Gagliardi Irene, Campolo Federica, Borges de Souza Patricia, Rossi Lucrezia, Albertelli Manuela, Grillo Federica, Caputi Luigi, Mazza Massimiliano, Faggiano Antongiulio, Zatelli Maria Chiara
Section of Endocrinology and Internal Medicine, Department of Medical Sciences, University of Ferrara, Ferrara, Italy.
Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
Neuroendocrinology. 2025;115(5):422-433. doi: 10.1159/000541346. Epub 2024 Oct 24.
Clinical presentation and genetic profile of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are highly variable, hampering their management. Sequencing of circulating tumor DNA from liquid biopsy (LB) has been proposed as a less invasive alternative to solid biopsy (SB). Our aim was to compare the mutational profile (MP) provided by LB with that deriving from SB in GEP-NETs.
SB and LB were derived simultaneously from 6 GEP-NET patients. A comparative targeted next-generation sequencing (NGS) analysis was performed on DNA from SB and LB to evaluate the mutational status of 11 genes (MEN1, DAXX, ATRX, MUTYH, SETD2, DEPDC5, TSC2, ARID1A, CHECK2, MTOR, and PTEN).
Patients (M:F = 2:1; median age 64 years) included 3 with pancreatic and 3 with ileal NETs. NGS detected a median number of 55 variants/sample in SB and 66.5 variants/sample in LB specimens (mutational burden: 0.2-1.9 and 0.3-1.8 mut/Mb, respectively). Missense and nonsense mutations were prevalent in both, mainly represented by C>T transitions. ARID1A, MTOR, and ATRX were consistently mutated in SB, and ARID1A, TSC2, MEN1, PTEN, SETD2, and MUTYH were consistently mutated in LB. DAXX mutations were absent in LB. Seventeen recurrent mutations were shared between SB and LB; in particular, MTOR single-nucleotide variants c.G4731A and c.C2997T were shared by 5 out of 6 patients. Hierarchical clustering supported genetic similarity between SB and LB.
This pilot study explores the applicability of LB in GEP-NET MP evaluation. Further studies with larger cohorts are needed to validate LB and to define the clinical impact.
胃肠胰神经内分泌肿瘤（GEP-NETs）的临床表现和基因特征高度可变，这给其治疗带来了阻碍。液体活检（LB）中循环肿瘤DNA的测序已被提议作为实体活检（SB）的一种侵入性较小的替代方法。我们的目的是比较LB提供的突变谱（MP）与GEP-NETs中SB的突变谱。
同时从6例GEP-NET患者获取SB和LB样本。对SB和LB的DNA进行比较靶向二代测序（NGS）分析，以评估11个基因（MEN1、DAXX、ATRX、MUTYH、SETD2、DEPDC5、TSC2、ARID1A、CHECK2、MTOR和PTEN）的突变状态。
患者（男:女 = 2:1；中位年龄64岁）包括3例胰腺NET和3例回肠NET。NGS在SB样本中检测到的变异中位数为每个样本55个，在LB样本中为66.5个（突变负荷：分别为0.2 - 1.9和0.3 - 1.8个突变/Mb）。错义突变和无义突变在两者中均很常见，主要由C>T转换代表。ARID1A、MTOR和ATRX在SB中持续发生突变，ARID1A、TSC2、MEN1、PTEN、SETD2和MUTYH在LB中持续发生突变。LB中未检测到DAXX突变。SB和LB之间共有17个复发突变；特别是，MTOR单核苷酸变异c.G4731A和c.C2997T在6例患者中的5例中都存在。层次聚类支持SB和LB之间的基因相似性。
这项初步研究探讨了LB在GEP-NET MP评估中的适用性。需要更大样本量的进一步研究来验证LB并确定其临床影响。
