Retrospective study of distributions of FcGRIIa-131 and FcGRIIIa-158 polymorphisms and clinical response to cetuximab in metastatic colorectal cancer (mCRC)
Ontology highlight
ABSTRACT:
DISEASE(S): Colorectal Cancer
PROVIDER: 2619688 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:Detection of single feature polymorphisms comparing five barley genotypes. Gene expression under unstressed and drought stressed conditions. Tissue from five entire five day old seedlings from drought stress or unstressed growth conditions was used for RNA extraction. For Barke, Morex and Stepoe the two types of RNA were pooled. For Oregon Wolfe Barley Dominant and Recessive (OWBs), the two types of RNA were handled separately. Targets from three biological replicates of each genotype-treatment were generated and transcript levels were determined using Affymetrix Barley1 GeneChip arrays. Probe set, followed by single probe, comparisons between genotypes allows the identification of single feature polymorphisms in comparisons between genotypes. For the OWBs, comparisons between stressed and unstressed conditions defines stress-regulated genes. Keywords: repeat
2005-08-25 | GSE3170 | GEO
Project description:PurposeWe aimed to identify new predictive biomarkers for cetuximab in first-line treatment for patients with RAS wild-type metastatic colorectal cancer (mCRC).MethodsThe study included patients with KRAS wild-type unresectable liver-limited mCRC treated with chemotherapy with or without cetuximab. Next-generation sequencing was done for single nucleotide polymorphism according to custom panel. Potential predictive biomarkers were identified and integrated into a predictive model within a training cohort. The model was validated in a validation cohort.ResultsThirty-one of 247(12.6%) patients harbored RAS mutations. In training cohort (N=93), six potential predictive genes, namely, ATP6V1B1, CUL9, ERBB2, LY6G6D, PTCH1, and RBMXL3, were identified. According to predictive model, patients were divided into responsive group (n=66) or refractory group (n=27). In responsive group, efficacy outcomes were significantly improved by addition of cetuximab to chemotherapy. In refractory group, no benefit was observed. Interaction test was significant across all endpoints. In validation cohort (N=123), similar results were also observed.ConclusionsIn the first-line treatment of mCRC, the predictive model integrating six new predictive mutations divided patients well, indicating a promising approach to further refine patient selection for cetuximab on the basis of RAS mutations.
| S-EPMC6165607 | biostudies-literature
Project description:Detection of single feature polymorphisms comparing five barley genotypes. Gene expression under unstressed and drought stressed conditions. Tissue from five entire five day old seedlings from drought stress or unstressed growth conditions was used for RNA extraction. For Barke, Morex and Stepoe the two types of RNA were pooled. For Oregon Wolfe Barley Dominant and Recessive (OWBs), the two types of RNA were handled separately. Targets from three biological replicates of each genotype-treatment were generated and transcript levels were determined using Affymetrix Barley1 GeneChip arrays. Probe set, followed by single probe, comparisons between genotypes allows the identification of single feature polymorphisms in comparisons between genotypes. For the OWBs, comparisons between stressed and unstressed conditions defines stress-regulated genes. Experiment Overall Design: Three genotypes, three replicates each. Two additional genotypes, two sets of three replicates each.
2008-06-12 | E-GEOD-3170 | biostudies-arrayexpress
Project description:The insulin-like growth factor 1 (IGF1) signaling pathway is an important growth-regulatory pathway, which plays a crucial role in colorectal cancer (CRC) proliferation, differentiation, migration, angiogenesis, and apoptosis. Previous studies showed that hyperactivation of the IGF1 receptor (IGF1R) may result in resistance to anti-epidermal growth factor receptor-targeted treatment. We tested whether germline variations within the IGF1 pathway are associated with clinical outcome in wild-type (wt) KRAS drug-refractory metastatic CRC (mCRC) patients who were treated with cetuximab monotherapy (IMC-0144).Formalin-fixed, paraffin-embedded (FFPE) tissue samples of 130 drug-refractory mCRC patients enrolled in IMC-0144, a phase II clinical trial of cetuximab monotherapy, were analyzed. gDNA was extracted from dissected FFPE tumor tissue, and KRAS mutation status and six potentially functional IGF1 and IGF1R polymorphisms were analyzed using direct DNA sequencing or PCR-RFLP. Tumor response analysis was based on recursive partitioning, and survival analyses were based on univariate and multivariate hazard regression models.In univariate and multivariate analyses, five IGF pathway single-nucleotide polymorphisms were significantly associated with progression-free survival (PFS) and/or overall survival (OS). In multivariate combined risk allele analysis, the additive model for PFS and OS was significantly associated with the number of risk alleles in wt KRAS patients (P = 0.001 and P = 0.02, respectively). In addition, wt KRAS patients harboring IGF1 rs2946834 A/A genotype had a 50% objective response rate compared with 0% for A/G genotype.These results indicate that IGF1 pathway polymorphisms are potential predictive/prognostic molecular markers for cetuximab efficacy in wt KRAS mCRC patients. Prospective biomarker-embedded clinical trials are warranted to validate our findings. Clin Cancer Res; 16(22); 5591-602. ©2010 AACR.
