scholarly journals Genomic alterations and abnormal expression of APE2 in multiple cancers

2020 ◽  
Author(s):  
Katherine A. Jensen ◽  
Xinghua Shi ◽  
Shan Yan
Keyword(s):  
Dna Repair ◽  
Mrna Expression ◽  
Cancer Patients ◽  
Tumor Tissue ◽  
Excision Repair ◽  
The Cancer Genome Atlas ◽  
Genomic Alterations ◽  
Abnormal Expression ◽  
Multiple Cancers ◽  
Cancer Types

AbstractAlthough APE2 plays essential roles in base excision repair and ATR-Chk1 DNA damage response (DDR) pathways, it remains unknown how the APE2 gene is altered in the human genome and whether APE2 is differentially expressed in cancer patients. Here, we report multiple-cancer analyses of APE2 genomic alterations and mRNA expression from cancer patients using available data from The Cancer Genome Atlas (TCGA). We observe that APE2 genomic alterations occur at ~17% frequency in 14 cancer types (n= 21,769). Most frequent somatic mutations of APE2 appear in uterus (2.89%) and skin (2.47%) tumor samples. Furthermore, APE2 expression is upregulated in tumor tissue compared with matched non-malignant tissue across 5 cancer types including kidney, breast, lung, liver, and uterine cancers, but not in prostate cancer. We also examine the mRNA expression of 13 other DNA repair and DDR genes from matched samples for 6 cancer types. We show that APE2 mRNA expression is positively correlated with PCNA, APE1, XRCC1, PARP1, Chk1, and Chk2 across these 6 tumor tissue types; however, groupings of other DNA repair and DDR genes are correlated with APE2 with different patterns in different cancer types. Taken together, this study demonstrates alterations and abnormal expression of APE2 from multiple cancers.

scholarly journals Radioresistance of Human Cancers: Clinical Implications of Genetic Expression Signatures

2021 ◽  
Vol 11 ◽  
Author(s):  
Sven de Mey ◽  
Inès Dufait ◽  
Mark De Ridder
Keyword(s):  
Mrna Expression ◽  
Cancer Patients ◽  
Clinical Relevance ◽  
Expression Patterns ◽  
Molecular Data ◽  
The Cancer Genome Atlas ◽  
Gene Set ◽  
Gene Sets ◽  
Cancer Genome Atlas ◽  
Cancer Types

Although radiotherapy is given to more than 50% of cancer patients, little progress has been made in identifying optimal radiotherapy - drug combinations to improve treatment efficacy. Using molecular data from The Cancer Genome Atlas (TCGA), we extracted a total of 1016 cancer patients that received radiotherapy. The patients were diagnosed with head-and-neck (HNSC - 294 patients), cervical (CESC - 166 patients) and breast (BRCA - 549 patients) cancer. We analyzed mRNA expression patterns of 50 hallmark gene sets of the MSigDB collection, which we divided in eight categories based on a shared biological or functional process. Tumor samples were split into upregulated, neutral or downregulated mRNA expression for all gene sets using a gene set analysis (GSEA) pre-ranked analysis and assessed for their clinical relevance. We found a prognostic association between three of the eight gene set categories (Radiobiological, Metabolism and Proliferation) and overall survival in all three cancer types. Furthermore, multiple single associations were revealed in the other categories considered. To the best of our knowledge, our study is the first report suggesting clinical relevance of molecular characterization based on hallmark gene sets to refine radiation strategies.

Constitutive mRNA expression of DNA repair-related genes as a biomarker for clinical radio-resistance: A pilot study in prostate cancer patients receiving radiotherapy

2006 ◽  
Vol 82 (8) ◽  
pp. 593-604 ◽  
Author(s):  
Jörg Hümmerich ◽  
Gisela Werle-Schneider ◽  
Odilia Popanda ◽  
Oktay Celebi ◽  
Jenny Chang-Claude ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Pilot Study ◽  
Mrna Expression ◽  
Cancer Patients

Customizing Cisplatin Based on Quantitative Excision Repair Cross-Complementing 1 mRNA Expression: A Phase III Trial in Non–Small-Cell Lung Cancer

