Molecular profiling in patients (pts) with upper gastrointestinal (UGI) cancers correlated with clinical outcome

e22042 Background: Recent efforts have expanded our understanding of the molecular pathogenesis of UGI cancers and how oncogenes and tumor suppressor genes play a role in both carcinogenic and metastatic processes. These markers may serve as prognostic and/or predictive factors for recurrence following resection and resistance to radiotherapy and chemotherapy. Gene expression levels of thymidylate synthase (TS), thymidylate phosphorylase (TP), epidermal growth factor receptor (EGFR) and excision repair cross complementing (ERCC-1) have been shown to be associated with outcomes in lung, gastric and colon cancer. We evaluated TS, ERCC-1, EGFR and TP gene expression levels in patients with UGI cancers. Methods: This was a retrospective study of 80 pts with UGI cancers evaluated at USC who underwent molecular profiling. The primary objective was to determine a correlation between TS, TP, ERCC1 and EGFR and correlate with clinical outcome. Characteristics of these 80 pts: (16 females, 64 males ); median age 61 years (range 34–85); tumor types evaluated - 32 (40%) esophageal, 24(30%) gastric, 24(30%) GE junction; stages- 53 % IV, 21% III, 12% II, 2% I were evaluated for intratumoral gene expression of TS, TP, ERCC-1, & EGFR by real time quantitative PCR using Taqman technology from microdisected paraffin-embedded tumor sections. Results: High TS expression was associated with shorter OS (12.8 months vs. 23.7 months p=0.036). A significant correlation was found between TP & ERCC-1 (p=0.0078, r=0.37); TP & TS (p=0.0128, r=0.35); TP & EGFR (p=0.0065, r=0.39); TS & ERCC-1 (p=0.0004, r=0.39); ERCC-1 & EGFR (p=0.025, r=0.30). No statistically significant relationship was found between TS & EGFR (p=0.06,r=0.25). There was no correlation of ERCC-1, TP, & EGFR with OS that reached statistical significance. Conclusions: TS mRNA levels were shown to be associated with OS in UGI tumors, consistent with data reported in colon cancer. TS gene expression was significantly associated with expression levels of ERCC-1. In addition, ERCC1 was associated with EGFR. These data show for the first time that molecular pathways of cytotoxic agents are linked to the EGFR pathway suggesting that sensitivity to fluoropyrimidines, oxaliplatin, and EGFR inhibitors may be associated. No significant financial relationships to disclose.

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Decreased Levels of Microfibril-Associated Glycoprotein (MAGP)-1 in Patients with Colon Cancer and Obesity Are Associated with Changes in Extracellular Matrix Remodelling

International Journal of Molecular Sciences ◽

10.3390/ijms22168485 ◽

2021 ◽

Vol 22 (16) ◽

pp. 8485

Author(s):

Iranzu Gómez de Segura ◽

Patricia Ahechu ◽

Javier Gómez-Ambrosi ◽

Amaia Rodríguez ◽

Beatriz Ramírez ◽

...

Keyword(s):

