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Establishment of patient-derived xenografts from patients with gastrointestinal stromal tumors: analysis of clinicopathological characteristics related to engraftment success.

ABSTRACT: Patient-derived xenografts (PDXs) can represent the heterogeneity and histological characteristics of tumors and are thus useful for testing the efficacy of anti-cancer drugs; however, PDXs are difficult to generate, especially for gastrointestinal stromal tumor (GIST). We analyzed the clinicopathologic factors associated with the successful establishment of GIST PDX in NOD.Cg-Prkdcscid IL2rgtm1Wjl/SzJ mice. We used 185 GIST tumor fragments from patients who underwent surgical resection prior to (n?=?66; 35.7%) and after treatment (n?=?119; 64.3%) with tyrosine kinase inhibitors. The overall success rate of PDX establishment was 17%; in univariate analysis, engraftment success was associated with after TKI treatment, larger tumor size, higher mitotic count, higher Ki-67 index, higher cellularity, presence of tumor necrosis, primary mutations in KIT exon 11, and originating from metastatic lesions. In multivariate analysis, higher Ki-67 index, after TKI treatment, and larger tumor size were independent factors for engraftment success. Immunohistochemistry in representative samples further corroborated the above results. These results will be useful in the establishment of PDX models from GISTs.

SUBMITTER: Na YS

PROVIDER: S-EPMC7224375 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Establishment of patient-derived xenografts from patients with gastrointestinal stromal tumors: analysis of clinicopathological characteristics related to engraftment success.

Na Young-Soon YS Ryu Min-Hee MH Park Young Soo YS Lee Chae-Won CW Lee Ju-Kyung JK Park Yangsoon Y Park Jung Min JM Ma Jungeun J Kang Yoon-Koo YK

Scientific reports 20200514 1

Patient-derived xenografts (PDXs) can represent the heterogeneity and histological characteristics of tumors and are thus useful for testing the efficacy of anti-cancer drugs; however, PDXs are difficult to generate, especially for gastrointestinal stromal tumor (GIST). We analyzed the clinicopathologic factors associated with the successful establishment of GIST PDX in NOD.Cg-Prkdc<sup>scid</sup> IL2rg<sup>tm1Wjl</sup>/SzJ mice. We used 185 GIST tumor fragments from patients who underwent surgi ...[more]

PMID: 32409663

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Project description:BACKGROUND:Patient-derived xenograft (PDX) models increasingly are used in translational research. However, the engraftment rates of patient tumor samples in immunodeficient mice to PDX models vary greatly. METHODS:Tumor tissue samples from 308 patients with non-small cell lung cancer were implanted in immunodeficient mice. The patients were followed for 1.5 to approximately 6 years. The authors performed histological analysis of PDXs and some residual tumor tissues in mice with failed PDX growth at 1 year after implantation. Quantitative polymerase chain reaction and enzyme-linked immunoadsorbent assay were performed to measure the levels of Epstein-Barr virus genes and human immunoglobulin G in PDX samples. Patient characteristics were compared for PDX growth and overall survival as outcomes using Cox regression analyses. Disease staging was based on the 7th TNM staging system. RESULTS:The overall engraftment rate for PDXs from patients with non-small cell lung cancer was 34%. Squamous cell carcinomas had a higher engraftment rate (53%) compared with adenocarcinomas. Tumor samples from patients with stage II and stage III disease and from larger tumors were found to have relatively high engraftment rates. Patients whose tumors successfully engrafted had worse overall survival, particularly those individuals with adenocarcinoma, stage III or stage IV disease, and moderately differentiated tumors. Lymphoma formation was one of the factors associated with engraftment failure. Human CD8-positive and CD20-positive cells were detected in residual samples of tumor tissue that failed to generate a PDX at 1 year after implantation. Human immunoglobulin G was detected in the plasma of mice that did not have PDX growth at 14 months after implantation. CONCLUSIONS:The results of the current study indicate that the characteristics of cancer cells and the tumor immune microenvironment in primary tumors both can affect engraftment of a primary tumor sample.

Project description:Gastrointestinal stromal tumors (GISTs) represent a spectrum of tumors characterized by variable behaviors and activating mutations in KIT proto-oncogene, receptor tyrosine kinase (KIT) or platelet derived growth factor receptor α (PDGFRA) genes. However, whether genotype analysis should be regarded as a prognostic indicator remains unclear. In the present study, clinicopathological data and the mutation phenotypes of KIT and PDGFRA genes were assessed in a series of 302 patients with GISTs at a single center. Univariate and multivariate Cox regression analyses were performed to identify the clinicopathological and mutational factors associated with relapse-free survival (RFS) in patients who had undergone complete primary GIST resection. KIT and PDGFRA mutations were identified in 233 (77.2%) and 30 (9.9%) cases, respectively. The following clinicopathological parameters were significantly associated with a shorter RFS: Male, non-gastric tumor origin, larger tumor size (>5 cm), high mitotic activity (>5/50 high-power fields), necrosis and epithelioid morphology. Tumors at non-gastric sites, with high National Institutes of Health risk classification, high World Health Organization (WHO) grade and KIT deletion involving codons 557/558/559 exhibited a significantly higher risk of progression. In the Cox regression model, KIT deletion involving codons 557/558/559, non-gastric origin and high WHO grade were independent indicators of RFS. The adverse prognosis associated with KIT deletions involving codons 557/558/559 was also observed for gastric GISTs. Conversely, spindle morphology, KIT exon 11 substitution and PDGFRA exon 18 mutation were associated with a longer RFS and lower rate of relapse. Furthermore, the coexistence of KIT exon 11 deletion and exon 13 duplication was observed in one tumor, with adverse prognostic features. Heterogeneity affecting morphology, immunostaining and genotype was identified in 4 cases. In addition, the presence of succinate dehydrogenase-deficient GIST was found in 5 cases (3.6%). In conclusion, the tumor genotype with regard to KIT and PDGFRA mutations exhibited prognostic significance for the risk of GIST progression and may be helpful for the optimization of tailored adjuvant therapy.

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Establishment of patient-derived xenografts from patients with gastrointestinal stromal tumors: analysis of clinicopathological characteristics related to engraftment success.

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Establishment of patient-derived xenografts from patients with gastrointestinal stromal tumors: analysis of clinicopathological characteristics related to engraftment success.

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