Lan Xiaolei, Gao Hua, Wang Fei, Feng Jie, Bai Jiwei, Zhao Peng, Cao Lei, Gui Songbai, Gong Lei, Zhang Yazhuo
Key Laboratory of Central Nervous System Injury Research, Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, P.R. China; Department of Neurosurgery, The Affiliated Hospital of Medical College, Qingdao University, Qingdao, Shandong 266071, P.R. China.
Key Laboratory of Central Nervous System Injury Research, Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, P.R. China.
Oncol Lett. 2016 Oct;12(4):2319-2328. doi: 10.3892/ol.2016.5029. Epub 2016 Aug 16.
Pituitary adenomas exhibit a wide range of behaviors. The prediction of invasion or malignant behavior in pituitary adenomas remains challenging. The objective of the present study was to identify the genetic abnormalities associated with invasion in sporadic pituitary adenomas. In the present study, the exomes of six invasive pituitary adenomas (IPA) and six non-invasive pituitary adenomas (nIPA) were sequenced by whole-exome sequencing. Variants were confirmed by dideoxynucleotide sequencing, and candidate driver genes were assessed in an additional 28 pituitary adenomas. A total of 15 identified variants were mainly associated with angiogenesis, metabolism, cell cycle phase, cellular component organization, cytoskeleton and biogenesis immune at a cellular level, including 13 variants that occurred as single nucleotide variants and 2 that comprised of insertions. The messenger RNA (mRNA) levels of diffuse panbronchiolitis critical region 1 (DPCR1), KIAA0226, myxovirus (influenza virus) resistance, proline-rich protein BstNI subfamily 3, PR domain containing 2, with ZNF domain, RIZ1 (PRDM2), PR domain containing 8 (PRDM8), SPANX family member N2 (SPANXN2), TRIO and F-actin binding protein and zinc finger protein 717 in IPA specimens were 50% decreased compared with nIPA specimens. In particular, DPCR1, PRDM2, PRDM8 and SPANXN2 mRNA levels in IPA specimens were approximately four-fold lower compared with nIPA specimens (P=0.003, 0.007, 0.009 and 0.004, respectively). By contrast, the mRNA levels of dentin sialophospho protein, EGF like domain, multiple 7 (EGFL7), low density lipoprotein receptor-related protein 1B and dynein, axonemal, assembly factor 1 (LRRC50) were increased in IPA compared with nIPA specimens (P=0.041, 0.037, 0.022 and 0.013, respectively). Furthermore, decreased PRDM2 expression was associated with tumor recurrence. The findings of the present study indicate that DPCR1, EGFL7, the PRDM family and LRRC50 in pituitary adenomas are modifiers of tumorigenesis, and most likely contribute to the development of oncocytic change and to the invasive tumor phenotype.
垂体腺瘤表现出广泛的行为特征。预测垂体腺瘤的侵袭性或恶性行为仍然具有挑战性。本研究的目的是确定散发性垂体腺瘤中与侵袭相关的基因异常。在本研究中，通过全外显子测序对6例侵袭性垂体腺瘤（IPA）和6例非侵袭性垂体腺瘤（nIPA）的外显子进行了测序。通过双脱氧核苷酸测序确认变异，并在另外28例垂体腺瘤中评估候选驱动基因。总共鉴定出15个变异，主要在细胞水平上与血管生成、代谢、细胞周期阶段、细胞成分组织、细胞骨架和生物合成免疫相关，其中包括13个单核苷酸变异和2个插入变异。与nIPA标本相比，IPA标本中弥漫性细支气管炎关键区域1（DPCR1）、KIAA0226、抗黏液病毒（流感病毒）、富含脯氨酸蛋白BstNI亚家族3、含PR结构域2（含ZNF结构域）、RIZ1（PRDM2）、含PR结构域8（PRDM8）、SPANX家族成员N2（SPANXN2）、TRIO和F-肌动蛋白结合蛋白以及锌指蛋白717的信使核糖核酸（mRNA）水平降低了50%。特别是，IPA标本中DPCR1、PRDM2、PRDM8和SPANXN2的mRNA水平比nIPA标本低约四倍（分别为P = 0.003、0.007、0.009和0.004）。相比之下，与nIPA标本相比，IPA中牙本质涎磷蛋白、EGF样结构域、多个7（EGFL7）、低密度脂蛋白受体相关蛋白1B和轴丝动力蛋白装配因子1（LRRC50）的mRNA水平升高（分别为P = 0.041、0.037、0.022和0.013）。此外，PRDM2表达降低与肿瘤复发相关。本研究结果表明，垂体腺瘤中的DPCR1、EGFL7、PRDM家族和LRRC50是肿瘤发生的调节因子，很可能促进嗜酸性细胞变化的发展和侵袭性肿瘤表型的形成。