Gene Expression ◽

Colon Cancer ◽

Extracellular Matrix ◽

Matrix Protein ◽

Extracellular Matrix Protein ◽

Mrna Levels ◽

Expression Levels ◽

The Impact ◽

Ht 29 ◽

Gene Expression Levels

Objective: The protein microfibril-associated glycoprotein (MAGP)-1 constitutes a crucial extracellular matrix protein. We aimed to determine its impact on visceral adipose tissue (VAT) remodelling during obesity-associated colon cancer (CC). Methods: Samples obtained from 79 subjects (29 normoponderal (NP) (17 with CC) and 50 patients with obesity (OB) (19 with CC)) were used in the study. Circulating concentrations of MAGP-1 and its gene expression levels (MFAP2) in VAT were analysed. The impact of inflammation-related factors and adipocyte-conditioned media (ACM) on MFAP2 mRNA levels in colon adenocarcinoma HT-29 cells were further analysed. The effects of MAGP-1 in the expression of genes involved in the extracellular matrix (ECM) remodelling and tumorigenesis in HT-29 cells was also explored. Results: Obesity (p < 0.01) and CC (p < 0.001) significantly decreased MFAP2 gene expression levels in VAT whereas an opposite trend in TGFB1 mRNA levels was observed. Increased mRNA levels of MFAP2 after the stimulation of HT-29 cells with lipopolysaccharide (LPS) (p < 0.01) and interleukin (IL)-4 (p < 0.01) together with a downregulation (p < 0.05) after hypoxia mimicked by CoCl2 treatment was observed. MAGP-1 treatment significantly enhanced the mRNA levels of the ECM-remodelling genes collagen type 6 α3 chain (COL6A3) (p < 0.05), decorin (DCN) (p < 0.01), osteopontin (SPP1) (p < 0.05) and TGFB1 (p < 0.05). Furthermore, MAGP-1 significantly reduced (p < 0.05) the gene expression levels of prostaglandin-endoperoxide synthase 2 (COX2/PTGS2), a key gene controlling cell proliferation, growth and adhesion in CC. Interestingly, a significant decrease (p < 0.01) in the mRNA levels of MFAP2 in HT-29 cells preincubated with ACM from volunteers with obesity compared with control media was observed. Conclusion: The decreased levels of MAGP-1 in patients with obesity and CC together with its capacity to modulate key genes involved in ECM remodelling and tumorigenesis suggest MAGP-1 as a link between AT excess and obesity-associated CC development.

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Abstract PO-226: Gene expression levels correlation to colon cancer disparities amongst African and Caucasian American men

10.1158/1538-7755.disp21-po-226 ◽

2022 ◽

Author(s):

Darryl A. Sams ◽

Dana R. Marshall

Keyword(s):

Gene Expression ◽

Colon Cancer ◽

Cancer Disparities ◽

Caucasian American ◽

Expression Levels ◽

Gene Expression Levels

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Codon usage is an important determinant of gene expression levels largely through its effects on transcription

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1606724113 ◽

2016 ◽

Vol 113 (41) ◽

pp. E6117-E6125 ◽

Cited By ~ 122

Author(s):

Zhipeng Zhou ◽

Yunkun Dang ◽

Mian Zhou ◽

Lin Li ◽

Chien-hung Yu ◽

...

Keyword(s):

Gene Expression ◽

Codon Usage ◽

Important Determinant ◽

Mrna Translation ◽

Mrna Levels ◽

Protein Coding ◽

Expression Levels ◽

Highly Expressed Genes ◽

The Impact ◽

Gene Expression Levels

Codon usage biases are found in all eukaryotic and prokaryotic genomes, and preferred codons are more frequently used in highly expressed genes. The effects of codon usage on gene expression were previously thought to be mainly mediated by its impacts on translation. Here, we show that codon usage strongly correlates with both protein and mRNA levels genome-wide in the filamentous fungus Neurospora. Gene codon optimization also results in strong up-regulation of protein and RNA levels, suggesting that codon usage is an important determinant of gene expression. Surprisingly, we found that the impact of codon usage on gene expression results mainly from effects on transcription and is largely independent of mRNA translation and mRNA stability. Furthermore, we show that histone H3 lysine 9 trimethylation is one of the mechanisms responsible for the codon usage-mediated transcriptional silencing of some genes with nonoptimal codons. Together, these results uncovered an unexpected important role of codon usage in ORF sequences in determining transcription levels and suggest that codon biases are an adaptation of protein coding sequences to both transcription and translation machineries. Therefore, synonymous codons not only specify protein sequences and translation dynamics, but also help determine gene expression levels.