2007 ◽  
Vol 25 (19) ◽  
pp. 2747-2754 ◽  
Author(s):  
Manuel Cobo ◽  
Dolores Isla ◽  
Bartomeu Massuti ◽  
Ana Montes ◽  
Jose Miguel Sanchez ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Mrna Expression ◽  
Cell Lung Cancer ◽  
Tumor Tissue ◽  
Excision Repair ◽  
Objective Response ◽  
Small Cell ◽  
Phase Iii ◽  
Small Cell Lung

Purpose Although current treatment options for metastatic non–small-cell lung cancer (NSCLC) rely on cisplatin-based chemotherapy, individualized approaches to therapy may improve response or reduce unnecessary toxicity. Excision repair cross-complementing 1 (ERCC1) has been associated with cisplatin resistance. We hypothesized that assigning cisplatin based on pretreatment ERCC1 mRNA levels would improve response. Patients and Methods From August 2001 to October 2005, 444 stage IV NSCLC patients were enrolled. RNA was isolated from pretreatment biopsies, and quantitative real-time reverse transcriptase PCR assays were performed to determine ERCC1 mRNA expression. Patients were randomly assigned in a 1:2 ratio to either the control or genotypic arm before ERCC1 assessment. Patients in the control arm received docetaxel plus cisplatin. In the genotypic arm, patients with low ERCC1 levels received docetaxel plus cisplatin, and those with high levels received docetaxel plus gemcitabine. The primary end point was the overall objective response rate. Results Of 444 patients enrolled, 78 (17.6%) went off study before receiving one cycle of chemotherapy, mainly due to insufficient tumor tissue for ERCC1 mRNA assessment. Of the remaining 346 patients assessable for response, objective response was attained by 53 patients (39.3%) in the control arm and 107 patients (50.7%) in the genotypic arm (P = .02). Conclusion Assessment of ERCC1 mRNA expression in patient tumor tissue is feasible in the clinical setting and predicts response to docetaxel and cisplatin. Additional studies are warranted to optimize methodologies for ERCC1 analysis in small tumor samples and to refine a multibiomarker profile predictive of patient outcome.

Evaluation of thymidylate synthase and ERCC1 mRNA levels as predictive markers in colorectal cancer patients treated with S-1 and oxaliplatin

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15071-e15071
Author(s):  
H. Kuramochi ◽  
K. Hayashi ◽  
G. Nakajima ◽  
H. Kamikozuru ◽  
M. Yamamoto
Keyword(s):  
Colorectal Cancer ◽  
Mrna Expression ◽  
Real Time ◽  
Cancer Patients ◽  
Thymidylate Synthase ◽  
Excision Repair ◽  
Mrna Levels ◽  
Expression Levels ◽  
Colorectal Cancer Patients ◽  
Mrna Expression Levels

e15071 Background: Oxaliplatin has been widely used for the treatment of colorectal cancer. The mechanism of action of platinum compounds such as oxaliplatin is to bind to a DNA molecule in the form of a platinum-DNA-adduct. Excision repair cross complementation group 1 (ERCC1), which plays a major role in the nucleotide excision pathway, has a polymorphism in codon 118, and is reported to be associated with a resistance to platinum-based therapy. Thymidylate synthase (TS) and dehydropyrimidine dehydrogenase (DPD) are key enzymes of 5-FU metabolism and are well known to be associated with a response to 5-FU-based therapy. Methods: Twenty-one colorectal cancer patients (male:female = 7:14; median age, 65) treated with a combination of oxaliplatin and S-1 as a first-line therapy were analyzed for ERCC1 codon 118 polymorphism and the mRNA expression levels of TS, ERCC1, and DPD. Formalin-fixed paraffin- embedded surgical specimens were used and t-RNA and DNA were extracted. The mRNA expression levels were measured using real-time RT-PCR, and the polymorphism was analyzed using the allelic discrimination method together with real-time PCR. Results: No correlation was observed between ERCC1 codon118 polymorphism and any response to the chemotherapy. ERCC1 mRNA levels tended to be higher in the patients with wild-type homozygous alleles in codon 118 than in those with at least one mutant allele(1.19 vs.0.68: p= 0.15). Patients with both high TS and ERCC1 mRNA levels showed a significantly lower response rate than the others (25% vs. 67%, p=0.02). No relationship was seen between DPD mRNA expression levels and the response. Conclusions: The mRNA expression levels of TS and ERCC1 appear to be useful markers for the treatment of S-1 and oxaliplatin. No particular usefulness of ERCC1 codon 118 polymorphism was verified. No significant financial relationships to disclose.

