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Two distinct classes of thymic tumors in patients with MEN1 show LOH at the MEN1 locus.
Endocrine-Related Cancer ( IF 3.9 ) Pub Date : 2021-10-04 , DOI: 10.1530/erc-21-0226 Adel Mandl 1 , James M Welch 1 , Gayathri Kapoor 1 , Vaishali I Parekh 1 , David S Schrump 2 , R Taylor Ripley 3 , Mary F Walter 4 , Jaydira Del Rivero 2 , Smita Jha 1 , William F Simonds 1 , Robert T Jensen 5 , Lee S Weinstein 1 , Jenny E Blau 1 , Sunita K Agarwal 1
Endocrine-Related Cancer ( IF 3.9 ) Pub Date : 2021-10-04 , DOI: 10.1530/erc-21-0226 Adel Mandl 1 , James M Welch 1 , Gayathri Kapoor 1 , Vaishali I Parekh 1 , David S Schrump 2 , R Taylor Ripley 3 , Mary F Walter 4 , Jaydira Del Rivero 2 , Smita Jha 1 , William F Simonds 1 , Robert T Jensen 5 , Lee S Weinstein 1 , Jenny E Blau 1 , Sunita K Agarwal 1
Affiliation
Patients with the multiple endocrine neoplasia type 1 (MEN1) syndrome carry germline heterozygous loss-of-function mutations in the MEN1 gene which predisposes them to develop various endocrine and non-endocrine tumors. Over 90% of the tumors show loss of heterozygosity (LOH) at chromosome 11q13, the MEN1 locus, due to somatic loss of the wild-type MEN1 allele. Thymic neuroendocrine tumors (NETs) or thymic carcinoids are uncommon in MEN1 patients but are a major cause of mortality. LOH at the MEN1 locus has not been demonstrated in thymic tumors. The goal of this study was to investigate the molecular aspects of MEN1-associated thymic tumors including LOH at the MEN1 locus and RNA-sequencing (RNA-Seq) to identify genes associated with tumor development and potential targeted therapy. A retrospective chart review of 294 patients with MEN1 germline mutations identified 14 patients (4.8%) with thymic tumors (12 thymic NETs and 2 thymomas). LOH at the MEN1 locus was identified in 10 tumors including the 2 thymomas, demonstrating that somatic LOH at the MEN1 locus is also the mechanism for thymic tumor development. Unsupervised principal component analysis and hierarchical clustering of RNA-Seq data showed that thymic NETs formed a homogenous transcriptomic group separate from thymoma and normal thymus. KSR2 (kinase suppressor of Ras 2), that promotes Ras-mediated signaling, was abundantly expressed in thymic NETs, a potential therapeutic target. The molecular insights gained from our study about thymic tumors combined with similar data from other MEN1-associated tumors may lead to better surveillance and treatment of these rare tumors.
中文翻译:
MEN1 患者的两种不同类型的胸腺肿瘤在 MEN1 基因座处显示 LOH。
患有多发性内分泌肿瘤 1 型 (MEN1) 综合征的患者在 MEN1 基因中携带种系杂合功能丧失突变,这使他们易患各种内分泌和非内分泌肿瘤。由于野生型 MEN1 等位基因的体细胞丢失,超过 90% 的肿瘤在染色体 11q13(MEN1 基因座)处显示杂合性 (LOH) 丢失。胸腺神经内分泌肿瘤 (NETs) 或胸腺类癌在 MEN1 患者中并不常见,但却是导致死亡的主要原因。MEN1 基因座的 LOH 尚未在胸腺肿瘤中得到证实。本研究的目的是研究 MEN1 相关胸腺肿瘤的分子方面,包括 MEN1 基因座的 LOH 和 RNA 测序 (RNA-Seq),以确定与肿瘤发展和潜在靶向治疗相关的基因。对 294 名 MEN1 种系突变患者的回顾性图表回顾确定了 14 名患者(4.8%)患有胸腺肿瘤(12 名胸腺 NETs 和 2 名胸腺瘤)。在包括 2 个胸腺瘤在内的 10 个肿瘤中鉴定了 MEN1 基因座的 LOH,证明 MEN1 基因座的体细胞 LOH 也是胸腺肿瘤发展的机制。无监督的主成分分析和 RNA-Seq 数据的层次聚类表明,胸腺 NETs 形成了一个与胸腺瘤和正常胸腺分开的同质转录组。促进 Ras 介导的信号传导的 KSR2(Ras 2 激酶抑制因子)在潜在治疗靶点胸腺 NET 中大量表达。
更新日期:2021-09-01
中文翻译:
MEN1 患者的两种不同类型的胸腺肿瘤在 MEN1 基因座处显示 LOH。
患有多发性内分泌肿瘤 1 型 (MEN1) 综合征的患者在 MEN1 基因中携带种系杂合功能丧失突变,这使他们易患各种内分泌和非内分泌肿瘤。由于野生型 MEN1 等位基因的体细胞丢失,超过 90% 的肿瘤在染色体 11q13(MEN1 基因座)处显示杂合性 (LOH) 丢失。胸腺神经内分泌肿瘤 (NETs) 或胸腺类癌在 MEN1 患者中并不常见,但却是导致死亡的主要原因。MEN1 基因座的 LOH 尚未在胸腺肿瘤中得到证实。本研究的目的是研究 MEN1 相关胸腺肿瘤的分子方面,包括 MEN1 基因座的 LOH 和 RNA 测序 (RNA-Seq),以确定与肿瘤发展和潜在靶向治疗相关的基因。对 294 名 MEN1 种系突变患者的回顾性图表回顾确定了 14 名患者(4.8%)患有胸腺肿瘤(12 名胸腺 NETs 和 2 名胸腺瘤)。在包括 2 个胸腺瘤在内的 10 个肿瘤中鉴定了 MEN1 基因座的 LOH,证明 MEN1 基因座的体细胞 LOH 也是胸腺肿瘤发展的机制。无监督的主成分分析和 RNA-Seq 数据的层次聚类表明,胸腺 NETs 形成了一个与胸腺瘤和正常胸腺分开的同质转录组。促进 Ras 介导的信号传导的 KSR2(Ras 2 激酶抑制因子)在潜在治疗靶点胸腺 NET 中大量表达。