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Associations of various clinicopathologic parameters with rH2AX and 53BP1 expression levels by IHC and IF.
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Simple Summary
Aberrations of DNA damage repair (DDR) pathways enable the transformation of pre-neoplastic lesions, but their roles are barely understood in gastrointestinal stromal tumors (GISTs). The targeted next-generation sequencing of GISTs has demonstrated heterozygous deletions (HetDels) as frequent aberrations of DDR genes, usually lacking...
Contexts in source publication
Context 1
... γ-H2AX H-score of the combined none/very low-/low-risk cases was not only significantly higher than that of adjacent normal tissues (p = 0.04), but was also noticeably lower than that of the joint group of GISTs at the high and moderate risk levels (p < 0.001). As shown in Table 1, high γ-H2AX expressers assessed by IHC were found to be significantly more common in intestinal (p = 0.005), mitotically active (p < 0.001), and larger GISTs (as a continuous parameter: p = 0.01; dichotomized at 5 cm: p = 0.018). The IF staining of γ-H2AX (Figure 2A3-D3,G) showed only scarce foci of γ-H2AX in a very low percentage (generally <3%, Figure 2A3) of smooth muscle cells in the adjacent normal tissues, with one outlier at 10%. ...Context 2
... the high γ-H2AX expressers assessed by IF were not related to tumor location or size, these tumors exhibited significantly higher mitotic activity (p < 0.001). According to both the NIH scheme and the NCCN guidelines, significantly increased proportions of GISTs with elevated risk levels were found when using either IHC or IF (all p ≤ 0.001, Table 1). Figure 2. Immunohistochemical and immunofluorescence expressions of rH2AX in gastrointestinal stromal tumors across various risk categories. ...Context 3
... differences were also equally robust in the comparisons between normal tissue and the joint group of none/very low-/low-risk cases (p < 0.001), and between two joint groups, namely, the none/very low-/low-risk versus moderate/high-risk cases (p < 0.001). As shown in Table 1, high 53BP1 expressers assessed by IHC exhibited significantly higher mitotic activity (p = 0.016) and increased proportions of cases classified into higher risk levels by both the NIH risk scheme and the NCCN guidelines (both p ≤ 0.001), but they showed no association with tumor size or location. Regarding the IF staining of 53BP1 (Figure 3A3-D3,G), only a few foci of 53BP1 were identified in a low percentage (generally <10%, Figure 3A3) of the adjacent smooth muscle cells, except for one outlier reaching 20%. ...Citations
... In our cohort, we identified two patients with alterations in the DNA damage response genes CHEK2 and FANCA. Two other studies have also identified alterations in DNA damage response genes in GIST [45,50]. It will be interesting to see if GISTs with alterations in DNA damage response genes respond to poly (ADP-ribose) polymerase (PARP) inhibitors. ...
Simple Summary
Most gastrointestinal stromal tumors (GISTs) are driven by activating mutations in KIT and PDGFRA or alterations in the succinate dehydrogenase (SDH) complex. A small fraction of GISTs lack alterations in KIT, PDGFRA, and the SDH complex, so-called “triple-negative” GISTs. We assessed clinical genomic sequencing, treatment, and survival outcomes in a cohort of 20 triple-negative GISTs. Genomic alterations were most commonly seen in the RAS/RAF/MAPK pathway and the DNA damage response pathway. Compared to KIT/PDGFRA mutant GIST, limited benefit was observed with imatinib in triple-negative GIST. In-depth molecular profiling can be helpful in identifying driver mutations and guiding therapy.
