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Transcriptome Signature of Immune Cells Post Reovirus Treatment in KRAS Mutated Colorectal Cancer
Cancer Management and Research ( IF 2.5 ) Pub Date : 2021-08-27 , DOI: 10.2147/cmar.s324203 Elisha J Fogel 1 , Avishai Samouha 1 , Sanjay Goel 2 , Radhashree Maitra 1, 2
Cancer Management and Research ( IF 2.5 ) Pub Date : 2021-08-27 , DOI: 10.2147/cmar.s324203 Elisha J Fogel 1 , Avishai Samouha 1 , Sanjay Goel 2 , Radhashree Maitra 1, 2
Affiliation
Purpose: Reovirus propagates with high efficiency in KRAS mutated colorectal cancer (CRC). About 45– 50% of CRC patients possess a KRAS mutation. Oncolytic reovirus treatment in combination with chemotherapy was tested in patients possessing KRAS mutated metastatic CRC. This study evaluates the biological responses to reovirus treatment by determining the gene expression patterns in RAS-related signaling pathways.
Methods: Reovirus was administered as a 60-min intravenous infusion for 5 consecutive days every 28 days, at a tissue culture infective dose (TCID50) of 3× 1010. Peripheral blood mononuclear cells (PBMCs) were isolated from whole-blood pre- and post-reovirus administration at 48 hr, day-8, and day-15. Clariom_D_Human_Assay was used to determine the expression of vital genes compared to pre-reovirus treatment by RNA sequencing. Using exported sample signals, ΔΔCt method was used to analyze the fold changes of genes within seven gene pathways. Significance was calculated by students-two-tail-t-test. Hierarchical clustering dendrogram was constructed by calculating Pearson’s correlation coefficients.
Results: As compared to the control, SOS1[48 hr; 2.49X], RRAS [48 hr; 2.24X], PIK3CB [D8, D15; 2.27X, 3.16X], MIR 16– 2 [D15; 1.70X], CHORDC1 [48 hr, D15; 1.89X, 4.54X], RTN4 [48 hr; 4.66X], FAM96A [48 hr; 4.54X], NFKB [D8, D15; 19.0X, 1.42X], CASP8 [D8, D15; 2.11X, 1.77X], and CASP9 [D8; 1.45X] are upregulated post-reovirus. NOS3 [D15; 0.61X], SYNE1 [D8, D15; 0.78X, 0.71X], ANGPT1 [D8; 0.62X], VEGFB [48 hr, D8, D15; 0.44X, 0.28X, 0.28X], JUN [D15; 0.69X], and IGF2 [D8; 0.73X] are downregulated post-reovirus. Fold change values were significant [p< 0.05].
Conclusion: This study highlights reovirus as a novel treatment option for KRAS mutated CRC and showcases its effect on the expression of crucial genes.
Keywords: transcriptome, reovirus, CRC, KRAS, CASP8, CHORDC1, RTN4, VEGFB
中文翻译：
KRAS 突变结直肠癌呼肠孤病毒治疗后免疫细胞的转录组特征
目的：呼肠孤病毒在KRAS突变的结直肠癌 (CRC)中高效繁殖。大约 45-50% 的 CRC 患者具有KRAS突变。在患有KRAS突变的转移性 CRC的患者中测试了溶瘤呼肠孤病毒治疗与化学疗法的结合。本研究通过确定 RAS 相关信号通路中的基因表达模式来评估呼肠孤病毒治疗的生物学反应。
方法：呼肠孤病毒每 28 天连续 5 天静脉输注 60 分钟，组织培养感染剂量 (TCID 50 ) 为 3×10 10. 在 48 小时、第 8 天和第 15 天，从全血前和后呼肠孤病毒给药中分离外周血单个核细胞 (PBMC)。Clariom_D_Human_Assay 用于确定与通过 RNA 测序进行的呼肠孤病毒前处理相比重要基因的表达。使用输出的样本信号，使用ΔΔCt方法分析7个基因通路内基因的倍数变化。显着性通过学生双尾t检验计算。通过计算皮尔逊相关系数构建层次聚类树状图。
结果：与对照相比，SOS1 [48 小时；2.49X]，RRAS [48 小时；2.24X]、PIK3CB [D8、D15；2.27X, 3.16X], MIR 16-2 [D15; 1.70X],CHORDC1 [48 小时，D15；1.89X、4.54X]、RTN4 [48 小时；4.66X]，FAM96A [48 小时；4.54X]、NFKB [ D8、D15；19.0X, 1.42X], CASP8 [D8, D15; 2.11X、1.77X] 和CASP9 [D8；1.45X] 是呼肠孤病毒后上调的。NOS3 [D15; 0.61X]、SYNE1 [D8、D15；0.78X, 0.71X], ANGPT1 [D8; 0.62X]，VEGFB [48 小时，D8，D15；0.44X, 0.28X, 0.28X], JUN [D15; 0.69X]和IGF2 [D8；0.73X] 是呼肠孤病毒后下调的。倍数变化值显着 [p<0.05]。
结论：本研究强调呼肠孤病毒是KRAS的一种新型治疗选择突变的CRC并展示其对关键基因表达的影响。
关键词：转录组，呼肠孤病毒，CRC，KRAS，CASP8，CHORDC1，RTN4，VEGFB
更新日期：2021-08-26
Methods: Reovirus was administered as a 60-min intravenous infusion for 5 consecutive days every 28 days, at a tissue culture infective dose (TCID50) of 3× 1010. Peripheral blood mononuclear cells (PBMCs) were isolated from whole-blood pre- and post-reovirus administration at 48 hr, day-8, and day-15. Clariom_D_Human_Assay was used to determine the expression of vital genes compared to pre-reovirus treatment by RNA sequencing. Using exported sample signals, ΔΔCt method was used to analyze the fold changes of genes within seven gene pathways. Significance was calculated by students-two-tail-t-test. Hierarchical clustering dendrogram was constructed by calculating Pearson’s correlation coefficients.
