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  • 1
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    Predictive value of CDC37 gene expression for targeted therapy in metastatic colorectal cancer (mCRC).
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 16_suppl ( 2022-06-01), p. 3586-3586
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. 3586-3586
    Abstract: 3586 Background: HSP90 mediated chaperoning is a well-conserved biological mechanism for stabilization and activation of kinases. More than 60% of human kinases including VEGFR, CRAF, CSF1R, and FGFR are target of HSP90 (client kinases), whereas EGFR is non-client. CDC37 is a specific co-chaperone determining selectivity of client kinases recognized by HSP90. We hypothesized that gene expression levels of CDC37 have predictive values for anti-angiogenic therapies in mCRC. Methods: The subjects of this study were mCRC patients treated with regorafenib (REGO, Japanese retrospective cohort) and those treated with bevacizumab (BEV) or cetuximab (CET) in combination with first-line chemotherapy (CALGB/SWOG 80405 trial cohort). CDC37 expression levels were measured using RNA isolated from FFPE samples by nCounter gene expression profiling (Nanostring) and HiSeq 2500 (Illumina) in the Japanese and CALGB/SWOG 80405 cohorts, respectively. Overall survival (OS) and progression-free survival (PFS) were compared between patients with high CDC37 expression ( CDC37-H) and those with low expression ( CDC37-L), grouped by median cutoff value in each cohort. Results: In total, 484 patients were included (50 treated with REGO, 227 treated with BEV, and 207 treated with CET). In REGO-treated patients, CDC37-H showed significantly better OS (median 11.3 vs 6.0 months, adjusted hazard ratio [HR] 0.24, 95% confidence interval [CI] 0.11-0.54, p 〈 0.01) and PFS (median 3.5 vs 1.9 months, adjusted HR 0.51, 95% CI 0.28-0.94, p = 0.03) compared to CDC37-L. Similarly, in BEV-treated patients, CDC37-H showed significantly better PFS (median 13.5 vs 9.6 months, adjusted HR 0.59, 95% CI 0.43-0.79, p 〈 0.01) and numerically better OS (median 34.1 vs 29.4 months, adjusted HR 0.81, 95% CI 0.60-1.11, p = 0.20) compared to CDC37-L. However, in CET-treated patients, CDC37-H and CDC37-L patients showed similar OS (median 33.7 vs 26.1 months, adjusted HR 1.00, 95% CI 0.73-1.38, p = 0.98) and PFS (median 11.3 vs 11.0 months, adjusted HR 1.08, 95% CI 0.81-1.45, p = 0.60). Significant interaction was observed between CDC37 expression and treatment in terms of PFS in the CALGB/SWOG 80405 cohort ( p = 0.01). Conclusions: Our results suggest patients with CDC37-dependent ( CDC37-H) tumors may derive more benefit from REGO and BEV both of which target HSP90 client kinases or signaling pathways, but not from CET which target HSP90 non-client kinase. Further validation studies are warranted to develop a novel personalized approach for targeted therapies based on CDC37 expression in mCRC patients. Support: U10CA180821, U10CA180888; Pfizer, Genentech; https://acknowledgments.alliancefound.org. ClinicalTrials.gov Identifier: NCT00265850.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.16_suppl.3586
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
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  • 2
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    Predictive value of CDC37 gene expression for targeted therapy in metastatic colorectal cancer
    Elsevier BV ; 2024
    In:  European Journal of Cancer Vol. 201 ( 2024-04), p. 113914-
    Details
    In: European Journal of Cancer, Elsevier BV, Vol. 201 ( 2024-04), p. 113914-
    Type of Medium: Online Resource
    ISSN: 0959-8049
    URL: Article
    DOI: 10.1016/j.ejca.2024.113914
    RVK:
    XA 42017.A
    RVK:
    XA 42017
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2024
    detail.hit.zdb_id: 1120460-6
    detail.hit.zdb_id: 1468190-0
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  • 3
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    The role of PP2A variants to predict outcome in patients (pts) with metastatic colorectal cancer (mCRC): Data from FIRE-3 and TRIBE trials.
