通过内镜超声引导的细针穿刺材料的基因组和转录组预测分析：一项前瞻性多中心研究

Predictive genomic and transcriptomic analysis on endoscopic ultrasound-guided fine needle aspiration materials from primary pancreatic adenocarcinoma: a prospective multicentre study

EBioMedicine

影响因子:10.8

分区:医学1区 Top / 医学：研究与实验1区

发表日期:2024 Nov

作者: Rémy Nicolle, Cindy Canivet, Laurent Palazzo, Bertrand Napoléon, Mira Ayadi, Camille Pignolet, Jérôme Cros, Sophie Gourgou, Janick Selves, Jérôme Torrisani, Nelson Dusetti, Pierre Cordelier, Louis Buscail, Barbara Bournet,

DOI: 10.1016/j.ebiom.2024.105373

摘要

我们利用内镜超声引导的细针穿刺活检进行细胞病理诊断，并采集原发肿瘤的核酸，无论疾病阶段如何。纳入397例确认患有胰腺腺癌的患者，进行多中心前瞻性随访。提取了通过内镜超声引导的细针穿刺活检获得的原发肿瘤材料中的DNA和mRNA，分别采用靶向深度测序和RNA测序进行分析。KRAS突变的变异等位基因频率用于评估肿瘤细胞含量，所有肿瘤阶段中均在15%到20%之间。转移性原发肿瘤的分子特征显著不同于其他类型肿瘤，更频繁存在TP53突变（p=0.0002），较少出现RNF43突变，且具有更多的基础样RNA组分（p=0.001）。与改善总生存期相关的分子标志物包括：接受一线铂类化疗的患者中，同源重组缺陷基因突变（p=0.025）；接受放化疗的局部晚期肿瘤患者中，野生型TP53（p=0.01）。GemPred转录组特征与接受吉西他滨一线治疗的局部晚期或转移性胰腺癌患者的总生存期显著相关（p=0.019）。肿瘤的基因组和转录组联合分析有助于区分转移性肿瘤与其他类型肿瘤，并可辅助预测铂类或吉西他滨化疗及放化疗的总生存期。

Abstract

We apply endoscopic ultrasound-guided fine needle aspiration biopsy to cytopathologically diagnose and sample nucleic acids from primary tumours regardless of the disease stage.397 patients with proven pancreatic adenocarcinoma were included and followed up in a multicentre prospective study. DNA and mRNA were extracted from materials of primary tumours obtained by endoscopic ultrasound-guided fine needle aspiration biopsy and analysed using targeted deep sequencing and RNAseq respectively.The variant allele frequency of the KRAS mutation was used to evaluate the tumour cellularity, ranging from 15 to 20% in all cells, regardless of the tumour stage. The molecular profile of metastatic primary tumours significantly differed from other types of tumours, more frequently having TP53 mutations (p = 0.0002), less frequently having RNF43 mutations, and possessing more basal-like mRNA component (p = 0.001). Molecular markers associated with improved overall survival were: mutations in homologous recombination deficiency genes in patients who received first-line platinum-based chemotherapy (p = 0.025) and wild-type TP53 gene in patients with locally advanced tumours who received radio-chemotherapy (p = 0.01). The GemPred transcriptomic profile was associated with a significantly better overall survival in patients with locally advanced or metastatic pancreatic cancer who received a gemcitabine-based first-line treatment (p = 0.019).The combination of genomic and transcriptomic analyses of primary pancreatic tumours enables us to distinguish metastatic tumours from other tumour types. Our molecular strategy may assist in predicting overall survival outcomes for platinum or gemcitabine-based chemotherapies, as well as radio-chemotherapy.Institut National Du Cancer (BCB INCa_7294), CHU of Toulouse, Inserm and Ligue Nationale Contre le Cancer (CIT program).