Introduction the objective was to evaluate the impact of IDH1 R132H mutation, MGMT methylation and PD-L1 expression in high grade glioma that received standard therapy (surgery, radiation and chemotherapy) to overall survival (OS). Methods this is a retrospective study of 35 high grade glioma cases. Genotyping of IDH1 gene alteration on the mutation hotspot R132 (Sanger sequencing method with Applied Biosystems 3500 Genetic Analyzer), EZ DNA Methylation-Gold kit (Zymo Research) is used to study the methylation, Cell line BT549 (ATCC HTB-122) and HCT-116 (ATCC CCL-247) were used as unmethylated control and partially methylated control respectively. Anti-human PD-L1 antibody clone E1L3N ® from Cell Signalling Technology (USA) and Rabbit XP ® were used to see PDL-1 expression. Results anaplastic astrocytoma cases had more MGMT promoter methylation (50%) than glioblastoma multiforme (GBM) (20%), more IDH1 R132H mutation (42%) than GBM (4.3%). Immunohistochemistry tumor proportion score method (TPS) identified 17% and 8.7% were PD-L1 positive in AA and GBM groups, respectively. Cases with IDH1 R132H mutation and MGMT methylation still showed better OS although with high PD-L1 expression. Conclusion IDH1 R132H mutation and MGMT methylation were good prognostic markers. High expression of PD-L1 apparently might not indicate poor overall survival in the presence of IDH1 R132 mutation and MGMT methylation.
Background: Tumor cells express programmed death ligand-1 (PD-L1) through several biological processes, thereby having different clinical significance depending on the underlying mechanism of expression. Currently, mechanisms leading to PDL1 gene expression in colorectal cancer (CRC) are not fully understood. Methods: We investigated 98 Indonesia CRC patients to determine PD-L1 protein expressions and their correlations with PD-L1 gene copy number status, tumor infiltrating lymphocytes (TILs), tumor mutational profile, as well as clinicopathologic features. Results: Our investigation demonstrated that 18% of patients positively expressed PD-L1. Further analysis on PD-L1 copy number revealed that all PD-L1 + tumors had normal copy number, indicating that the expression of PD-L1 was not a consequence of genetic amplification of PD-L1. From TILs analysis, there was a significant increase of CD8 in all tumor cells expressing PD-L1 (P=0.0051), indicating that the inducible PD-L1 expression was the prominent mechanism occurred in CRC. Furthermore, the expression of PD-L1 in this CRC population was significantly associated with high frequency of MSI compared to the remainder PD-L1tumors (P=0.0001), suggesting the natural immunogenicity of tumors via MSI status plays role in attracting immune response. On the other hand, p53 mutations which were frequently observed within Indonesian CRCs (76.5%), they were not associated with PD-L1 expression (p=0.1108), as well as KRAS gene (29.6%; p=0.5772) and BRAF gene mutations (5%; p=0.2171). Conclusion: Our study demonstrated that PD-L1 expressions in CRC were predominantly found as a consequence of infiltrating CD8 T lymphocytes that in part arise in the setting of microsatellite instability. Taken together, our findings further support the role of adaptive immune resistance to drive PD-L1 induction in tumor microenvironment and may provide important rationale for strategy implementation of immunotherapy for CRC cases.
clinical course has been reported to occur during pregnancy. Pregnancy-associated plasma protein-A (PAPP-A) is a metalloproteinase that cleaves insulin-like growth factor 1 (IGF-1) from a circulating complex formed with insulin-like growth factor binding protein 4 (IGFBP4). Increased bioavailability of IGF1 subsequently impacts on tumour biology. PAPP-A is produced in increasing levels until term by the syncytiotrophoblast cells in the human placenta. High levels of PAPP-A have been associated with progression in other tumour types. Methods: Eleven breast cancer cell lines were examined to characterise the components of the PAPP-A/IGF axis in breast cancer. PAPP-A mRNA expression was analysed by quantitative RT-PCR. The effect of PAPP-A expression on cell migration in the MDA-MB-453 cell line was subsequently evaluated by using neutralising antibodies. An analysis of The Cancer Genome Atlas (TCGA) publicly available transcriptome profiling dataset was also performed, through specific query of expression clustering. Results: PAPP-A expression was noted in three of the cell lines. In the MDA-MB-453 cell line, which expressed high levels of PAPP-A, neutralising antibodies to PAPP-A and IGFBP4 significantly reduced migratory capabilities. Analysis of the TCGA dataset revealed that alteration (mainly upregulation) in PAPP-A expression resulted in worse overall survival (n ¼ 1104, p ¼ 0.13). Median survival with alteration in PAPP-A expression was 74 months compared with 113 months in patients without alteration in PAPP-A. Conclusions: Our data suggest that PAPP-A plays a role in the progression of breast cancer, which may be particularly relevant in pregnancy. The insights gained from this research open up the possibility of indirect and specific therapeutic targeting of IGF to halt the progression of breast cancer.
82 Background: The presence of the programmed death ligand-1 (PD-L1) has been used as biomarker to select patients and analyze responses to anti-PD-1/L1 antibodies. PD-L1 positivity may be a result of genetic mechanism leading to constitutive PD-L1 expression or inducible mechanism by T-cell presence. Each mechanism may have different significance and response to such therapy. In colorectal cancer (CRC), targeting immune checkpoint inhibitor has been recommended for patients with microsatellite instable (MSI). This study aimed to investigate the mechanism of PD-L1 gene activation in colorectal cancer (CRC) patients, particularly in MSI population. Methods: We have investigated 61 archived formalin fixed paraffin embedded CRC specimens of patients from Medistra Hospital, Jakarta admitted in 2010 - 2016. Immunohistochemistry was performed to measure expression of PD-L1 in tumor cells as well as MSI status using antibodies against PD-L1 and MMR (MLH1, MSH2, PMS2 and MSH6), respectively. Subset of PD-L1 positive patients was then assessed for copy number variations (CNVs) using Single Tube TaqMan CNA Gene CD247PD-L1. We also observed KRAS mutation to profile possible genetic mechanism leading to the presence or absence of PD-L1 expression. Results: Analysis of 61 CRC patients revealed 15 patients (24%) expressed PD-L1 on their tumor cell membranes. The prevalence of surface membrane PD-L1 was significantly higher in patients with MSI (87%; 7/8) compared to patients with microsatellite stable (MSS) patients (15%; 8/53) (P = 0.001). Although amplification of PD-L1 gene was not found among PD-L1 positive patients, low level amplification of PD-L1 gene was commonly observed in MSS patients (75%; 6/8) than in MSI patients (43%; 3/7). We found 26% of CRC patients harbored KRAS mutations (16/61), so far the distribution of KRAS status did not correlated with PD-L1 expression. Conclusions: Our data suggest genetic mechanism through amplification of PD-L1 seems not to be the mechanism underlying upregulation of PD-L1 expression in CRC patients. However, further studies are warranted to confirm the results.
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