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 15_suppl ( 2021-05-20), p. 3581-3581
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. 3581-3581
    Abstract: 3581 Background: Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase with functions that counter-balance kinase-mediated phosphorylation throughout cell signaling networks. PP2A was reported to upregulate the angiogenesis, while negatively regulate the pathways downstream of receptor tyrosine kinases at multiple nodes. Previous studies showed PP2A variants were associated with the increased risk of cancer. Therefore, we hypothesized that PP2A variants may predict first-line treatment outcome in mCRC pts treated with bevacizumab (bev)/cetuximab (cet)-based chemotherapy. Methods: Genomic DNA from blood samples of pts enrolled in two independent randomized trials, TRIBE (bev arm, n=215, as discovery cohort) and FIRE-3 (bev arm, n=107, as validation cohort; cet arm, n=129, as control cohort), was genotyped through the OncoArray, a customized array manufactured by Illumina including approximately 530K SNP markers. The impact on outcome of 17 selected SNPs in 3 main PP2A core subunits (PPP2CA, PPP2R1B, PPP2R1A), one phosphatase activator (PPP2R4) and 2 endogenous inhibitors (TIPRL, CIP2A) was analyzed. Results: In the discovery cohort, pts with PPP2R4 rs2541164 A/A (N=16) showed significantly shorter overall survival (15.3 vs 27.3 months) compared to carriers of any G allele (N=198) in both univariate (hazard ratio [HR] =1.8; 95% confidence interval [CI]: 1.1-3.1; p=0.02) and multivariate (HR=2.4; 95%CI: 1.4-4.4; p=0.006) analysis. These data were validated in the FIRE-3 bev cohort in both univariate (A/A vs. Any G: 17.3 vs 39.9 months, HR=2.8, 95%CI: 1.4-5.9, p=0.004) and multivariate (HR=4.3, 95%CI: 1.5-12.2, p=0.0095) analysis. Conversely, pts carrying CIP2A rs13069780 C/C (N=24) only showed significantly longer progression-free survival (17.7 vs 12.3 months) than carriers of any T allele (n=105) in the FIRE-3 cet cohort in both univariate (HR=0.6; 95%CI 0.4-0.99; p=0.04) and multivariate (HR=0.5; 95%CI 0.3-0.94; p=0.02) analysis, but no association were observed in the bev cohort of TRIBE and FIRE-3. Conclusions: Our study demonstrated for the first time that PPP2R4 polymorphisms could predict outcomes of bev-based treatment in mCRC patients; Meanwhile CIP2A polymorphism could predict outcomes of cet-based treatment in mCRC patients. These findings support a possible role of the PP2A variants in contributing to resistance to anti-VEGF/EGFR treatment.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.15_suppl.3581
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
    detail.hit.zdb_id: 2005181-5
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  • 4
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    Single cell RNA-sequence analysis to identify transcriptomic differences associated with treatment outcome and ethnicity in circulating tumor cells (CTCs) from patients (pts) with metastatic colorectal cancer (mCRC).
