<div>Abstract<p>Whether there is an association between SWI/SNF genomic alterations in tumors and response to immune checkpoint inhibitors (ICI) remains unclear because prior studies have focused on either an individual gene or a predefined set of genes. Herein, using mutational and clinical data from 832 ICI-treated patients who underwent whole-exome sequencing, including sequencing of all 31 genes of the SWI/SNF complex, we found that SWI/SNF complex alterations were associated with significantly improved overall survival (OS) in melanoma, clear-cell renal cell carcinoma, and gastrointestinal cancer, as well as improved progression-free survival (PFS) in non–small cell lung cancer. Including tumor mutational burden as a variable, the multivariate Cox regression analysis showed SWI/SNF genomic alterations had prognostic value in melanoma [HR, 0.63 (95% confidence interval, CI, 0.47–0.85), <i>P</i> = 0.003], clear-cell renal cell carcinoma [HR, 0.62 (95% CI, 0.46–0.85), <i>P</i> = 0.003], and gastrointestinal cancer [HR, 0.42 (95% CI, 0.18–1.01), <i>P</i> = 0.053]. Furthermore, we used the random forest method for variable screening, identifying 14 genes as a SWI/SNF signature for potential clinical application. Significant correlations were observed between SWI/SNF signature alterations and improved OS and PFS in all cohorts. This suggests that SWI/SNF gene alterations are associated with better clinical outcomes in ICI-treated patients and may serve as a predictive marker for ICI therapy in multiple cancers.</p></div>
e15250 Background: Predictive biomarkers of response to immune checkpoint inhibitors (ICIs) help to identify cancer patients who will benefit from immunotherapy. PRKDC is an important gene relates to DNA double-strand break (DSB) repair and central T-cell tolerance. We aim to investigate the association between PRKDC mutations and tumor mutation burden (TMB), tumor microenvironments (TME), and response to ICIs. Methods: The whole exome sequencing data of 4022 solid tumor samples from the Cancer Genome Atlas (TCGA) and the panel-based sequencing data of 4652 solid tumor samples from GenePlus-Beijing, China were used to analyze TMB. The mRNA expression data of 3541 solid tumor samples from TCGA was used to explore the effect of PRKDC mutation on TME. Four ICIs-treated cohorts were analyzed for verifying the correlation between PRKDC mutation and the response to ICIs. Results: In TCGA datasets and GenePlus datasets, we both found that the TMB in PRKDC mutation samples were significantly higher than PRKDC wild-type samples(P < 0.05, P<0.0001 respectively). When compare to other pivotal DNA damage response (DDR) genes, it showed an identical effect of the degree in TMB by PRKDC mutation with MMR ( PMS2/ MLH1/ MSH2/ MSH6) genes, POLE/D1 and BRCA1/2 mutation (P > 0.05). Further, in TCGA datasets, it showed that PRKDC mutation samples were associated with significant expression increase of CD8+ T cells, NK cells, immune-checkpoint, chemokines etc compared to PRKDC wild-type samples (P < 0.05). In ICIs-treated cohorts, we also found the PRKDC mutation was associated with superior survival(median PFS, not reached (NR) vs. 6.8 months HR, 0.2893 95% CI, 0.1255-0.6672 P = 0.0650, Hellmann cohort; median OS, 1184 days vs. 250 days HR, 0.5126 95% CI, 0.2715-0.9679 P = 0.1020, Allen cohort), and the superiority was significantly in multivariate Cox regression analyses (HR, 0.361 95% CI,0.155-0.841; P = 0.018, Allen cohort; HR, 0.240 95% CI,0.058-0.998; P = 0.050, Hellmann cohort). Conclusions: PRKDC mutations are associated with an increased TMB, an inflamed TME and a better response to ICIs, it may be a potential predictive biomarker for ICIs-immunotherapy.
Sorafenib is the first FDA‐approved therapeutic drug for molecular target medication on advanced‐stage hepatocellular carcinoma. It is reported that sorafenib could improve the survival of progression‐free patients for 4 to 6 months; however, most of the patients developed drug resistance. Thus, it is critical to reveal the biological mechanisms behind sorafenib resistance. In this study, a sorafenib‐resistant model was developed by exposing HepG2 cells to sorafenib with gradient increasing concentration, and the resistance‐related genes were screened by microarray. Real‐time qPCR was used to validate selected gene expression of the resistance model, and lentivirus vector‐mediated RNA interference was applied for specific gene knockdown. In addition, high‐throughput High Celigo Select (HCS) and flow cytometry were used to measure the effect on cellular proliferation and apoptosis. As a result, our study established a sorafenib‐resistant model with IC 50 of 9.988 μ M. The Affymetrix expression profile of the sorafenib‐resistant model showed 35 resistant‐related genes, and 91.4% of the resistant genes showed upregulation in HepG2 resistance cells. In addition, 20 genes were knocked down to measure cell proliferation, and MAP4K3 with high proliferation inhibiting phenotype was chosen for further study. Meanwhile, the HCS results revealed that shMAP4K3 transfection could downregulate resistant cell proliferation, and the flow cytometry results showed that cell apoptosis was significantly increased in the MAP4K3 knockdown group. In summary, MAP4K3 is a novel molecular marker for improving the drug sensitivity of sorafenib treatment in hepatocellular carcinoma.
Abstract The current tumour-node-metastasis (TNM) staging system alone cannot provide adequate information for prognosis and adjuvant chemotherapy benefits in patients with gastric cancer (GC). Pathomics, which is based on the development of digital pathology, is an emerging field that might improve clinical management. Herein, we propose a pathomics signature (PS GC ) that is derived from multiple pathomics features of haematoxylin and eosin-stained slides. We find that the PS GC is an independent predictor of prognosis. A nomogram incorporating the PS GC and TNM staging system shows significantly improved accuracy in predicting the prognosis compared to the TNM staging system alone. Moreover, in stage II and III GC patients with a low PS GC (but not in those with a high PS GC ), satisfactory chemotherapy benefits are observed. Therefore, the PS GC could serve as a prognostic predictor in patients with GC and might be a potential predictive indicator for decision-making regarding adjuvant chemotherapy.
To observe the lethal effect of multidrug resistance gene (MDR1) antisense RNA combined with oxaliplatin and 5-FU on drug-resistant rectal carcinoma cells.PC-MDR1 plasmid including MDR1 was constructed with gene cloning techniques. The drug-resistant cancer cells (8348R) were transferred with the plasmids, and the positive neoplasm cells were selected with G418. Green fluorescent protein (GFP) gene was used as a reporting gene to monitor the gene transfer efficiency under the influence of oxaliplatin and 5-FU. The cytotoxicity and therapeutic effects of MDR1 anti-sense RNA combined with oxaliplatin and 5-FU were evaluated by colony-forming rate and MTT assay.A significant decrease of biological activity was observed in 8348R cells transferred with PC-MDR1, cell cycles were blocked in S phase, or in G2/M phase, and apoptosis rate of the cells increased. With treatment of oxaliplatin, the plasmid transfer efficiency in the drug-resistant cancer cells was improved about 18 times. Using an IC(50) dose of oxaliplatin and 5-FU combined with (MDR1) anti-sense RNA, 75 percent of 8348R cells were killed, which was significant higher than that of the control cells.Combined MDR1 antisense RNA with oxaliplatin and 5-FU has a synergistic effect of killing drug-resistant cancer cells and may be a promising method for treating drug-resistant rectal carcinoma.
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