Tumor immunogenomic features determine outcomes in metastatic colorectal cancer patients treated with standard-of-care combinations of bevacizumab and cetuximab
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ABSTRACT:
PROVIDER: PRJNA805525 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17982900_1.fastq.gz | Fastqsanger.gz | |||
| SRR17982900_2.fastq.gz | Fastqsanger.gz | |||
| SRR17983000_1.fastq.gz | Fastqsanger.gz | |||
| SRR17983000_2.fastq.gz | Fastqsanger.gz | |||
| SRR17983100_1.fastq.gz | Fastqsanger.gz |
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Project description:CALGB/SWOG 80405 was a randomized phase III trial in first-line mCRC patients treated with bevacizumab, cetuximab, or both, plus chemotherapy. We tested the effect of tumor immune features on OS. Primary tumors (N=554) were profiled by RNAseq. Immune signatures of macrophages, lymphocytes, TGF-β, INF-γ, wound healing, and cytotoxicity were measured. CIBERSORTx scores of naive and memory B cells, plasma cells, CD8+ T cells, resting and activated memory CD4+ T cells, M0 and M2 macrophages, and activated mast cells were measured. Increased M2 macrophage score (HR 6.30, 95% CI 3.0-12.15) and TGF-β signature expression (HR 1.35, 95% CI 1.05-1.77) were associated with shorter OS. Increased scores of plasma cells (HR 0.55, 95% CI 0.38-0.87) and activated memory CD4+ T cells (HR 0.34, 95% CI 0.16-0.65) were associated with longer OS. Using optimal cutoffs from these four features, patients were categorized as having either 4, 3, 2, or 0-1 beneficial features associated with longer OS, and the median (95% CI) OS decreased from 42.5 (35.8-47.8), to 31.0 (28.8-34.4), 25.2 (20.6-27.9), and 17.7 (13.5-20.4) months respectively (p-value 3.48e-11). New immune features can be further evaluated to improve patient response. They provide the rationale for more effective immunotherapy strategies.
2022-02-16 | GSE196576 | GEO
Project description:PurposeCALGB/SWOG 80405 was a randomized phase III trial in first-line patients with metastatic colorectal cancer treated with bevacizumab, cetuximab, or both, plus chemotherapy. We tested the effect of tumor immune features on overall survival (OS).Experimental designPrimary tumors (N = 554) were profiled by RNA sequencing. Immune signatures of macrophages, lymphocytes, TGFβ, IFNγ, wound healing, and cytotoxicity were measured. CIBERSORTx scores of naive and memory B cells, plasma cells, CD8+ T cells, resting and activated memory CD4+ T cells, M0 and M2 macrophages, and activated mast cells were measured.ResultsIncreased M2 macrophage score [HR, 6.30; 95% confidence interval (CI), 3.0-12.15] and TGFβ signature expression (HR, 1.35; 95% CI, 1.05-1.77) were associated with shorter OS. Increased scores of plasma cells (HR, 0.55; 95% CI, 0.38-0.87) and activated memory CD4+ T cells (HR, 0.34; 95% CI, 0.16-0.65) were associated with longer OS. Using optimal cutoffs from these four features, patients were categorized as having either 4, 3, 2, or 0-1 beneficial features associated with longer OS, and the median (95% CI) OS decreased from 42.5 (35.8-47.8) to 31.0 (28.8-34.4), 25.2 (20.6-27.9), and 17.7 (13.5-20.4) months respectively (P = 3.48e-11).ConclusionsNew immune features can be further evaluated to improve patient response. They provide the rationale for more effective immunotherapy strategies.
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Project description:Cetuximab is an epidermal growth factor receptor (EGFR)-blocking antibody approved for treatment of metastatic colorectal cancer. We examined differences in global gene expression between the syngeneic DiFi colorectal cancer cells, and a subline of DiFi cells with acquired resistance to cetuximab (DiFi5). We used Affymetrix HG-U133A array to compare the expression pattern of genes that are up-regulated or down-regulated between the parental DiFi colorectal cancer cells and the cetuximab-resistant DiFi5 cells. We generated a cetuximab-resistant DiFi subline, termed DiFi5, by chronic exposure of parental DiFi cells to serially increased doses of cetuximab (from 0.5 nM to 5 nM) for over 1 year. The resulting DiFi5 subline exhibits significant resistance to cetuximab-induced apoptosis. After we confirmed that the phenotype was stable over a period of time of more than 6 months, the RNA from DiFi and DiFi5 cells were extracted and hybridized to an Affymetrix HG-U133A array according to the manufacturerâs instructions. Following the hybridization, the array was scanned using a laser confocal scanner, and microarray image data were analyzed using DNA-Chip Analyzer (dChip), version 1.3, by the Sequencing and Microarray Facility at MD Anderson Cancer Center.
2016-07-17 | E-GEOD-71210 | biostudies-arrayexpress
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2012-12-01 | E-GEOD-36790 | biostudies-arrayexpress
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Project description:10 cell lines (five cetuximab sensitive and five cetuximab resistant) were selected for gene copy number array analysis on the Affymetrix SNP 6.0 platform. 39 protein coding genes were amplified in cetuximab resistant cells and normal in sensitive cells, all present on genomic regions 11q22.1 or 5p13-15. Five genes were selected for quantitative PCR verification, namely, YAP1 and TRPC6 (11q22.1) and PDCD6, TPPP, and PTGER4 (5p13-15). An extended panel of totally 10 cetuximab resistant and 10 sensitive cell lines verified that YAP1 amplified cells are cetuximab resistant. YAP1 gene amplification was highly correlated to the YAP1 mRNA expression, which was significantly higher in cetuximab resistant cells than in sensitive. YAP1 downregulation resulted in increased cetuximab sensitivity in one of two cetuximab resistant cell lines investigated and growth inhibition in another. We conclude that YAP1 is a marker for cetuximab resistance in head and neck cancer.
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