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 15_suppl ( 2021-05-20), p. 3041-3041
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. 3041-3041
    Abstract: 3041 Background: CTCs are a promising diagnostic and prognostic biomarker in colorectal cancer. The analysis of CTCs at the single-cell level may allow to capture tumor heterogeneity and identify novel prognostic and predictive markers in mCRC. Our aim was to evaluate whether the transcriptome profile of CTCs was associated with progression-free survival (PFS) in pts receiving treatment for mCRC and whether we could identify significant differences based on pts’ ethnicity. Methods: Single CTCs were prospectively collected from 25 pts undergoing treatment for mCRC at the USC/Norris Comprehensive Cancer Center between April and October 2019. Pre-treatment peripheral blood was processed using CTC-FIND comprised filter separation and immunomagnetic depletion of CD45/50-expressing cells to collect ultra-pure CTCs samples. After isolation to single cell, CTCs were processed by single cell RNA-sequence (scRNAseq). Principal component analysis was used for clustering expression data. DESeq2 was used to identify differentially expressed genes between pts with short ( 〈 150 days) and long term ( 〉 150 days) PFS, as well as between Hispanic and non-Hispanic ethnicity with control for FDR ( Q 〈 0.1). Ingenuity pathway analyses (IPA) of enriched pathway networks were performed. Results: Main pts characteristics were as follow: median age = 52 years; M/F = 18/7; Hispanics/non-Hispanics = 7/18; treatment line (n pts) = 1st (5), 2nd (11), ≥ 3rd (9). We identified 59 single CTC and CTC cluster from 22/25 pts (range 1-9, median = 2/pt). scRNAseq analysis identified two separate clusters of pts based on PFS (short term vs long term). Hispanic pts were mainly distributed within the short term PFS cluster. The IPA of the network of top 40 enriched pathways showed several pathways related with metabolism, such as Sirtuin signaling, mitochondrial dysfunction and oxidative phosphorylation, and IL6/JAK/STAT signaling pathways in pts with short term PFS ( Q 〈 0.05). When comparing Hispanic vs non-Hispanic pts, we detected enrichment of neuroinflammation signaling pathway in Hispanics, including CXCL8 (fold change, FC: 11.04), GAD2 (FC: 4.77), IRAK3 (FC: 17.06), PLCG2 (FC: 4.65) and TYROBP (FC: 8.43) (all Q 〈 0.05). Conclusions: In our study CTCs transcriptome profiles showed an association with PFS in pts receiving treatment for mCRC, with an enrichment in mitochondria-related pathways and IL6/JAK/STAT signaling in the CTCs of pts with shorter PFS. Additionally, CTCs scRNAseq identified differentially expressed genes in Hispanic pts, displaying enrichment in neuroinflammation signaling. These results highlight the potential of CTCs molecular profiling as a tool to identify novel prognostic and predictive biomarkers in mCRC and actionable molecular pathways which may impact tumor spread and treatment response
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.15_suppl.3041
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
    detail.hit.zdb_id: 2005181-5
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  • 5
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    Globo H expression in metastatic colorectal cancer (CRC).
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 15_suppl ( 2021-05-20), p. 3527-3527
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. 3527-3527
    Abstract: 3527 Background: Globo H is a carbohydrate antigen that is highly expressed on the cell surface of epithelial cancers but not in normal tissue, and has been reported to correlate with poor prognosis. An attractive therapeutic target, Globo H-targeted agents are being tested in early clinical trials (e.g., OBI-833, a Globo H antigen conjugated to a mutated diphtheria toxin with potential antineoplastic activities, and OBI-999, an antibody-drug conjugate (ADC) consisting of a Globo H monoclonal antibody with a synthetic antineoplastic agent). We aim to describe the molecular features associated with Globo H expression in CRC. Methods: A total of 7,604 CRC tumors were tested by Caris Life Sciences (Phoenix, AZ) by NextGen DNA and RNA sequencing. The expression of β3GalT5, FUT-1 and FUT-2 were evaluated as surrogates for Globo H expression as they are the key enzymes in its biosynthesis. An average z-score of the 3 genes (GloboH) and of β3GalT5 (B3) alone were calculated; tumors with top quartile z-scores were considered expression-high (Q4) and bottom quartile, expression-low (Q1). QuantiSEQ was used to assess immune cell infiltration in the tumor microenvironment (TME). Statistical significance was determined using chi-square/Fisher-Exact and adjusted for multiple comparisons (q 〈 0.05). Consensus molecular subtype (CMS) was developed using RNA