Tumor organoids improve mutation detection of pancreatic ductal adenocarcinoma

• Published in: Scientific reports Vol. 14; no. 1; pp. 25468 - 14
• Main Authors: Farshadi, Elham Aida, Wang, Wenya, Mohammad, Farzana, van der Oost, Elise, Doukas, Michail, van Eijck, Casper H. J., van de Werken, Harmen J. G., Katsikis, Peter D.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 26.10.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 631/1647/48; 631/67/1504/1713; Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biopsy; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - pathology; Exome Sequencing; Female; Fluorouracil - pharmacology; Fluorouracil - therapeutic use; FOLFIRINOX treatment; Genomic profile; Genomics; Humanities and Social Sciences; Humans; Irinotecan - pharmacology; Irinotecan - therapeutic use; Leucovorin - therapeutic use; Leukocytes (mononuclear); Male; Middle Aged; multidisciplinary; Mutation; Mutation detection; Organoids; Organoids - pathology; Oxaliplatin - pharmacology; Oxaliplatin - therapeutic use; Pancreas; Pancreatic cancer; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - pathology; Patient-derived organoids; Peripheral blood mononuclear cells; Science; Science (multidisciplinary); Tumor cellularity; Tumors; Whole genome sequencing; Genomic profile; Patient-derived organoids; FOLFIRINOX treatment; Mutation detection; Pancreatic cancer; Tumor cellularity
• ISSN: 2045-2322; 2045-2322
• 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.