Expression of DNA repair and replication genes in non-small cell lung cancer (NSCLC): a role for thymidylate synthetase (TYMS)

Kotoula, Vassiliki; Krikelis, Dimitrios; Karavasilis, Vasilios; Κoletsa, Triantafyllia; Eleftheraki, Anastasia G; Televantou, Despina; Christodoulou, Christos; Dimoudis, S.T.; Korantzis, Ioannis; Pectasides, Dimitrios; Syrigos, Konstantinos; Kosmidis, P.; Fountzilas, George

doi:10.1186/1471-2407-12-342

Cited by 27 publications

(17 citation statements)

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“…In-vitro studies have shown that overexpression of TYMS is sufficient to transform immortalized mammalian cells to a malignant phenotype [ 6 ]. Studies analyzing TYMS expression in cohorts of clinical samples reported a link between TYMS up-regulation and adverse clinical behavior in many solid tumor types including lung [ 7 ], breast [ 8 ], gastric [ 9 ], colorectal [ 10 ], and renal cell cancers [ 11 ]. Also for prostate cancer, some studies involving 52–172 patients have suggested that TYMS expression levels may be linked to unfavorable tumor phenotype [ 12 – 15 ].…”

Section: Introductionmentioning

confidence: 99%

Overexpression of thymidylate synthase (TYMS) is associated with aggressive tumor features and early PSA recurrence in prostate cancer

et al. 2015

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Thymidylate synthase (TYMS) plays a role in DNA synthesis and is a target for 5-fluorouracil. In this study TYMS was analyzed by immunohistochemistry on a tissue microarray containing 11,152 prostate cancers. TYMS expression was higher in neoplastic than in normal prostate epithelium and was detectable in 72.9% of 10,223 interpretable cancers. It was considered strong in 21.9%, moderate in 33.4% and weak in 17.6% of tumors. TYMS overexpression was associated with deletions at 5q21 (p < 0.0001), 6q15 (p < 0.0001) and 3p13 (p = 0.0083) and gradually increased with the total number of these deletions present in the respective cancer sample (p < 0.0001). TYMS expression was unrelated to PTEN deletions (p = 0.9535) but tightly linked to high Gleason grade, advanced pathological tumor stage and early PSA recurrence (p < 0.0001). The prognostic value of TYMS was independent from the ERG status and deletions at 3p13, 5q21, and 6q15. In multivariate analyses the prognostic role of TYMS expression was independent of Gleason grade, pT stage, preoperative PSA, pN stage, or resection margins. TYMS expression analysis might result in clinically useful information in prostate cancer. The striking link to some but not all chromosomal aberrations might suggest a mechanistical link with specific types of DNA damage.

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Section: Introductionmentioning

confidence: 99%

Overexpression of thymidylate synthase (TYMS) is associated with aggressive tumor features and early PSA recurrence in prostate cancer

et al. 2015

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“…TYMS (Thymidylate Synthetase) protein plays a critical role in DNA replication and repair [73]. Mutations in its enhancer region, resulting in an overexpression of TYMS, are associated with several cancers and response to chemotherapy [74].…”

Section: Discussionmentioning

confidence: 99%

Exploring the druggable space around the Fanconi anemia pathway using machine learning and mechanistic models

Esteban

Peña‐Chilet

Loucera

et al. 2019

Preprint

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BackgroundIn spite of the abundance of genomic data, predictive models that describe phenotypes as a function of gene expression or mutations are difficult to obtain because they are affected by the curse of dimensionality, given the disbalance between samples and candidate genes. And this is especially dramatic in scenarios in which the availability of samples is difficult, such as the case of rare diseases.ResultsThe application of multi-output regression machine learning methodologies to predict the potential effect of external proteins over the signaling circuits that trigger Fanconi anemia related cell functionalities, inferred with a mechanistic model, allowed us to detect over 20 potential therapeutic targets.ConclusionsThe use of artificial intelligence methods for the prediction of potentially causal relationships between proteins of interest and cell activities related with disease-related phenotypes opens promising avenues for the systematic search of new targets in rare diseases.