seq data. Results: When the 3 genes were considered, GloboH-H tumors showed higher prevalence of CMS1 and CMS4 (23.8% vs. 12%; 38.7% vs. 29.4%) and lower prevalence of CMS2 (40% vs. 18.7%) compared to GloboH-L. Similar patterns of CMS distribution were seen for B3 alone. B3-H tumors were significantly more frequently TMB-H ( 〉 =10) (11.4% vs. 8.3%), PD-L1 positive (5.7% vs. 3.4%) and MSI-H/dMMR (8.3% vs. 5.5%). Strong positive associations were seen with mutations in BRAF, KRAS, RSPO3 fusion, and cMYC amplification with B3 alone and GloboH (all q 〈 0.05). Anti-tumor CD4+ T cells and NK cells were increased in the TME with increased expression of GloboH and B3 (q 〈 0.05). However, immune suppressive neutrophils and Tregs were also increased. Dendritic cells were negatively associated with B3 expression while endothelial cells and fibroblasts showed a positive association with GloboH and B3. Conclusions: The association with TMB-H, MSI-H, and PD-L1 status suggests that in some tumors Globo H may be a promising target for combination therapy with immune checkpoint inhibition. The association with different cell populations suggests manipulating the cellular balance in the TME as an approach to improve the efficacy of treatment. NK cell checkpoint inhibitors are in clinical trials and might be utilized in high Globo H cancers; treatments inducing DCs in tumors have been shown to enhance responses to BRAF and PD-L1 blockade and might be applicable in the context of Globo H immunotherapy to overcome Treg immune suppression. Anti-Globo H vaccines and ADCs might be particularly effective in BRAF and KRAS-mutant CRC patients.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.15_suppl.3527
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
    detail.hit.zdb_id: 2005181-5
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  • 6
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    Comprehensive molecular analysis of microsatellite-stable (MSS) tumors with high mutational burden in gastrointestinal (GI) cancers.
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  Journal of Clinical Oncology Vol. 38, No. 15_suppl ( 2020-05-20), p. 3631-3631
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. 3631-3631
    Abstract: 3631 Background: Mutational signatures contributing to high tumor mutation burden (TMB-H) independent from microsatellite instability-high (MSI-H) status are not well-studied. We aimed to characterize specific molecular features of a large cohort of GI tumors with TMB-H & MSS. Methods: We sequenced23392 GI tumors, including 2707 gastroesophageal (GE), 11616 colorectal (CRC), and 9069 others. Samples were analyzed using Next-generation sequencing (NGS) and immunohistochemistry (IHC) (Caris Life Sciences, Phoenix, AZ). MMR/MSI status was evaluated by a combination of IHC, Fragment Analysis and NGS. Tumors with TMB ≥ 17 mutations/Mb were defined as TMB-H. PD-L1 was tested by IHC [22C3 (CPS score, positivity: CPS ≥ 1%) in GE tumors and SP142 (Positivity: TPS ≥ 5%) in other cancers]. Findings were compared in four groups (TMB-H/L & MSI-H/MSS) using Fisher-Exact or Chi-square and adjusted for multiple comparison by Benjamini-Hochberg. Significance was determined by adjusted (adj) p 〈 .05. Results: Overall, TMB-H & MSS was observed in 1% of patients (pts) (n = 237, including 45 GE, 124 CRC, 68 others), while TMB-H & MSI-H, TMB-L & MSS, TMB-L & MSI-H were observed in 4% (n = 936), 94.4% (n = 22089) and 0.6% (n = 130) respectively. Compared to other groups, TMB-H & MSS showed the most prevalent amplifications (AMPs), including CCND1 (5.6%), FGF3/4/19 (4.9%, 4.3%, 4.4%) , MYC (4.3%) (Top 5, adj p 〈 .05), and the highest mutation rates in POLE (21.6%), RB1 (13.1%), CDC73 (10.3%), RUNX1 (6.5%), and genes involved in PI3K & MAPK ( PIK3R1 17%, mTOR 3.4%, MAP2K1 3.8% , MAP2K4 5.6%) and Wnt ( APC 48.5% , SMAD2 6.5% , TCF7L2 3.8%) pathways (adj p 〈 .05). The rates of HER2 AMP and high-expression (IHC) were the highest in TMB-H & MSS, followed by TMB-L & MSS, TMB-H & MSI-H, TMB-L & MSI-H (adj p 〈 .0001); PD-L1 positive rate was similar between TMB-H & MSS and TMB-L & MSI-H, while the highest and lowest in TMB-H & MSI-H and TMB-L & MSS respectively in GE and other GI cancers (adj p 〈 .01) (Table). Conclusions: This is the largest study to investigate the special molecular landscape of pts with TMB-H & MSS in GI cancers. Our data may provide novel insights for pt selection and more effective targeted combination immunotherapies (e.g. HER2, PI3K inhibitors) in GI cancers. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2020.38.15_suppl.3631
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
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  • 7
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    Molecular correlates of MAEA expression in colorectal cancer (CRC).