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ERCC1 and RRM1 but not EGFR gene expression is predictive of shorter survival in advanced non-small cell lung cancer (NSCLC)

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.10030 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 10030-10030

Author(s):

G. Selvaggi ◽

P. Ceppi ◽

M. Volante ◽

S. Saviozzi ◽

S. Novello ◽

...

Keyword(s):

Gene Expression ◽

Excision Repair ◽

Growth Factor Receptor ◽

Needle Aspiration ◽

Differential Sensitivity ◽

Mrna Levels ◽

Female Ratio ◽

Expression Levels ◽

Egfr Expression ◽

Formalin Fixed Paraffin Embedded

10030 Background: Pivotal studies indicate a role of excision repair cross-complementation 1 (ERCC1) and ribonucleotide reductase M1 (RRM1) in conferring a differential sensitivity to cytotoxic chemotherapy and epidermal growth factor receptor (EGFR) has been recently deeply investigated in NSCLC. Methods: We retrospectively collected 70 formalin-fixed paraffin-embedded (FFPE) bronchoscopic/fine needle aspiration biopsies of NSCLC to investigate the expression levels of ERCC1, RRM1 and EGFR by Real-Time PCR (Lord R et al. Clin Cancer Research 2002, 8:2286–91). Results were correlated with survival using the Kaplan-Meier method. Results: Sixty-one (87%) specimens were successfully amplified. Median age was 62 years (range 26–75), male/ female ratio 44/17, stage III/IV 20/41; 43 patients received cisplatin-based chemotherapy; overall median survival (MS) was 13.3 months over a median follow-up time of 45 months. ERCC1 expression level ranged from 0.70 to 15.12, RRM1 0.60–17.82. By adopting cut-off values according to median expression levels, we found a strong correlation between ERCC1 and RRM1 mRNA levels (r=0.410; p<0.001). MS in patients with low ERCC1 was significantly longer (16.9 vs 11.3 months, p<0.006) as well as in patients with low RRM1 (13.9 vs 10.9 months, p<0.03). Concomitant high expression levels of ERCC1 and RRM1 (n=26) are predictive of a worse outcome (13.9 vs 10.9 months, p<0.05). Among patients treated with cisplatin-based regimens, low ERCC1 levels were also predictive of a significantly longer MS (23.0 vs 11.6 months, p<0.002). A lower median ERCC1 level (3.2 vs 4.7) and a correlation with a better outcome were also observed in females vs males. No correlation between gene expression levels and histology was reported. No significant correlation between EGFR expression levels (range 0.5–85.8) and survival was found, even when different cut-off values were tested. Conclusions: This retrospective study further validates ERCC1 and RRM1 as good candidates genes to customize chemotherapy. Prospective studies based on the selection of patients according to genes expression levels are a research priority in early and advanced stages of NSCLC. [Table: see text]

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Correlation of messenger RNA expression patterns of ERCC1, TS, EGFR, and VEGFR2 with KRAS and BRAF mutational status in advanced colorectal cancer: Implications for targeted therapies.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.4_suppl.383 ◽

2013 ◽

Vol 31 (4_suppl) ◽

pp. 383-383

Author(s):

Martin K. H. Maus ◽

Craig Stephens ◽

Stephanie H. Astrow ◽

Peter Philipp Grimminger ◽

Dongyun Yang ◽

...

Keyword(s):

