■高分化胰腺神经内分泌肿瘤(PNETs)可以是非功能性的或功能性的,例如胰岛素瘤和胰高血糖素瘤。大多数PNETs是零星的,但是PNETs也发生在遗传性综合症中,主要是多发性内分泌瘤1型(MEN1)。Knudson假说指出了第二个,MEN1中的躯体打击是MEN1综合征PNET的原因。近年来,关于散发性和遗传性PNETs中遗传体细胞事件的报道已经出现,为更详细的病理生理学分子理解提供基础。在这篇系统综述和荟萃分析中,我们对人类G1/G2级PNETs中聚集的频繁遗传改变和潜在驱动事件进行了整理和统计分析.
■根据2020年系统评价和荟萃分析(PRISMA)报告指南的首选报告项目进行了系统搜索。在Pubmed中使用整个外显子组搜索已发表的研究,全基因组,或靶向基因组(+400个基因)测序的人G1/G2PNETs在2023年9月25日进行。来自已发表研究的14个数据集包括221名患者和225名G1/G2PNETs的数据,它们被分为散发性肿瘤,和遗传性肿瘤,和种系状态未知的肿瘤。Further,无功能和有功能的PNETs分为两组进行通路评估.整理后的遗传分析是使用“maftools”R包进行的。
■零星的PNETs占72.0%(162/225),遗传性PNET13.3%(30/225),未知种系状态14.7%(33/225)。最常见的基因是MEN1,体细胞变异和拷贝数变异总体上占42%(95/225);遗传性PNETs(MEN1,VHL,CHEK2,BRCA2,PTEN,CDKN1B,和/或MUTYH)57%(16/30);散发性PNETs36%(58/162);未知种系状态64%(21/33)。MEN1点突变/indel分布在整个MEN1中。总的来说,DAXX(16%,37/225)和ATRX变体(12%,27/225)也有大量错义突变聚集在与组蛋白结合相关的突变热点中,和转位酶活性,分别。DAXX突变在具有MEN1突变的PNETs中更频繁地发生,p<0.05。虽然功能正常的PNETs共享很少的变异基因,无功能的PNETs在与磷酸肌醇3-激酶相关的基因中有更多的复发性变异,Wnt,NOTCH,和受体酪氨酸激酶-Ras信号通路。
■G1/G2PNETs的体细胞遗传改变是多样的,但是零星与零星之间存在明显差异世袭,和功能与非功能性PNETs。对遗传改变的理解增加可能导致在分化良好的PNETs的肿瘤发生中识别更多的驱动因素和驱动热点。可能为识别新的药物靶标提供基础。(由诺和诺德基金会资助,授权号NNF19OC0057915)。
UNASSIGNED: Well-differentiated pancreatic neuroendocrine tumors (PNETs) can be non-functional or functional, e.g. insulinoma and glucagonoma. The majority of PNETs are sporadic, but PNETs also occur in hereditary syndromes, primarily multiple endocrine neoplasia type 1 (
MEN1). The Knudson hypothesis stated a second, somatic hit in
MEN1 as the cause of PNETs of
MEN1 syndrome. In the recent years, reports on genetic somatic events in both sporadic and hereditary PNETs have emerged, providing a basis for a more detailed molecular understanding of the pathophysiology. In this systematic review and meta-analysis, we made a collation and statistical analysis of aggregated frequent genetic alterations and potential driver events in human grade G1/G2 PNETs.
UNASSIGNED: A systematic search was performed in concordance with the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) reporting guidelines of 2020. A search in Pubmed for published studies using whole exome, whole genome, or targeted gene panel (+400 genes) sequencing of human G1/G2 PNETs was conducted at the 25th of September 2023. Fourteen datasets from published studies were included with data on 221 patients and 225 G1/G2 PNETs, which were divided into sporadic tumors, and hereditary tumors with pre-disposing germline variants, and tumors with unknown germline status. Further, non-functioning and functioning PNETs were distinguished into two groups for pathway evaluation. The collated genetical analyses were conducted using the \'maftools\' R-package.
UNASSIGNED: Sporadic PNETs accounted 72.0% (162/225), hereditary PNETs 13.3% (30/225), unknown germline status 14.7% (33/225). The most frequently altered gene was MEN1, with somatic variants and copy number variations in overall 42% (95/225); hereditary PNETs (germline variations in
MEN1, VHL, CHEK2, BRCA2, PTEN, CDKN1B, and/or MUTYH) 57% (16/30); sporadic PNETs 36% (58/162); unknown germline status 64% (21/33). The
MEN1 point mutations/indels were distributed throughout
MEN1. Overall, DAXX (16%, 37/225) and ATRX-variants (12%, 27/225) were also abundant with missense mutations clustered in mutational hotspots associated with histone binding, and translocase activity, respectively. DAXX mutations occurred more frequently in PNETs with
MEN1 mutations, p<0.05. While functioning PNETs shared few variated genes, non-functioning PNETs had more recurrent variations in genes associated with the Phosphoinositide 3-kinase, Wnt, NOTCH, and Receptor Tyrosine Kinase-Ras signaling onco-pathways.
UNASSIGNED: The somatic genetic alterations in G1/G2 PNETs are diverse, but with distinct differences between sporadic vs. hereditary, and functional vs. non-functional PNETs. Increased understanding of the genetic alterations may lead to identification of more drivers and driver hotspots in the tumorigenesis in well-differentiated PNETs, potentially giving a basis for the identification of new drug targets. (Funded by Novo Nordisk Foundation, grant number NNF19OC0057915).