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 16_suppl ( 2022-06-01), p. 3128-3128
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. 3128-3128
    Abstract: 3128 Background: Macrophage Erythroblast Attacher (MAEA) plays an important role in actin cytoskeleton rearrangement in macrophages and erythroid cells. We previously reported that MAEA suppresses migration, invasion and enhances chemosensitivity in CRC cell lines. Here we aimed to characterize the molecular features associated with MAEA gene expression in CRC. Methods: 14416 CRC were tested at Caris Life Sciences (Phoenix, AZ) with NextGen Sequencing on DNA (592 genes or WES) and RNA (WTS). Top quartile transcripts per million (TPM) for MAEA expression were considered high (Q4) while bottom quartile low (Q1). Consensus molecular subtypes (CMS) were assessed using RNAseq. Cell infiltration (CI) in the tumor microenvironment (TME) was estimated by QuantiSEQ. X 2 and Fisher-Exact tests were used and significance was determined as P-value adjusted for multiple comparisons ( Q 〈 0.05). Results: MAEA expression was highest in rectal tumors (13.6 median TPM) followed by transverse and right-sided tumors (13.0 and 12.8, respectively) and lowest in left-sided tumors (12.5). Overall, MAEA TPM were associated with higher tumor mutational burden (≥ 10 Mut/Mb) (11.8% vs. 8.2%) and dMMR/MSI-H (8.7% vs. 5.1%) ( Q 〈 0.0001); however, the association with TMB was not observed in MSS tumors. In the MSS cohort, MAEA expression was the highest in CMS4 (14.9 median TPM) followed by CMS1 (12.5), CMS2 (11.9), and the lowest in CMS3 (10.3, all intergroup Q 〈 0.05). MAEA high was associated with lower mutation rates of APC and amplification of FLT1/ FLT3 while higher mutation rates of ASXL1, KMT2A/C/D, SMARCA4, FBXW7, PTEN, RNF43, BRCA2, HNF1A in the overall cohort ( Q 〈 0.05). In the MSS cohort, FBXW7 mutation significance with MAEA high expression held true ( Q 〈 0.05) while MAEA high expression trended to associate with higher mutation rates of KMT2D, SMARCA4, PTEN, BRCA2 mutations, and a lower frequency of FLT1/ FLT3 CNA ( P 〈 0.05 but Q 〉 0.05). High MAEA was associated with higher immune CI in the TME, including B cells, macrophages (M1 and M2), neutrophils, NK cells, Tregs, CD4+ T cells and myeloid dendritic cells both in the overall cohort and in MSS tumors (fold change: 1.11-1.33, all Q 〈 0.001). Conclusions: Our data show a strong association between MAEA gene expression and distinct molecular features (including CMS and immune biomarkers) and TME cell infiltration in CRC. These findings suggest that targeting MAEA may have relevant clinical applications in selected CRC subgroups and MAEA may be an important player in determining the composition of the TME.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.16_suppl.3128
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
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  • 8
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    Comprehensive gene expression analysis of IDH1/2 mutant biliary cancers (BC).
