2018-01-26
期刊：
影响因子：
--
通讯作者：
Ness SA
中科院分区：
文献类型：
--
作者：
Frerich CA;Brayer KJ;Painter BM;Kang H;Mitani Y;El-Naggar AK;Ness SA
涎腺腺样囊性癌（ACC）的相对罕见性及其生长缓慢但具有侵袭性的性质使患者分层的分子标记物的发展变得复杂。为了分析与ACC的长期病程和诊断后5年或更长时间形成的转移有关的分子差异，对68个ACC肿瘤样本进行了详细的RNA测序（RNA-seq）分析，从存档的福尔马林固定石蜡包埋（FFPE）样本开始，直到25岁，以便获得临床结果。使用统计学峰值发现方法将表达MYB或MYBL 1的肿瘤（具有重叠的基因表达特征）与既不表达癌基因又显示独特表型的组进行分类。MYB或MYBL 1的表达与SOX 4和EN 1基因的表达密切相关，表明它们是ACC肿瘤中Myb蛋白的直接靶点。无监督分层聚类确定了一个亚组，约20%的患者总体生存率极差（中位数低于30个月），并且具有类似胚胎干细胞的独特基因表达特征。结果提供了一种策略，用于对ACC患者进行分层，并确定作为个性化治疗候选者的高风险，不良结局组。
The relative rarity of salivary gland adenoid cystic carcinoma (ACC) and its slow growing yet aggressive nature has complicated the development of molecular markers for patient stratification. To analyze molecular differences linked to the protracted disease course of ACC and metastases that form 5 or more years after diagnosis, detailed RNA-sequencing (RNA-seq) analysis was performed on 68 ACC tumor samples, starting with archived, formalin-fixed paraffin-embedded (FFPE) samples up to 25 years old, so that clinical outcomes were available. A statistical peak-finding approach was used to classify the tumors that expressed MYB or MYBL1, which had overlapping gene expression signatures, from a group that expressed neither oncogene and displayed a unique phenotype. Expression of MYB or MYBL1 was closely correlated to the expression of the SOX4 and EN1 genes, suggesting that they are direct targets of Myb proteins in ACC tumors. Unsupervised hierarchical clustering identified a subgroup of approximately 20% of patients with exceptionally poor overall survival (median less than 30 months) and a unique gene expression signature resembling embryonic stem cells. The results provide a strategy for stratifying ACC patients and identifying the high-risk, poor-outcome group that are candidates for personalized therapies.