Association of EGFR mutation or ALK rearrangement with expression of DNA repair and synthesis genes in never-smoker females with pulmonary adenocarcinoma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 10527-10527
Author(s):  
Xiaoxia Chen ◽  
Shengxiang Ren ◽  
Peng Kuang ◽  
ChunXia Su ◽  
Jiayu Li ◽  
...  
Keyword(s):  
Dna Repair ◽  
Mrna Expression ◽  
Egfr Mutation ◽  
Excision Repair ◽  
Egfr Mutations ◽  
Mrna Levels ◽  
Alk Rearrangement ◽  
Anaplastic Lymphoma ◽  
Alk Positive ◽  
Nsclc Patients

10527 Background: Epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) rearrangement was found not only predict the efficacy of targeted drugs, but also associate with the efficacy of chemotherapy drugs in non-small cell lung cancer (NSCLC) patients. We investigated the relationship of EGFR mutation status or ALK rearrangement and DNA repair or synthesis genes, such as excision repair cross-complementing 1 (ERCC1), ribonucleotide reductase subunit M1 (RRM1), thymidylate synthetase (TS) and breast cancer gene one (BRCA1) gene expression, as a potential explanation for these observations. Methods: In this surgical series, 104 resected lung adenocarcinomas from nonsmoker females were analyzed concurrently for the EGFR mutation, ALK rearrangement status and mRNA expression of ERCC1, RRM1, TS and BRCA1 genes. EGFR mutation detection was performed by the method of ADx-ARMS, ALK rearrangement was detected by PCR and the mRNA expression of different genes were tested using the method of real-time PCR. Results: 73 (70.2%) patients harbored EGFR mutations and 10 (9.6%) had ALK rearrangement. The ERCC1 mRNA level in patients with EGFR mutation was 3.44±1.94×10-3 , which is significantly lower than in the patients with ALK positive and both negative(4.60±1.95×10-3 and 4.95±2.33×10-3 respectively, P=0.010). While the TS mRNA levels were significantly lower in the patients with EGFR mutation(1.15±1.38×10-3 VS 2.69±3.97×10-3, P=0.006) or ALK positive (1.21±0.78×10-3VS 2.69±3.97×10-3, P=0.020) than in patients with both negative. Conclusions: NSCLC specimens harboring activating EGFR mutations are more likely to express low ERCC1 and TS mRNA levels, while NSCLC patients with ALK rearrangement are more likely to express low TS mRNA levels, which could be helpful to select a proper chemotherapy regimen for NSCLC patients with known EGFR mutation or ALK fusion status.

Variations in DNA repair genomic alterations and tumor mutation burden in biliary tract cancer (BTC) subtypes.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 263-263 ◽  
Author(s):  
Reham Abdel-Wahab ◽  
Siraj Mahamed Ali ◽  
Mitesh J. Borad ◽  
Rachna T. Shroff ◽  
Lawrence Kwong ◽  
...  
Keyword(s):  
Dna Repair ◽  
Distinct Pattern ◽  
The Cancer Genome Atlas ◽  
Tumor Type ◽  
Dna Repair Genes ◽  
Genomic Alterations ◽  
Tract Cancer ◽  
Tumor Mutational Burden ◽  
Tissue Specimens ◽  
Repair Genes

