e21517 Background: Melanoma is one of the most aggressive and immunogenic tumors. Current immunotherapies using immune checkpoint inhibitors such as CTLA4 and PD1 to stimulate T cell-mediated tumor killing significantly improved the overall survival of patients with metastatic melanoma. However, the clinical predictors of response to these therapies are still not fully characterized. Previous studies have shown that the high gene expression of Ankyrin repeat domain 36 (ANKRD36) can lead to the occurrence and poor prognosis of colon cancer and kidney cancer. In this study, we aimed to explore the role of ANKRD36 mutation in the prognosis of melanoma immune checkpoint inhibitors (ICIs). Methods: Public data of patients treated with ICIs(ipilimumab) from Van Allen (n = 110) cohort were obtained and analyzed. In survival analysis, Kaplan-Meier curves were compared by log-rank test, and the hazard ratio (HR) was determined through a multivariable Cox regression model. The potential mechanism was subsequently explored through RNA expression data from The Cancer Genome Atlas (TCGA). Results: The frequency of ANKRD36 mutation in the Van Allen cohort and TCGA cohort was 7.2% (8 in 110) and 1.56% (7 in 448) respectively. We further analyzed the Kaplan Meier curve and multiple Cox regression model of the Allen cohort and found that the survival of the mutant type in immunotherapy was significantly shorter than that of the wild-type group (PFS: HR = 3.09 [95% CI: 1.47, 6.51], p = 0.002; OS: HR = 2.33 [95% CI: 1.12, 4.86], p = 0.02). Both mutant type and tumor metastasis would have negative effects on immunotherapy(PFS: HR = 3.66 [95% CI: 1.71, 7.85], p < 0.001***; OS: HR = 3.16 [95% CI: 1.47, 6.82], p = 0.003**). Analysis of the transcriptome data from the TCGA database found that resting CD4 memory T cells is highly expressed in ANKRD36 mutant patients (p = 0.032), which may indicate that the patient's immune system did not activate the anti-tumor immune mechanism. Conclusions: In our study, the frequency of ANKRD36 mutations was investigated in clinical and TCGA cohorts, which may provide useful information for guiding patient treatment. ANKRD36 mutation may be a negative predictor of ICIs in patients with melanoma and play a role in prognosis.
e17503 Background: Cervical cancer is the fourth most common cancer in women worldwide. Metastasis and invasion of cervical cancer are closely related to the tumor microenvironment. As an effective treatment, chemoradiotherapy plays a vital role in immune-related cells and factors. However, little is known about the effect of chemoradiotherapy on the immune microenvironment in cervical cancers. Therefore, we studied the immune microenvironment alterations before and after chemoradiotherapy and analyzed their prognostic significance in cervical cancer patients. Methods: We recruited 15 patients with stage IB1-IVA cervical squamous cell carcinoma. Pelvic intensity-modulated radiotherapy (IMRT) was performed with conventional segmentation of 2Gy per irradiation (IB3 stage was treated with synchronous cisplatin for weeks), FFPE samples pre-treatment, and one-week after-chemoradiotherapy were conducted an exploratory biomarker analysis based on gene expression profiling (GEP). The panel of 289 genes was customized based on critical genes and pathways during tumor immunoregulation (e.g., tumor antigen release, T cell activation, and immune metabolism). The differential expressed genes between these two groups were then assessed. Results: Forty-two genes were found to be differentially expressed, with 21 genes having > 1.5-fold mean expression difference after chemoradiotherapy. Analysis of important GO terms and KEGG pathways indicated that the pathways enriched by different genes are located in immune-related pathways, specifically, T cell activation (GO-BP), cytokine activity (GO-MF), and cytokine-cytokine receptor interaction (KEGG). After-chemoradiotherapy, the enrichment of tumor-infiltrating lymphocytes (TILs) varied greatly, especially the macrophages. Conclusions: This study preliminarily demonstrated that chemoradiotherapy caused the release of pro-inflammatory like CCR7 and CD69 and immune cell (macrophages) infiltration alterations after chemoradiotherapy in cervical cancer patients.
e21593 Background: Immune checkpoint blockade has shown significant promise as an anticancer treatment and anti–CTLA-4 treatment prolongs overall survival in patients with melanoma. Vascular endothelial growth factor-C (VEGF-C), a member of the VEGF gene family, has been characterised as a prime mediator of lymphangiogenesis and angiogenic growth factors that promote the growth and metastasis of neoplasms. Previous studies provided evidence that VEGF-C correlated with poorer survival in melanoma. We aimed to determine the association of VEGF-C mutations with melanoma survival to immune checkpoint inhibitors (ICI). Methods: Data from Allen study (n = 110, anti- CTLA-4 therapy) was obtained and analyzed. Meanwhile, we extracted skin cutaneous melanoma (SKCM) RNA data from The Cancer Genome Atlas (TCGA). In survival analysis, Kaplan-Meier curves were compared by log-rank test, and the hazard ratio (HR) was determined through a multivariable Cox regression model. Using the Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) algorithm, the relative proportions of 22 types of infiltrating immune cells were determined in TCGA cohort. Results: In Allen cohort, the frequency of VEGFR-C mutation was 5.45% (6 in 110). Meanwhile, the frequency of VEGFR-C mutation in TCGA cohort was 7.37% (33 in 448). VEGFR-C-mutant (VEGFR-C-mut) group showed a poorer progression-free survival (PFS) (HR, 2.34; 95%CI, 1.01 to 5.4, p = 0.041) and overall survival (OS) (HR, 2.84, 95%CI, 1.22 to 6.62, p = 0.012) than the VEGFR-C-wild (VEGFR-C-wt) group, based on results of the log-rank test and Kaplan-Meier analysis. Moreover, COX proportional hazards model analysis showed VEGFR-C mutation was associated with poorer PFS (HR, 2.54; 95%CI, 1.04-6.25, p = 0.0042;) and OS (HR, 3.25; 95%CI, 1.30-8.12, p = 0.0117) compared with VEGFR-C-wt. In addition, we identified that the levels of naive B cells and resting CD4+ memory T cells were more abundant in VEGFR-C-mut group according to CIBERSORT algorithm. Conclusions: In our study, the frequency of VEGFR-C mutation in melanoma was investigated in Allen and TCGA cohorts, which might provide useful information to guide precision medicine. VEGFR-C mutation may serve as a potential negative predictor of response to anti-CTL4 treatment in melanoma via higher levels of naive B cells and resting CD4+ memory T cells.
Anaplastic lymphoma kinase ( ALK ) gene rearrangement is an essential driver mutation identified in approximately 5% of non-small cell lung cancers (NSCLCs). The results of clinical trials have demonstrated the impressive efficacy of ALK tyrosine kinase inhibitors (ALK-TKIs). Besides the classic EML4-ALK fusions, a growing list of gene fusion partners for ALK in NSCLC have been identified with heterogeneous clinical responses to ALK-TKIs. However, a LOC101927967-ALK fusion has not been reported in NSCLC. Herein, a novel LOC101927967 downstream intergenic region ALK fusion in an early-stage patient with lung adenocarcinoma was first identified by next-generation sequencing (NGS) and verified by immunohistochemical staining (IHC) and fluorescence in situ hybridization (FISH), which might provide a treatment option for postoperative recurrence.
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