Gene Expression ◽

Colorectal Cancer ◽

Mrna Expression ◽

Advanced Colorectal Cancer ◽

Expression Patterns ◽

Mrna Levels ◽

Expression Levels ◽

Mutational Status ◽

Mrna Expression Levels ◽

Gene Expression Levels

383 Background: Gene expression levels of ERCC1, TS, EGFR and VEGFR2 may have predictive value for the personalized use of standard chemotherapeutics as well as agents targeting the EGFR and VEGF pathways and the efficacy of EGFR directed monoclonal antibodies like panitumumab and cetuximab has been confirmed to be dependent on wt KRAS and wt BRAF in patients with advanced colorectal cancer. We investigated the correlations between KRAS/BRAF mutational status and the mRNA expression levels of these genes. Methods: Formalin-fixed paraffin-embedded tumor specimens from 600 patients with advanced colorectal adenocarcinoma were microdissected and DNA and RNA was extracted. Specifically designed primers and probes were used to detect 7 different base substitutions in codon 12 and 13 of KRAS, V600E mutations in BRAF and the expression levels of ERCC1, TS, EGFR and VEGFR2 by RT-PCR. Results: Mt KRAS tumors had significantly lower TS and EGFR gene expression levels compared with wt KRAS (p<0,001), whereas mt BRAF tumors showed significantly increased TS and EGFR mRNA levels compared to wt BRAF (p<0,001). Mt BRAF tumors showed significantly higher mRNA levels than mt KRAS tumors (p<0,001). ERCC1 and VEGFR2 mRNA levels were significantly down-regulated in mt KRAS specimen (p<0,001), but showed no significant correlation with BRAF mutational status. Conclusions: KRAS and BRAF mutations are associated with opposite mRNA expression levels for TS and EGFR. Recently, resistance to BRAF inhibition in mt BRAF colorectal tumors has been shown in preclinical models to be associated with up-regulation of EGFR. Our data suggests that BRAF mutants are associated with high EGFR levels at the time of diagnosis, and not necessarily part of an acquired mechanism of resistance. Significantly lower mRNA expression levels of VEGFR2 in mt KRAS tumors may explain lower response to angiogenesis inhibition seen in the TML study.

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Dynamics Affect Nitrogen Retention, Ileal Amino Acid Digestibility, and Gene Expression Levels of Digestive Enzymes at Three Stages in Pigs Fed Two Levels of Low-Protein Diets

10.20944/preprints201911.0216.v1 ◽

2019 ◽

Author(s):

Li Wu ◽

Qinghua He ◽

Wen Zhen ◽

Tiejun Li ◽

Peng Liao

Keyword(s):

Gene Expression ◽

Amino Acid ◽

Treatment Group ◽

Protein Intake ◽

Digestive Enzymes ◽

Growing Pigs ◽

Mrna Levels ◽

Expression Levels ◽

Three Stages ◽

Gene Expression Levels

This study was conducted to determine the dynamic effects of dietary crude protein (CP) intake on nitrogen (N) balance, ileal amino acid digestibility, and gene expression levels of digestive enzymes at three stages in pigs. In Experiment 1, 18 growing pigs (average body weight (BW) = 9.5 kg) were randomly assigned to one of three treatments (n = 6/treatment group), including normal (20% CP), low (17% CP), and very low (14% CP) protein intake. In Experiment 2, 18 growing pigs (average BW = 30 kg) were allotted randomly to one of three treatments (n = 6/treatment group), including normal (18% CP), low (15% CP), and very low (12% CP) protein intake. In Experiment 3, 18 growing pigs (average BW = 45 kg) were assigned randomly to one of three treatments (n = 6/treatment group), including normal (16% CP), low (13% CP), and very low (10% CP) protein intake. Growing pigs fed the 14% CP and 17% CP diets had lower final BW (P < 0.05) and average daily gain (ADG) (P < 0.05) compared to pigs fed the 20% CP diet. Reducing the dietary CP level from 20 to 14% decreased urinary N excretion by 52.8% (P < 0.001) in Experiment 1. Reducing the dietary CP level from 18 to 12% decreased urinary N excretion by 55.3% (P < 0.001) and reduced fecal N excretion by 34% (P < 0.05) in Experiment 2. Reducing the dietary CP level from 16 to 10% decreased urinary N excretion by 56.4% (P < 0.001) and fecal N excretion by 47.1% (P < 0.001) in Experiment 3. Pigs fed the very low (14%, 12%, and 10% CP) diets showed higher digestibility for CP (P < 0.05), His (P < 0.05), Ile (P < 0.05), Phe (P < 0.05), Thr (P < 0.05), Trp (P < 0.05), Glu (P < 0.05), and Ser (P < 0.05) compared to pigs fed the normal (20%, 18%, and 16% CP) diets among the three experiments. Pigs fed the very low (14%, 12%, and 10% CP) diets showed higher mRNA levels for chymotrypsin C (P < 0.01 in Experiment 1 and 2; P < 0.05 in Experiment 3) compared to pigs fed the normal (20%, 18%, and 16% CP) diets among the three experiments. These results indicated that a reduction in dietary CP by 6% limited the growth performance of growing pigs, and a reduction of dietary CP by 3% supplemented with essential amino acids could reduce the excretion of N into the environment without affecting weight gain.