263 Background: DNA repair genomic alterations (GAs) have been identified in 12% of Intrahepatic cholangiocarcinoma (IHCCA), 26% of extrahepatic CCA (EHCCA) and 8% of gallbladder cancer (GBC) patients (pts) ( Cancer 2016;122:3838–3847). Recently, the Cancer Genome Atlas (TCGA) has described more than 20 mutated DNA repair genes, many of which were not previously represented in prior reports. DNA repair GAs including MSI are associated with higher tumor mutational burden (TMB). Our study aim is to identify variations in the frequency of DNA repair GAs in IHCCA, EHCCA, and GBC. Methods: Hybrid capture-based next-generation sequencing of 422 fixed formalin paraffin embedded (FFPE) tissue blocks of BTC including; 270 IHCCA, 60 EHCCA, and 92 GBC was performed. We included 20 DNA repair genes and classified them as "direct" DNA repair genes ( ATM, ATR, BRCA1, BRCA2, FANCA, FANCD2, MLH1, MSH2, MSH6, PALB2, POLD1, POLE, PRKDC, RAD50, SLX4) and "caretaker" genes that induce genomic instability ( BAP1, CDK12, MLL3, TP53, BLM). We calculated TMB on 1.1 Mb of sequenced DNA in 205 tissue specimens [138 IHCCA, 23 EHCCA, and 44 GBC] and classified into three groups; high (TMB-H; ≥ 20 mut/Mb), intermediate (TMB-I; 6-19mut/Mb) and low (TMB-L; < 6mut/Mb). Results: A distinct pattern of DNA repair GAs in each tumor type was detected. (Table 1). DNA repair GAs were more commonly noted in both EHCCA and GB (63%) as compared with IHCAA (45.2%) (p= .002). Direct DNA repair GAs were highest within EHCCA (25%), while indirect DNA GAs were predominant in GBC (59.8%) (p= 0.04 and 0.001, respectively). The frequency of TMB-H and TMB-I differed significantly between BTC subtypes. Pts with EHCCA and GBC had significantly higher TMB-H and TMB-I versus IHCCA. Conclusions: The frequency of DNA repair GA’s is higher in EHCCA and GBC as compared with IHCCA. These results may have implications for clinical trials with DNA repair inhibitors and immune checkpoint blockers. [Table: see text]

scholarly journals TAK1 mRNA Expression in the Tumor Tissue of Locally Advanced Head and Neck Cancer Patients

2008 ◽  
Vol 2 ◽  
pp. 117762500800200
Author(s):  
Beatriz Honorato ◽  
Juan Alcalde ◽  
Rafael Martinez-Monge ◽  
Natalia Zabalegui ◽  
Jesús Garcia-Foncillas
Keyword(s):  
Head And Neck Cancer ◽  
Head And Neck ◽  
Mrna Expression ◽  
Cancer Patients ◽  
Neck Cancer ◽  
Tumor Tissue ◽  
Locally Advanced ◽  
Advanced Head

scholarly journals Substantial Batch Effects in TCGA Exome Sequences Undermine Pan-Cancer Analysis of Germline Variants

2018 ◽  
Author(s):  
Roni Rasnic ◽  
Nadav Brandes ◽  
Or Zuk ◽  
Michal Linial
Keyword(s):  
Cancer Patients ◽  
Variant Calling ◽  
Batch Effect ◽  
Cancer Predisposition ◽  
The Cancer Genome Atlas ◽  
Batch Effects ◽  
Germline Variants ◽  
Predisposition Genes ◽  
Cancer Types ◽  
Pan Cancer

ABSTRACTBackgroundIn recent years, research on cancer predisposition germline variants has emerged as a prominent field. The identity of somatic mutations is based on a reliable mapping of the patient germline variants. In addition, the statistics of germline variants frequencies in healthy individuals and cancer patients is the basis for seeking candidates for cancer predisposition genes. The Cancer Genome Atlas (TCGA) is one of the main sources of such data, providing a diverse collection of molecular data including deep sequencing for more than 30 types of cancer from >10,000 patients.MethodsOur hypothesis in this study is that whole exome sequences from healthy blood samples of cancer patients are not expected to show systematic differences among cancer types. To test this hypothesis, we analyzed common and rare germline variants across six cancer types, covering 2,241 samples from TCGA. In our analysis we accounted for inherent variables in the data including the different variant calling protocols, sequencing platforms, and ethnicity.ResultsWe report on substantial batch effects in germline variants associated with cancer types. We attribute the effect to the specific sequencing centers that produced the data. Specifically, we measured 30% variability in the number of reported germline variants per sample across sequencing centers. The batch effect is further expressed in nucleotide composition and variant frequencies. Importantly, the batch effect causes substantial differences in germline variant distribution patterns across numerous genes, including prominent cancer predisposition genes such as BRCA1, RET, MAX, and KRAS. For most of known cancer predisposition genes, we found a distinct batch-dependent difference in germline variants.ConclusionTCGA germline data is exposed to strong batch effects with substantial variabilities among TCGA sequencing centers. We claim that those batch effects are consequential for numerous TCGA pan-cancer studies. In particular, these effects may compromise the reliability and the potency to detect new cancer predisposition genes. Furthermore, interpretation of pan-cancer analyses should be revisited in view of the source of the genomic data after accounting for the reported batch effects.

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