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  Journal of Clinical Oncology Vol. 38, No. 15_suppl ( 2020-05-20), p. 4598-4598
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. 4598-4598
    Abstract: 4598 Background: Isocitrate dehydrogenases (IDH) mutations (mut) identify a distinct subtype of BC that has yet to be fully characterized. We recently showed that IDH1/2 mutant (mIDH) BC harbor specific gene alterations involving chromatin remodeling and DNA repair, and a differential immune markers profile compared to other mIDH GI tumors. Here we aim to further dissect the molecular profile of mIDH BC through a comprehensive gene expression profiling analysis. Methods: 524 BC samples (303 intrahepatic cholangiocarcinoma, IHCC, 67 extrahepatic cholangiocarcinoma, EHCC, 141 gallbladder, 13 unspecified) collected between February to December of 2019 were included. Samples were analyzed using NextGen DNA sequencing (NextSeq, 592 gene panel), whole transcriptome RNA sequencing (NovaSeq) and immunohistochemistry (Caris Life Sciences, Phoenix, AZ). EBseq was used to identify differentially expressed genes in mIDH vs wild type (WT) tumors with control for FDR ( Q 〈 0.2). Pathway and functional enrichment analysis was performed using g:Profiler and Enrichr. Results: mIDH frequency in our cohort was 11.4% (60/524), with higher prevalence of IDH1 mut (8.8%). IHCC showed the highest mut prevalence: IDH1 13.5%, IDH2 4.6%. mIDH was more common in females ( P = 0.0036). A total of 774 genes were significantly differentially expressed between mIDH and WT: 582 underexpressed (Fold change, FC: 0.025~0.699); 192 overexpressed (FC: 1.43~3.3). Pathway enrichment showed a significant decrease of gene expression in cytokine-cytokine receptor interaction ( Q = 0.002) and inflammatory response genes ( Q = 0.005) in mIDH. Interferon-γ- and PD1 signaling-related genes expression was significantly lower in mIDH vs WT ( Q = 0.02) including IFNG (FC 0.32), NKG7 (FC 0.36), CD8B (FC 0.37), BATF (FC 0.40), PD1 (FC 0.53), SLAMF6 (FC 0.55) and PD-L2 (FC 0.60). Wnt and cadherin signaling were also enriched for altered expression in several genes in mIDH BC ( Q = 3.86e-7 and 〈 0.00001, respectively). Conclusions: To our knowledge, this is the largest and most extensive gene expression profiling study focused on mIDH BC. Our data show for the first time a distinct gene expression profile characterizing mIDH tumors which display significant downregulation of inflammatory response pathways and immune-related genes. These findings contribute to further the understanding of mIDH BC and may inform the future development of rational combination therapies.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2020.38.15_suppl.4598
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
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  • 9
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    Genetic variants in immunogenic cell death (ICD) relating genes to predict outcome in metastatic colorectal cancer (mCRC): Data from FIRE-3, TRIBE and MAVERICC trials.
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  Journal of Clinical Oncology Vol. 38, No. 4_suppl ( 2020-02-01), p. 187-187
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 4_suppl ( 2020-02-01), p. 187-187
    Abstract: 187 Background: ICD is an immune response against dead-cell antigens from cancer cells treated with cytotoxic and/or targeted therapies. Oxaliplatin (OHP) and cetuximab (Cet) are distinct drugs to elicit ICD, while most other anticancer agents kill cancer cells in a nonimmunogenic manner. We hypothesized that genetic variants in ICD-related genes could predictive efficacy of OHP and/or Cet in mCRC. Methods: We analyzed data of mCRC patients enrolled in three 1st-line randomized trials [FIRE-3: FOLFIRI+Cet vs FOLFIRI+bevacizumab (Bev), TRIBE: FOLFOXIRI+Bev vs FOLFIRI+Bev and MAVERICC: FOLFOX+Bev vs FOLFIRI+Bev]. Genomic DNA from blood samples was genotyped through the OncoArray, a custom array manufactured by Illumina. Candidate 14 SNPs in five ICD-related genes ( CALR, HMGB1, ANXA1, LRP1 and P2RX7) were tested for association with progression-free survival (PFS) and overall survival (OS), using Cox proportional