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Molecular determinants of capecitabine efficacy in colorectal cancer

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.3606 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 3606-3606

Author(s):

D. Vallbohmer ◽

H. Kuramochi ◽

D. Shimizu ◽

K. D. Danenberg ◽

J. N. Nielsen ◽

...

Keyword(s):

Gene Expression ◽

Colorectal Cancer ◽

Clinical Outcome ◽

Single Agent ◽

Progression Free Survival ◽

First Line ◽

Free Survival ◽

Expression Levels ◽

Cox 2 ◽

Gene Expression Levels

3606 Background: Capecitabine offers physicians a more convenient treatment for advanced colorectal cancer (CRC), with manageable toxicity and antitumor activity comparable to that of continuous-infusion therapies with 5-fluorouracil (5-FU). However, there are no validated and established predictive factors for clinical outcome of capecitabine efficacy in CRC. Therefore we investigated whether intratumoral mRNA expression levels of genes involved in the capecitabine/5-FU metabolism (cytidine deaminase (CDA), dihydropyrimidine dehydrogenase (DPD), folylpolyglutamate synthase (FPGS), gamma-glutamyl hydrolase (GGH), thymidine phosphorylase (TP), thymidylate synthase (TS)) and in angiogenesis (cyclooxygenase 2 (Cox-2), epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF)) are associated with the clinical outcome of patients with metastatic CRC treated with first-line capecitabine. Methods: Thirty-seven patients with metastatic CRC were enrolled in this study and treated with single agent capecitabine.The intratumoral mRNA levels of CDA, COX-2, DPD, EGFR, FPGS; GGH, TP, TS, and VEGF were assessed from paraffin-embedded tissue samples using laser-capture-microdissection methods and quantitative real-time PCR. Results: There were20 women and 17 men with a median age of 61 years (range 49–74). The median progression-free survival was 6.7 months (95% CI, 4.8–11.6 months), with a median follow up of 14.4 months (range: 1.3 to 18.7 months). Complete response was observed in 1 (3%), partial response in 6 (20%), stable disease in 14 (47%) and progressive disease in 9 (30%) patients (response was inevaluable in 7 patients). Higher gene expression levels of DPD were associated with resistance to capecitabine (P= 0.032; Kruskal-Wallis test). Patients with a lower mRNA amount of DPD (≤0.46) had a longer progression-free survival compared with patients that had a higher mRNA amount (8.0 vs. 3.3 months; adjusted P=0.048; log-rank test). Conclusions: This pilot study suggests that intratumoral gene expression levels of DPD may be useful to predict the clinical outcome of patients with metastatic CRC with first-line single agent capecitabine treatment. Our data are hypothesis generating and should be validated in larger and prospective clinical trials. [Table: see text]

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Use of multidrug-resistance gene (MDR1) expression levels to predict outcome to adjuvant cisplatin/gemcitabine based chemotherapy in patients with with locally advanced urothelial cancer

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e22081 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e22081-e22081

Author(s):

T. Gauler ◽

A. C. Hoffman ◽

P. Wild ◽

C. Leicht ◽

S. Bertz ◽

...

