Ban Xinchao, Mo Shengwei, Lu Zhaohui, Jia Congwei, Shao Huilin, Yan Jie, Chang Xiaoyan, Mao Xinxin, Wu Yan, Zhang Yue, Fan Xiaojie, Yu Shuangni, Chen Jie
Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Department of Pathology, Tianjin Medical University, Tianjin, China.
Neuroendocrinology. 2022;112(5):510-522. doi: 10.1159/000518413. Epub 2021 Jul 12.
Recent studies have suggested that alternative lengthening of telomeres (ALT) is associated with metastasis and poor survival in pancreatic neuroendocrine tumors (PanNETs). This study evaluated whether this association is applicable to Chinese patients as well as the potential somatic mutations associated with ALT.
We assessed the prevalence of ALT by performing telomere-specific fluorescence in situ hybridization and analyzed DAXX/ATRX expression using immunohistochemistry in 112 Chinese patients with PanNETs to evaluate the association between ALT and clinical outcomes. A subset of the noninsulinoma samples (28/60) was subjected to Sanger sequencing and targeted sequencing.
The ALT-positive phenotype was identified in 23.2% (26/112) of the samples. The clinicopathologic factors significantly associated with progression in the noninsulinoma (n = 60) cohort were the female sex (p = 0.006), Ki-67 index (p < 0.001), World Health Organization grade (p = 0.031), and ALT positivity (p = 0.013). Patients with ALT-positive PanNETs had significantly shorter progression-free survival than those with ALT-negative PanNETs in the entire cohort (p < 0.001), noninsulinoma subgroup (p = 0.01), and G2 subgroup (p = 0.001). ALT-positive samples frequently harbored somatic mutations in DAXX, ATRX, MEN1, SETBP1, PRKDC, and GNAS.
We confirmed that ALT positivity is an effective risk predictor, especially in the noninsulinoma and G2 subgroups. ALT is also related to somatic mutations in MEN1, SETBP1, PRKDC, and GNAS, in addition to DAXX and ATRX.
近期研究表明，端粒替代延长（ALT）与胰腺神经内分泌肿瘤（PanNETs）的转移及不良预后相关。本研究评估了这种关联是否也适用于中国患者，以及与ALT相关的潜在体细胞突变情况。
我们通过进行端粒特异性荧光原位杂交评估ALT的发生率，并采用免疫组织化学方法分析112例中国PanNETs患者的DAXX/ATRX表达，以评估ALT与临床结局之间的关联。对一部分非胰岛素瘤样本（28/60）进行桑格测序和靶向测序。
在23.2%（26/112）的样本中鉴定出ALT阳性表型。在非胰岛素瘤（n = 60）队列中，与疾病进展显著相关的临床病理因素为女性（p = 0.006）、Ki-67指数（p < 0.001）、世界卫生组织分级（p = 0.031）和ALT阳性（p = 0.013）。在整个队列（p < 0.001）、非胰岛素瘤亚组（p = 0.01）和G2亚组（p = 0.001）中，ALT阳性的PanNETs患者的无进展生存期显著短于ALT阴性的患者。ALT阳性样本中DAXX、ATRX、MEN1、SETBP1、PRKDC和GNAS经常发生体细胞突变。
我们证实ALT阳性是一种有效的风险预测指标，尤其是在非胰岛素瘤和G2亚组中。除了DAXX和ATRX外，ALT还与MEN1、SETBP1、PRKDC和GNAS中的体细胞突变有关。