Results: As compared to the control, SOS1[48 hr; 2.49X], RRAS [48 hr; 2.24X], PIK3CB [D8, D15; 2.27X, 3.16X], MIR 16– 2 [D15; 1.70X], CHORDC1 [48 hr, D15; 1.89X, 4.54X], RTN4 [48 hr; 4.66X], FAM96A [48 hr; 4.54X], NFKB [D8, D15; 19.0X, 1.42X], CASP8 [D8, D15; 2.11X, 1.77X], and CASP9 [D8; 1.45X] are upregulated post-reovirus. NOS3 [D15; 0.61X], SYNE1 [D8, D15; 0.78X, 0.71X], ANGPT1 [D8; 0.62X], VEGFB [48 hr, D8, D15; 0.44X, 0.28X, 0.28X], JUN [D15; 0.69X], and IGF2 [D8; 0.73X] are downregulated post-reovirus. Fold change values were significant [p< 0.05].
Conclusion: This study highlights reovirus as a novel treatment option for KRAS mutated CRC and showcases its effect on the expression of crucial genes.
Keywords: transcriptome, reovirus, CRC, KRAS, CASP8, CHORDC1, RTN4, VEGFB
中文翻译：
KRAS 突变结直肠癌呼肠孤病毒治疗后免疫细胞的转录组特征
目的：呼肠孤病毒在KRAS突变的结直肠癌 (CRC)中高效繁殖。大约 45-50% 的 CRC 患者具有KRAS突变。在患有KRAS突变的转移性 CRC的患者中测试了溶瘤呼肠孤病毒治疗与化学疗法的结合。本研究通过确定 RAS 相关信号通路中的基因表达模式来评估呼肠孤病毒治疗的生物学反应。
方法：呼肠孤病毒每 28 天连续 5 天静脉输注 60 分钟，组织培养感染剂量 (TCID 50 ) 为 3×10 10. 在 48 小时、第 8 天和第 15 天，从全血前和后呼肠孤病毒给药中分离外周血单个核细胞 (PBMC)。Clariom_D_Human_Assay 用于确定与通过 RNA 测序进行的呼肠孤病毒前处理相比重要基因的表达。使用输出的样本信号，使用ΔΔCt方法分析7个基因通路内基因的倍数变化。显着性通过学生双尾t检验计算。通过计算皮尔逊相关系数构建层次聚类树状图。
结果：与对照相比，SOS1 [48 小时；2.49X]，RRAS [48 小时；2.24X]、PIK3CB [D8、D15；2.27X, 3.16X], MIR 16-2 [D15; 1.70X],CHORDC1 [48 小时，D15；1.89X、4.54X]、RTN4 [48 小时；4.66X]，FAM96A [48 小时；4.54X]、NFKB [ D8、D15；19.0X, 1.42X], CASP8 [D8, D15; 2.11X、1.77X] 和CASP9 [D8；1.45X] 是呼肠孤病毒后上调的。NOS3 [D15; 0.61X]、SYNE1 [D8、D15；0.78X, 0.71X], ANGPT1 [D8; 0.62X]，VEGFB [48 小时，D8，D15；0.44X, 0.28X, 0.28X], JUN [D15; 0.69X]和IGF2 [D8；0.73X] 是呼肠孤病毒后下调的。倍数变化值显着 [p<0.05]。
结论：本研究强调呼肠孤病毒是KRAS的一种新型治疗选择突变的CRC并展示其对关键基因表达的影响。
关键词：转录组，呼肠孤病毒，CRC，KRAS，CASP8，CHORDC1，RTN4，VEGFB
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