Keyword(s):

Gene Expression ◽

Urothelial Cancer ◽

Locally Advanced ◽

Mdr1 Gene ◽

Mrna Levels ◽

Expression Levels ◽

Mdr1 Gene Expression ◽

Mdr1 Expression ◽

Advanced Urothelial Cancer ◽

Gene Expression Levels

e22081 Background: The human MDR1 gene encodes an integral membrane protein, P glycoprotein (Pgp), whose function is the energy dependent export of substances from the inside of cells, and from membranes, to the outside. MDR1 mRNA levels have been shown to influence metabolism of cancer drugs. We tested whether MDR1 gene expression is associated with outcome in patients with locally advanced bladder cancer. Methods: 43 formalin fixed paraffin embedded (FFPE) tumor samples from patients with locally advanced and/or lymph node-positive bladder cancer undergoing treatment with cisplatin/gemcitabine were analyzed.FFPE tissues were dissected using laser-captured microdissection and analyzed for MDR1 expression using a quantitative real- time RT-PCR method. Gene expression values (relative mRNA levels) are expressed as ratios between the target gene and internal reference gene (beta-actin). Results: MDR1 was significantly correlated to overall survival. We included tumor stage (pT), lymph node status (pN) and the blood vessel invasion along with the measured gene expression in a stepwise multivariate Cox proportional hazards regression model. The overall model fit had a significance level of p=0.04 (<0.05). The relative risk for shorter survival in patients with High MDR1 expression was 1.9. Conclusions: These results suggest that MDR1 gene expression levels predict response and overall survival in patients with locally advanced urothelial cancer. MDR1 gene expression levels may allow the selection of patients who benefit likely from adjuvant cisplatin/gemcitabine based chemotherapy. Further studies are warranted to study this association. [Table: see text]

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Quantitative gene expression underlying 18f-fluorodeoxyglucose uptake in colon cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.3_suppl.653 ◽

2015 ◽

Vol 33 (3_suppl) ◽

pp. 653-653

Author(s):

Bodil E. Engelmann ◽

Tina Binderup ◽

Andreas Kjær ◽

Annika Loft ◽

Thomas A. Gerds ◽

...

Keyword(s):

Gene Expression ◽

Colon Cancer ◽

Fdg Pet ◽

Standardized Uptake Value ◽

Normal Colonic Mucosa ◽

Imaging Method ◽

Glucose Transporter 1 ◽

Expression Levels ◽

Pet Ct ◽

Gene Expression Levels

653 Background: Positron emission tomography (PET) with the glucose analogue 18F-fluorodeoxyglucose (FDG) is widely used in oncologic imaging. This study examines the molecular mechanism underlying the detection of colon cancer (CC) by FDG-PET. Methods: Pre-operative PET/CT scans and tissue samples from primary CC and surrounding normal mucosa were obtained from 42 patients. FDG uptake was quantified using maximal standardized uptake value (SUVmax). The expression of ki67, glucose transporter 1 (GLUT-1), hexokinase 1 (HK1), hexokinase 2 (HK2), vascular endothelial growth factor (VEGF), hypoxia-inducible factor 1α (HIF1α) and carbonic anhydrase IX (CaIX) mRNA was examined by quantitative real time reverse transcriptase-polymerase chain reaction. Results: All primary tumours showed increased uptake of FDG. The mean SUVmax was 15.0 (range 5.3 – 37.8). No correlation was found between tumour size and SUVmax. Mean gene expression levels of GLUT1, HK2, ki67, HIF1α, VEGF and CaIX, but not HK1, were significantly higher in primary tumours than in surrounding normal colonic mucosa. Linear regressions pairing tumour SUVmax with gene expression levels showed significant correlations between SUVmax and HK2, ki67 and CaIX, respectively. Conclusions: These results confirm FDG PET/CT as a functional imaging method in CC, and that FDG accumulation reflects molecular events related to glycolysis, cell proliferation, hypoxia, but not angiogenesis.

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