Abstract 2148: Robust detection of somatic genetic alterations in pancreatic cancer ascites

Cancer Research(2023)

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Abstract Introduction: Regardless of the stage at diagnosis most patients with pancreatic ductal adenocarcinoma develop peritoneal disease and some malignant ascites (MA) as well. Prior studies have shown that MA negatively affects overall treatment efficacy and survival. Despite the clinical significance of MA it has not been studied to any great extent. Methods: We collected MA and matched normal tissue samples at autopsy from 20 PDAC patients who were initially diagnosed at stages IIB to IV. Whole exome or targeted sequencing was previously performed on each PDAC. Each MA sample was centrifuged twice at 4000 RPM first and then at 15000 RPM to separate the cell pellet (CP) from the cell-free ascites fluid. We next extracted DNA from the CP, matched normal tissue, and the cell-free DNA (cfDNA) from the ascites fluid, and all were submitted to the Genomics Core for MSK-IMPACT, a targeted cancer gene panel representing 505 genes. Results: Results of the first five patients are complete and the remaining are in process. Comparison of the CPs and/or cfDNA to the matched tumor samples indicated 100% concordance for detected variants. However, the somatic alterations of the CP specifically versus the matched cfDNA were divergent in all patients analyzed thus far. Virtually all copy number alterations in all patients were deep deletions (range 66 to 187 cancer genes deleted) affecting multiple DNA repair pathways including homologous recombination deficiency and microsatellite repair. Conclusions: Samples of MA, when both the cell pellet and cfDNA are sequenced, accurately represent the genetic features of the matched PDAC tissue and may serve as an alternative mode of sampling for precision medicine. Differences in the genetics of the CP versus the cfDNA suggest polyclonality in the peritoneal space. Moreover, the finding of deep deletions in targetable DNA repair pathways suggest a therapeutic vulnerability for exploration. Given that paracentesis is often performed in the palliative setting and may be performed multiple times over the course of a patients’ management, it also offers an opportunity to determine how clonal dynamics in the peritoneal space change over time. Patients with MA have poor overall survival compared to patients without MA so these patients may benefit from this type of tracking which could potentially help with their treatment. Citation Format: Rajya L. Kappagantula, Alvin P. Makohon-Moore, Shigeaki Umeda, Elias-Ramzey R. Karnoub, Jerry P. Melchor, Laura D. Wood, Christine A. Iacobuzio-Donahue. Robust detection of somatic genetic alterations in pancreatic cancer ascites [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2148.
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pancreatic cancer ascites,somatic genetic alterations
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