Department of Pulmonary Medicine, Erasmus University Medical Center, PO Box 2040, Rotterdam, 3000 CA, The Netherlands.
Department of Immunology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, PO Box 2040, Rotterdam, 3000 CA, The Netherlands.
Sci Rep. 2024 Oct 26;14(1):25468. doi: 10.1038/s41598-024-75888-y.
Pancreatic ductal adenocarcinoma (PDAC) presents challenges in detecting somatic mutations due to its complex cellular composition. This study investigated the utility of patient-derived organoids (PDOs) to overcome these obstacles and enhance somatic mutation identification. Surgically resected PDAC tumors and their paired PDOs from 21 patients were examined. Whole-exome sequencing (WES) of tumor tissue, organoids, and peripheral blood mononuclear cells was performed to identify somatic mutations. Our findings demonstrate that PDOs retained about 80% of the somatic mutations from the original tumors, showing high concordance in mutation types. PDOs exhibited increased tumor purity and uncovered key driver mutations, aiding in identifying clinically relevant genomic alterations. Moreover, eight cycles of FOLFIRINOX treatment did not significantly alter the mutational landscape at the DNA level, indicating the stability of the mutational profile after therapeutic pressure in patients. In conclusion, PDOs are potentially important tools for exploring the somatic mutational landscape of PDAC. While they can reveal mutations that may be challenging to detect through traditional biopsy sequencing due to the inherently low tumor purity of PDAC, it is important to note that PDOs may not always fully recapitulate all mutations found in primary tumors. Despite this limitation, PDOs can still offer critical insights into the genomic complexities of PDAC, which is crucial for the development of personalized vaccines and therapies for this disease.
胰腺导管腺癌 (PDAC) 由于其复杂的细胞组成，在检测体细胞突变方面存在挑战。本研究探讨了患者来源的类器官 (PDO) 的应用，以克服这些障碍并增强体细胞突变的识别。对 21 名患者的手术切除的 PDAC 肿瘤及其配对的 PDO 进行了研究。对肿瘤组织、类器官和外周血单核细胞进行了全外显子组测序 (WES)，以鉴定体细胞突变。我们的研究结果表明，PDO 保留了原始肿瘤中约 80%的体细胞突变，在突变类型上具有高度一致性。PDO 显示出更高的肿瘤纯度，并揭示了关键的驱动突变，有助于识别临床相关的基因组改变。此外，八轮 FOLFIRINOX 治疗在 DNA 水平上并未显著改变突变景观，表明在患者接受治疗压力后，突变特征的稳定性。总之，PDO 是探索 PDAC 体细胞突变景观的潜在重要工具。虽然它们可以揭示由于 PDAC 固有的低肿瘤纯度而通过传统活检测序可能难以检测到的突变，但重要的是要注意 PDO 并不总是完全再现原发性肿瘤中发现的所有突变。尽管存在这种局限性，PDO 仍可提供对 PDAC 基因组复杂性的关键见解，这对于为这种疾病开发个性化疫苗和疗法至关重要。
