CREBBP Mutation as a Culprit for Negative SSTR2 PET in Neuroendocrine Tumors.

IF 2.5 4区医学 Q2 RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING

Molecular Imaging and Biology Pub Date : 2025-08-08 DOI:10.1007/s11307-025-02040-1

Arvin Haj-Mirzaian, Shadi A Esfahani, Umar Mahmood, Pedram Heidari

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引用次数: 0

Abstract

Purpose: This study aimed to elucidate the molecular and genetic factors contributing to negative ⁶⁸Ga-DOTATATE PET imaging in neuroendocrine tumors (NETs). By integrating whole exome sequencing (WES) and single-cell RNA sequencing (scRNA-seq), we sought to unravel the interplay between negative results of ⁶⁸Ga-DOTATATE PET and genetic mutations in NETs.

Methods: A total of 18 patients with lung, ileal, or pancreatic NETs who underwent ⁶⁸Ga-DOTATATE and ¹⁸F-FDG PET/CT scans as part of their initial diagnostic workup were retrospectively reviewed. WES analysis was conducted to investigate the genetic profile of circulating tumor cells of patients with negative ⁶⁸Ga-DOTATATE scans. Leveraging scRNA-seq and single-cell somatic variant calling analysis, we compared the mutation burden and genetic hallmarks of NET cells with high /positive SSTR2 expression to those with negative/low SSTR2 expression.

Results: Our analysis identified an association between negative ⁶⁸Ga-DOTATATE scans and reduced survival rates, regardless of tumor grade. WES highlighted a predominance of missense mutations, including CREBBP mutation, particularly in patients with negative PET results (incidence of %67 vs. %0). We observed a deleterious mutation in the SSTR2, likely accounting for the observed negative PET scans (incidence of %33). Single-cell single nucleotide variant (SNV) analysis showed that the total unique mutation burden in cells with negative/low SSTR2 expression was significantly higher compared to cells with positive/high expression; and notably, the CREBBP mutation was observed in more than 50% of patients and approximately 35% of NET cells. These results indicate that the frequency of CREBBP mutations is nearly as high as other well-known NET mutations such as MEN1, PTEN, and RB1. Additionally, CREBBP mutations are significantly more frequent in tumors with negative/low SSTR2 expression.

Conclusion: This study suggests that CREBBP mutations in NETs may potentially alter SSTR2 expression, indicating that patients with the mutated CREBBP genotype may not be suitable candidates for SSTR2-targeted PET imaging and radionuclide therapy.

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CREBBP突变是神经内分泌肿瘤中SSTR2 PET阴性的罪魁祸首。

目的：本研究旨在探讨神经内分泌肿瘤（NETs）中68Ga-DOTATATE PET显像阴性的分子和遗传因素。通过整合全外显子组测序（WES）和单细胞RNA测序（scRNA-seq），我们试图揭示68Ga-DOTATATE PET阴性结果与NETs基因突变之间的相互作用。方法：回顾性分析共18例肺、回肠或胰腺NETs患者，这些患者接受了68Ga-DOTATATE和18F-FDG PET/CT扫描，作为其初始诊断检查的一部分。采用WES分析68Ga-DOTATATE阴性患者循环肿瘤细胞的遗传谱。利用scRNA-seq和单细胞体细胞变异召唤分析，我们比较了SSTR2高/阳性表达的NET细胞与SSTR2负/低表达的NET细胞的突变负担和遗传特征。结果：我们的分析确定了阴性68Ga-DOTATATE扫描与降低生存率之间的关联，无论肿瘤级别如何。WES强调了错义突变的优势，包括CREBBP突变，特别是在PET结果阴性的患者中（发生率为%67比%0）。我们在SSTR2中观察到一个有害突变，这可能是观察到的PET扫描阴性的原因（发生率为%33）。单细胞单核苷酸变异（SNV）分析显示，SSTR2阴性/低表达细胞的总独特突变负荷显著高于阳性/高表达细胞；值得注意的是，在超过50%的患者和约35%的NET细胞中观察到CREBBP突变。这些结果表明CREBBP突变的频率几乎与其他已知的NET突变（如MEN1、PTEN和RB1）一样高。此外，CREBBP突变在SSTR2阴性/低表达的肿瘤中更为常见。结论：本研究提示NETs中CREBBP突变可能会改变SSTR2的表达，表明CREBBP基因型突变的患者可能不适合进行SSTR2靶向PET成像和放射性核素治疗。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Imaging and Biology 医学-核医学

CiteScore

6.90

自引率

3.20%

发文量

审稿时长

3 months

期刊介绍： Molecular Imaging and Biology (MIB) invites original contributions (research articles, review articles, commentaries, etc.) on the utilization of molecular imaging (i.e., nuclear imaging, optical imaging, autoradiography and pathology, MRI, MPI, ultrasound imaging, radiomics/genomics etc.) to investigate questions related to biology and health. The objective of MIB is to provide a forum to the discovery of molecular mechanisms of disease through the use of imaging techniques. We aim to investigate the biological nature of disease in patients and establish new molecular imaging diagnostic and therapy procedures. Some areas that are covered are: Preclinical and clinical imaging of macromolecular targets (e.g., genes, receptors, enzymes) involved in significant biological processes. The design, characterization, and study of new molecular imaging probes and contrast agents for the functional interrogation of macromolecular targets. Development and evaluation of imaging systems including instrumentation, image reconstruction algorithms, image analysis, and display. Development of molecular assay approaches leading to quantification of the biological information obtained in molecular imaging. Study of in vivo animal models of disease for the development of new molecular diagnostics and therapeutics. Extension of in vitro and in vivo discoveries using disease models, into well designed clinical research investigations. Clinical molecular imaging involving clinical investigations, clinical trials and medical management or cost-effectiveness studies.