hazards model. We tested treatment-by-SNP interactions in the following cohorts: combined TRIBE and MAVERICC (OHP-containing treatment vs non-OHP-containing treatment), and FIRE-3 (FOLFIRI+Cet vs FOLFIRI+Bev). An interaction p-value (i p) 〈 0.05 was considered significant. Results: Totally, 890 patients’ SNPs were available (FIRE-3: n = 236, TRIBE: n = 324, and MAVERICC: n = 330). In the combined TRIBE and MAVERICC cohorts [the reference of hazard ratio (HR) is non-OHP-containing treatment], a significant interaction was observed in ANXA1 rs1050305 (A/A: HR 0.96, Any G: HR 2.62, i p 〈 0.01), LRP1 rs1466535 (G/G: HR 1.39, Any A: HR 0.91, i p = 0.02), P2RX7 rs2230911 (C/C: HR 0.98, Any G: HR 1.76, i p = 0.03) and P2RX7 rs208294 (C/C: HR 1.82, Any T: HR 0.93, i p 〈 0.01) on OS. For PFS, that was observed in CALR rs110222 (G/G: HR 1.30, Any A: HR 0.87, i p = 0.02), HMGB1 rs1045411 (C/C: HR 0.85, Any T: HR 1.30, i p = 0.04) and HMGB1 rs1360485 (T/T: HR 0.81, Any C: HR 1.40, i p 〈 0.01). However, in the FIRE-3 cohort, no significant interactions were observed in any SNPs. Conclusions: Our results showed for the first time that SNPs in ICD-related genes may predict efficacy of OHP-containing treatment in mCRC. But the predictive values for Cet efficacy was not evident.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2020.38.4_suppl.187
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
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    Polymorphisms in the dopamine (DA) signaling to predict outcome in patients (pts) with metastatic colorectal cancer (mCRC): Data from TRIBE, MAVERICC, and FIRE-3 phase III trials.
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  Journal of Clinical Oncology Vol. 37, No. 15_suppl ( 2019-05-20), p. 3048-3048
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. 3048-3048
    Abstract: 3048 Background: Strong evidence supports the critical role of the gut-brain axis in modulating gastrointestinal function and homeostasis. Available data suggest an involvement of the dopaminergic pathway in CRC dynamics. DA could inhibit proliferation and migration of tumor endothelial cells and enhanced 5-fluorouracil efficacy in CRC preclinical models. Hence, we hypothesized that genetic variants in DA signaling may predict treatment outcomes in mCRC pts. Methods: The impact on outcome of 22 selected single nucleotide polymorphisms (SNPs) in 9 genes of the DA signaling pathway ( DRD1, DRD2, DRD3, DRD4, DRD5, TAAR1, SLC6A3, SLC18A2, PPP1R1B) was analyzed on a total of 884 pts enrolled in three independent randomized first-line trials: TRIBE (n = 324), MAVERICC (n = 324), and FIRE-3 (n = 236). Genomic DNA from blood samples of pts was genotyped through the OncoArray, a custom array manufactured by Illumina. A meta-analysis approach using the METASOFT software was used to quantify SNPs prognostic effects and heterogeneities across treatment arms. P values were adjusted for multiple testing using the false discovery rate (FDR) method. Results: Overall, DRD3 rs3732790, rs9817063 and rs2134655 showed a significant nominal p value ( P) in association with tumor response (TR) across trials ( P= 0.032, P= 0.021, P= 0.027, respectively). TAAR1 rs8192620 showed an association with both progression free survival (PFS) ( P= 0.01) and overall survival (OS) ( P= 0.033), similar to DA transporter SLC6A3 rs6347 ( P= 0.016 and P= 0.002, respectively). SLC6A3 rs6347 association with OS remained significant after FDR ( P FDR = 0.045). Subgroup analyses showed a significant association with PFS for DRD1 rs267410 and SLC6A3 rs2652510 in females ( P FDR = 0.056), and between SLC6A3 rs6347 and OS ( P FDR = 0.041) and SLC6A3 rs6876890 and TR ( P FDR = 0.05) in KRAS wild type. Conclusions: Our results suggest that SNPs in DA signaling may have a prognostic value in mCRC pts receiving first-line treatment. Upon validation, these findings may provide novel insight on the role of DA signaling in CRC and possibly contribute to open novel therapeutic perspectives.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2019.37.15_suppl.3048
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
    detail.hit.zdb_id: 2005181-5
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