Abstract
Objective: The vast majority of gastrointestinal stromal tumors (GISTs) are driven by activating mutations in KIT, PDGFRA, or components of the succinate dehydrogenase (SDH) complex (SDHA, SDHB, SDHC, and SDHD genes). A small fraction of GISTs lack alterations in KIT, PDGFRA, and SDH. We aimed to further characterize the clinical and genomic characteristics of these so-called “triple-negative” GISTs. Methods: We extracted clinical and genomic data from patients seen at MD Anderson Cancer Center with a diagnosis of GIST and available clinical next generation sequencing data to identify “triple-negative” patients. Results: Of the 20 patients identified, 11 (55.0%) had gastric, 8 (40.0%) had small intestinal, and 1 (5.0%) had rectal primary sites. In total, 18 patients (90.0%) eventually developed recurrent or metastatic disease, and 8 of these presented with de novo metastatic disease. For the 13 patients with evaluable response to imatinib (e.g., neoadjuvant treatment or for recurrent/metastatic disease), the median PFS with imatinib was 4.4 months (range 0.5–191.8 months). Outcomes varied widely, as some patients rapidly developed progressive disease while others had more indolent disease. Regarding potential genomic drivers, four patients were found to have alterations in the RAS/RAF/MAPK pathway: two with a BRAF V600E mutation and two with NF1 loss-of-function (LOF) mutations (one deletion and one splice site mutation). In addition, we identified two with TP53 LOF mutations, one with NTRK3 fusion (ETV6-NTRK3), one with PTEN deletion, one with FGFR1 gain-of-function (GOF) mutation (K654E), one with CHEK2 LOF mutation (T367fs*), one with Aurora kinase A fusion (AURKA-CSTF1), and one with FANCA deletion. Patients had better responses with molecularly targeted therapies than with imatinib. Conclusions: Triple-negative GISTs comprise a diverse cohort with different driver mutations. Compared to KIT/PDGFRA-mutant GIST, limited benefit was observed with imatinib in triple-negative GIST. In depth molecular profiling can be helpful in identifying driver mutations and guiding therapy.
... KIT exon 11 mutations account for more than 70 % of KIT mutations and promote tumorigenesis of GISTs [4]. GISTs with primary KIT exon 11 mutation performs the best therapy response to imatinib. ...
... KIT mutations typically affected the juxtamembrane domain encoded by exon 11 [2]. Previous studies showed that KIT exon 11 mutation accounted for a range from 61 % to 93.8 % of KIT mutations and was an independent prognostic factor for progression-free survival and overall survival of GISTs [4,25,26]. In this study, we found 71 % (45 of 63) GIST patients involved KIT exon 11 mutation. ...
Background
KIT exon 11 mutation in gastrointestinal stromal tumors (GISTs) is associated with treatment strategies. However, few studies have shown the role of imaging-based texture analysis in KIT exon 11 mutation in GISTs. In this study, we aimed to show the association between computed tomography (CT)-based texture features and KIT exon 11 mutation.
Methods
Ninety-five GISTs confirmed by surgery and identified with mutational genotype of KIT were included in this study. By amplifying the samples using over-sampling technique, a total of 183 region of interest (ROI) segments were extracted from 63 patients as training cohort. The 63 new ROI segments were extracted from the 63 patients as internal validation cohort. Thirty-two patients who underwent KIT exon 11 mutation test during 2021–2023 was selected as external validation cohort. The textural parameters were evaluated both in training cohort and validation cohort. Least absolute shrinkage and selection operator (LASSO) algorithms and logistic regression analysis were used to select the discriminant features.
Results
Three of textural features were obtained using LASSO analysis. Logistic regression analysis showed that patients’ age, tumor location and radiomics features were significantly associated with KIT exon 11 mutation (p < 0.05). A nomogram was developed based on the associated factors. The area under the curve (AUC) of clinical features, radiomics features and their combination in training cohort was 0.687 (95 % CI: 0.604–0.771), 0.829 (95 % CI: 0.768–0.890) and 0.874 (95 % CI: 0.822–0.926), respectively. The AUC of radiomics features in internal validation cohort and external cohort was 0.880 (95 % CI: 0.796–0.964) and 0.827 (95%CI: 0.667–0.987), respectively.
Conclusion
The CT texture-based model can be used to predict KIT exon 11 mutation in GISTs.
