Whole-exome sequencing of rectal neuroendocrine tumors.

IF 4.1 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM
Yuanliang Li, Yiying Guo, Zixuan Cheng, Chao Tian, Yingying Chen, Ruao Chen, Fuhuan Yu, Yanfen Shi, Fei Su, Shuhua Zhao, Zhizheng Wang, Jie Luo, Huangying Tan
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引用次数: 2

Abstract

The genetic characteristics of rectal neuroendocrine tumors (R-NETs) were poorly understood. Depicting the genetic characteristics may provide a biological basis for prognosis prediction and novel treatment development. Tissues of 18 R-NET patients were analyzed using whole-exome sequencing. The median tumor mutation burden (TMB) and microsatellite instability (MSI) were 1.15 Muts/MB (range, 0.03-23.28) and 0.36 (range, 0.00-10.97), respectively. Genes involved in P53 signaling, PI3K-AKT signaling, DNA damage repair, WNT signaling, etc. were frequently altered. Higher TMB (P = 0.078), higher CNV (P = 0.110), somatic mutation of CCDC168 (P = 0.049), HMCN1 (P = 0.040), MYO10 (P = 0.007), and amplification of ZC3H13 (P < 0.001) were associated with shorter OS. Potentially targetable gene alterations (PTGAs) were seen in 72% of the patients. FGFR1 amplification (22%) was the most common PTGA followed by BARD1 and BRCA2 mutation (each 17%). As for gene variations associated with the efficacy of immune checkpoint blockade (ICB), FAT1 alteration (39%) and PTEN depletion (28%) were commonly observed. In conclusion, frequently altered oncogenic pathways might contribute to the development and progression of R-NETs. Gene alterations significantly associated with prognosis might be potential novel targets. Targeted therapy might be a promising strategy as targetable alterations were prevalent in R-NETs. FAT1 alteration and PTEN depletion might be the main genetic alterations influencing the response to ICB besides overall low TMB and MSI in R-NETs.

Abstract Image

Abstract Image

Abstract Image

直肠神经内分泌肿瘤的全外显子组测序。
直肠神经内分泌肿瘤(R-NETs)的遗传特征尚不清楚。描述遗传特征可以为预后预测和新的治疗开发提供生物学基础。采用全外显子组测序对18例R-NET患者的组织进行分析。中位肿瘤突变负荷(TMB)和微卫星不稳定性(MSI)分别为1.15 Muts/MB(范围0.03 ~ 23.28)和0.36 Muts/MB(范围0.00 ~ 10.97)。参与P53信号、PI3K-AKT信号、DNA损伤修复、WNT信号等的基因频繁改变。较高的TMB (P = 0.078)、较高的CNV (P = 0.110)、CCDC168体细胞突变(P = 0.049)、HMCN1 (P = 0.040)、MYO10 (P = 0.007)和ZC3H13扩增(P < 0.001)与较短的生存期相关。72%的患者出现潜在靶向基因改变(PTGAs)。FGFR1扩增(22%)是最常见的PTGA,其次是BARD1和BRCA2突变(各17%)。至于与免疫检查点阻断(ICB)疗效相关的基因变异,常见的是FAT1改变(39%)和PTEN耗竭(28%)。总之,经常改变的致癌途径可能有助于R-NETs的发生和发展。与预后显著相关的基因改变可能是潜在的新靶点。靶向治疗可能是一种很有前途的策略,因为可靶向改变在R-NETs中很普遍。FAT1改变和PTEN缺失可能是影响R-NETs对ICB反应的主要遗传改变,除了总体低TMB和MSI。
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来源期刊
Endocrine-related cancer
Endocrine-related cancer 医学-内分泌学与代谢
CiteScore
7.80
自引率
2.60%
发文量
138
审稿时长
6-12 weeks
期刊介绍: Endocrine-Related Cancer is an official flagship journal of the Society for Endocrinology and is endorsed by the European Society of Endocrinology, the United Kingdom and Ireland Neuroendocrine Society, and the Japanese Hormones and Cancer Society. Endocrine-Related Cancer provides a unique international forum for the publication of high quality original articles describing novel, cutting edge basic laboratory, translational and clinical investigations of human health and disease focusing on endocrine neoplasias and hormone-dependent cancers; and for the publication of authoritative review articles in these topics. Endocrine neoplasias include adrenal cortex, breast, multiple endocrine neoplasia, neuroendocrine tumours, ovary, prostate, paraganglioma, parathyroid, pheochromocytoma pituitary, testes, thyroid and hormone-dependent cancers. Neoplasias affecting metabolism and energy production such as bladder, bone, kidney, lung, and head and neck, are also considered.
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