| S-EPMC2982939 | biostudies-literature
Project description:IntroductionImmunotherapy has limited efficacy in metastatic colorectal cancer (mCRC). Understanding mechanisms mediating immune resistance in microsatellite stable (MSS) colorectal tumors remains an ongoing challenge. Novel combination immunotherapy-based approaches have been developed under the rationale of overcoming immune resistance and developing effective immune response against colorectal tumor cells. Preclinical studies have demonstrated that cetuximab may modulate immune response to cancer cells. In this scenario, the inhibition of PD-L1 with IgG1 MAb avelumab in combination with anti-EGFR IgG1 monoclonal antibody cetuximab could be a strategy for potentiating antitumor activity. The CAVE phase II single-arm clinical trial provided the first evidence of clinical activity of combining cetuximab plus avelumab in 77 patients with RAS wild-type (WT) mCRC. This combination had a good toxicity profile, with a low rate of common grade 3 adverse events.Patients and methodsBased on results obtained with the CAVE clinical trial, here we describe the design and rationale for the phase II, randomized CAVE 2 clinical study of the combination of avelumab plus cetuximab as a rechallenge strategy in pre-treated RAS, BRAF WT mCRC patients treated in first line with chemotherapy in combination with cetuximab and who have had a clinical benefit (complete or partial response) from treatment. A total of 173 patients will be randomized (2:1) to cetuximab + avelumab (115) or cetuximab as a single agent (58). The primary endpoint is overall survival. Key secondary endpoints include overall response rate, progression-free survival, and safety. For each patient, before treatment, a blood sample will be obtained and analyzed for circulating free tumor DNA according to NGS (Foundation/Roche), to identify RAS/BRAF WT patients to be enrolled. The same procedure will be performed at the progression of the disease. Additional blood/plasma, tumor, and fecal samples will be collected and centrally stored for additional translational studies.DiscussionThis study will provide the rationale to test immunotherapy-based combinations in the clinical setting, offering new opportunities for RAS WT mCRC patients.Clinical trial registration[https://clinicaltrials.gov/ct2/show/NCT05291156], identifier [NCT05291156].
| S-EPMC9272566 | biostudies-literature
Project description:The Endoplasmic reticulum aminopeptidase I (ERAP1) trims peptides to their optimal size for binding to Major Histocompatibility Complex class I proteins. The natural polymorphism of this enzyme is associated with ankylosing spondylitis (AS) in epistasis with the major risk factor for this disease, HLA-B*27, suggesting a direct relationship between AS and HLA-B*27-bound peptides. Three polymorphisms that affect peptide trimming protect from AS: K528R, D575N/R725Q, and Q730E. We characterized and ranked the effects of each mutation, and their various combinations, by quantitative comparisons of the HLA-B*27 peptidomes from cells expressing distinct ERAP1 variants. Five features were examined: peptide length, N-terminal flanking residues, N-terminal residues of the natural ligands, internal sequences and affinity for B*27:05. Polymorphism at residue 528 showed the largest influence, affecting all five features regardless of peptide length. D575N/R725Q showed a much smaller effect. Yet, when co-occurring with K528R, it added to this latter change in decreasing ERAP1 activity. Polymorphism at residue 730 showed a significant influence on peptide length, reflecting differential trimming of nonamers and longer peptides. Accordingly, multiple features were affected by the Q730E mutation in a length-dependent way. The alterations induced in the B*27:05 peptidome by natural ERAP1 variants with different K528R/Q730E combinations reflected separate and additive effects of both mutations. Thus, the influence of ERAP1 on HLA-B*27 is very diverse at the population level, due to the multiplicity and complexity of ERAP1 variants, and to the distinct effects of their co-occurring polymorphisms, leading to significant modulation of disease risk among HLA-B*27-positive individuals.
