Despite prognostic grading and staging systems, it is a challenge to predict outcomes for patients with pancreatic neuroendocrine tumors (PanNETs). Sequencing studies of PanNETs have identified alterations in death domain-associated protein (DAXX) and alpha-thalassemia/mental retardation X-linked chromatin remodeler (ATRX). In tumors, mutations in DAXX or ATRX and corresponding loss of protein expression correlate with shorter times of disease-free survival and disease-specific survival of patients. However, DAXX or ATRX proteins were lost in only 50% of distant metastases analyzed. We performed whole-exome sequencing analyses of 20 distant metastases from 20 patients with a single nonsyndrome, nonfunctional PanNET. We found distant metastases contained alterations in multiple endocrine neoplasia type 1 (MEN1) (n = 8), ATRX (n = 5), DAXX (n = 5), TSC2 (n = 3), and DEP domain containing 5 (DEPDC5) (n = 3). We found copy number loss of cyclin dependent kinase inhibitor 2A (CDKN2A) in 15 metastases (75%) and alterations in genes that regulate chromatin remodeling, including set domain containing 2 (SETD2) (n = 4), AT-rich interaction domain 1A (ARID1A) (n = 2), chromodomain helicase DNA binding protein 8 (CHD8) (n = 2), and DNA methyl transferase 1 (DNMT1) (n = 2). In a separate analysis of 347 primary PanNETs, we found loss or deletion of DAXX and ATRX, disruption of SETD2 function (based on loss of H3 lysine 36 trimethylation), loss of ARID1A expression or deletions in CDKN2A in 81% of primary PanNETs with distant metastases. Among patients with loss or deletion of at least 1 of these proteins or genes, 39% survived disease-free for 5 years and 44% had disease-specific survival times of 10 years. Among patients without any of these alterations, 98% survived disease-free for 5 years and 95% had disease-specific survival times of 10 years. Therefore, primary PanNETs with loss of DAXX, ATRX, H3 lysine 36 trimethylation, ARID1A, and/or CDKN2A associate with shorter survival times of patients. Our findings indicate that alterations in chromatin-remodeling genes and CDKN2A contribute to metastasis of PanNETs.

中文翻译：

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染色质重塑蛋白和/或CDKN2A的丢失与胰腺神经内分泌肿瘤的转移和减少的患者生存时间有关。

尽管有预后分级和分期系统，但预测胰腺神经内分泌肿瘤（PanNETs）患者的预后仍是一项挑战。PanNETs的测序研究已经确定了死亡域相关蛋白（DAXX）和α-地中海贫血/智力障碍X连锁染色质重塑剂（ATRX）的改变。在肿瘤中，DAXX或ATRX突变以及相应的蛋白质表达损失与患者无病生存时间和疾病特异性生存时间缩短相关。但是，DAXX或ATRX蛋白仅在所分析的50％远处转移中丢失。我们对来自20个患有单一非综合征，无功能PanNET的患者的20个远处转移进行了全基因组测序分析。我们发现远处转移包含多发性内分泌肿瘤1型（MEN1）（n = 8），ATRX（n = 5），DAXX（n = 5），TSC2（n = 3），DEP域包含5（DEPDC5）（n = 3）。我们发现15个转移灶（75％）中细胞周期蛋白依赖性激酶抑制剂2A（CDKN2A）的拷贝数丢失和调节染色质重塑的基因的改变，包括含有2个（SETD2）的设定域（n = 4），富含AT的相互作用域1A （ARID1A）（n = 2），色域解旋酶DNA结合蛋白8（CHD8）（n = 2）和DNA甲基转移酶1（DNMT1）（n = 2）。在对347个主要PanNET的单独分析中，我们发现81％的远距离主要PanNET中DAXX和ATRX的丢失或缺失，SETD2功能的破坏（基于H3赖氨酸36三甲基化的丢失），ARID1A表达的丢失或CDKN2A中CDKN2A的缺失。转移。在这些蛋白质或基因中至少有一种丢失或缺失的患者中，39％的患者无病生存5年，而44％的疾病特异性生存时间为10年。在没有任何这些改变的患者中，98％的患者无病生存5年，95％的疾病特异性生存时间为10年。因此，丧失DAXX，ATRX，H3赖氨酸36三甲基化，ARID1A和/或CDKN2A的原发PanNETs与患者较短的生存时间相关。我们的发现表明，染色质重塑基因和CDKN2A的改变有助于PanNETs的转移。