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“…15 mRNA expression was assessed with qPCR and TaqMan Gene Expression Assays (Applied Biosystems/ Life Technologies) in an ABI7900HT system under default conditions for the following targets (assay ID, Genbank reference, amplicon location, size): ALK3 0 (Hs00608291_m1, NM_004304.4, exons 25-26, 125 bp) and ALK5 0 (Hs00608296_m1, NM_004304.4, exons 3-4, 86 bp). 15 mRNA expression was assessed with qPCR and TaqMan Gene Expression Assays (Applied Biosystems/ Life Technologies) in an ABI7900HT system under default conditions for the following targets (assay ID, Genbank reference, amplicon location, size): ALK3 0 (Hs00608291_m1, NM_004304.4, exons 25-26, 125 bp) and ALK5 0 (Hs00608296_m1, NM_004304.4, exons 3-4, 86 bp).…”

Section: Methodsmentioning

confidence: 99%

“…15 Descriptive statistics [distribution of continuous variables, bivariate correlations (the Spearman test), w 2 test (the Pearson test), parametric and nonparametric means comparisons] were applied with SPSS v.15 and with cutoffs for significance at 5%. 15 Descriptive statistics [distribution of continuous variables, bivariate correlations (the Spearman test), w 2 test (the Pearson test), parametric and nonparametric means comparisons] were applied with SPSS v.15 and with cutoffs for significance at 5%.…”

Section: Statisticsmentioning

confidence: 99%

Intact or Broken-apart RNA

Kotoula

Bobos²,

Vassilakopoulou³

et al. 2015

Applied Immunohistochemistry &Amp; Molecular Morphology

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Anaplastic lymphoma kinase (ALK) break-apart fluorescent in situ hybridization (FISH) is currently used in diagnostics for the selection of non-small cell lung cancer (NSCLC) patients to receive crizotinib. We evaluated ALK status in NSCLC with a novel ALK mRNA test based on the break-apart FISH concept, which we called break-apart transcript (BAT) test. ALK5' and ALK3' transcript patterns were established with qPCR for ALK-expressing controls including fusion-negative neuroblastomas, as well as fusion-positive anaplastic large cell lymphomas and NSCLC. The BAT test was evaluated on 271 RNA samples from routinely processed paraffin NSCLC tissues. Test results were compared with ALK FISH (n=121), immunohistochemical (IHC) analysis (n=86), and automated quantitative analysis (AQUA, n=83). On the basis of the nonoverlapping ALK BAT patterns in ALK-expressing controls (P<0.0001), 8/174 adenocarcinomas (4.6%) among 259 informative NSCLC were predicted as fusion positive. Overall concordance for paired method results was high (94.1% to 98.8%) but mainly concerned negative prediction because of the limited availability of positive-matched cases. Tumors with 100% cytoplasmic IHC staining of any intensity (n=3) were positive for AQUA, FISH, and BAT test; tumors with lower IHC positivity and different staining patterns were AQUA-negative. Upon multiple reevaluations, ALK gene status was considered as originally misinterpreted by FISH in 3/121 cases (2.5%). Tumors with >4 ALK gene copies were associated with longer overall survival upon first-line chemotherapy. In conclusion, application of the ALK BAT test on routinely processed NSCLC tissues yields the same fusion partner independent information as ALK break-apart FISH but is more robust and cost-effective. The BAT concept may be considered for the development of further drug-predictive translocation tests.

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Expression of DNA repair and replication genes in non-small cell lung cancer (NSCLC): a role for thymidylate synthetase (TYMS)

Cited by 27 publications

References 50 publications

Overexpression of thymidylate synthase (TYMS) is associated with aggressive tumor features and early PSA recurrence in prostate cancer

Overexpression of thymidylate synthase (TYMS) is associated with aggressive tumor features and early PSA recurrence in prostate cancer

Exploring the druggable space around the Fanconi anemia pathway using machine learning and mechanistic models

Intact or Broken-apart RNA

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