2018-04-10 | PXD008500 | Pride
Project description:Background: Genome-wide detection of single feature polymorphisms (SFP) in swine using transcriptome profiling of day 25 placental RNA by contrasting probe intensities from either Meishan or an occidental composite breed with Affymetrix porcine microarrays is presented. A linear mixed model analysis was used to identify significant breed-by-probe interactions. Results: Gene specific linear mixed models were fit to each of the log2 transformed probe intensities on these arrays, using fixed effects for breed, probe, breed-by-probe interaction, and a random effect for array. After surveying the day 25 placental transcriptome, 789 probes with a q-value ≤ 0.05 and |fold change| ≥ 2 for the breed-by-probe interaction were identified as candidates containing SFP. To address the quality of the bioinformatics approach, universal pyrosequencing assays were designed from Affymetrix exemplar sequences to independently assess polymorphisms within a subset of probes. Of those probes sampled from high-, medium-, and low-ranking categories, 20 of 27 were confirmed by pyrosequencing to contain SFPs. In most cases, the 25-mer probe sequence printed on the microarray diverged from Meishan, not occidental crosses. This analysis was used to define a set of highly reliable predicted SFPs according to their probability scores. Conclusions: By this method we detected transition and transversion single nucleotide polymorphisms, as well as insertions/deletions. These results demonstrate that this approach can identify polymorphisms between two breeds and/or lines of any species for which a short oligonucleotide array is available, and can be used to rapidly develop markers for genetic mapping and association analysis in species where high density genotyping platforms are otherwise unavailable. SNPs and INDELS discovered by this approach have been publicly deposited in NCBI’s SNP repository dbSNP. This method is an attractive bioinformatics tool for uncovering breed-by-probe interactions, for rapidly identifying expressed SNPs, for investigating potential functional correlations between gene expression and breed polymorphisms, and is robust enough to be used on any Affymetrix gene expression platform. Keywords: Transcriptional profiling of Day 25 porcine placentas
2008-02-09 | GSE10447 | GEO
Project description:Gut microbiota is involved in immune modulation and immune checkpoint inhibitors (ICIs) efficacy. Single-arm phase II CAVE-mCRC and CAVE-LUNG clinical trials investigated cetuximab + avelumab combination in RAS wild-type (WT) metastatic colorectal cancer (mCRC) and chemo-refractory nonsmall cell lung cancer (NSCLC) patients, respectively. A comprehensive gut microbiota genetic analysis was done in basal fecal samples of 14 patients from CAVE-mCRC trial with circulating tumor DNA (ctDNA) RAS/BRAF WT and microsatellite stable (MSS) disease. Results were validated in a cohort of 10 patients from CAVE-Lung trial. 16S rRNA sequencing revealed 23 027 bacteria species in basal fecal samples of 14 patients from CAVE-mCRC trial. In five long-term responding patients (progression-free survival [PFS], 9-24 months) significant increases in two butyrate-producing bacteria, Agathobacter M104/1 (P = .018) and Blautia SR1/5 (P = .023) were found compared to nine patients with shorter PFS (2-6 months). A significantly better PFS was also observed according to the presence or absence of these species in basal fecal samples. For Agathobacter M104/1, median PFS (mPFS) was 13.5 months (95% confidence interval [CI], 6.5-20.5 months) vs 4.6 months (95% CI, 1.8-7.4 months); P = .006. For Blautia SR1/5, mPFS was 5.9 months (95% CI, 2.2-9.7 months) vs 3.6 months (95% CI, 3.3-4.0 months); P = .021. Similarly, in CAVE-Lung validation cohort, Agathobacter M104/1 and Blautia SR1/5 expression were associated with PFS according to their presence or absence in basal fecal samples. Agathobacter and Blautia species could be potential biomarkers of outcome in mCRC, and NSCLC patients treated with cetuximab + avelumab. These findings deserve further investigation.
| S-EPMC9321613 | biostudies-literature
Project description:Genetic control of yeast chromatin acetylation epi-polymorphisms
2012-09-21 | E-MTAB-575 | biostudies-arrayexpress
Project description:ObjectivesTo assess the cost-effectiveness of cetuximab in combination with chemotherapy fluorouracil, oxaliplatin, and leucovorin (FOLFOX) or fluorouracil, irinotecan and leucovorin (FOLFIRI) compared to standard chemotherapy alone as a first-line treatment for metastatic colorectal cancer (mCRC) with positive KRAS wild type patients in Indonesia.MethodsA cost-utility analysis applying Markov model was constructed, with a societal perspective. Clinical evidence was derived from published clinical trials. Direct medical costs were gathered from hospital billings. Meanwhile, direct non-medical costs, indirect costs, and utility data were collected by directly interviewing patients. We applied 3% discount rate for both costs and outcomes. Probabilistic sensitivity analysis was performed to explore the model's uncertainty. Additionally, using payer perspective, budget impact analysis was estimated to project the financial impact of treatment coverage.ResultsThere was no significant difference in life years gained (LYG) between cetuximab plus FOLFOX/FOLFIRI and chemotherapy alone. The incremental QALY was only one month, and the incremental cost-effectiveness ratio (ICER) was approximately IDR 3 billion/QALY for cetuximab plus chemotherapy. Using 1-3 GDP per capita (IDR 215 million or USD 14,350) as the current threshold, the cetuximab plus chemotherapy was not cost-effective. The budget impact analysis resulted that if cetuximab plus chemotherapy remain included in the benefits package under the Indonesian national health insurance (NHI) system, the payer would need more than IDR 1 trillion for five years.ConclusionsThe combination of cetuximab and chemotherapy for mCRC is unlikely cost-effective and has a substantial financial impact on the system.
| S-EPMC10408081 | biostudies-literature