Biomarkers For Personalized Therapy Research Articles

Neuroimaging markers of aberrant brain activity and treatment response in schizophrenia patients based on brain complexity

The complexity of brain activity reflects its ability to process information, adapt to environmental changes, and transition between states. However, it remains unclear how schizophrenia (SZ) affects brain activity complexity, particularly its dynamic changes. This study aimed to investigate the abnormal patterns of brain activity complexity in SZ, their relationship with cognitive deficits, and the impact of antipsychotic medication. Forty-four drug-naive first-episode (DNFE) SZ patients and thirty demographically matched healthy controls (HC) were included. Functional MRI-based sliding window analysis was utilized for the first time to calculate weighted permutation entropy to characterize complex patterns of brain activity in SZ patients before and after 12 weeks of risperidone treatment. Results revealed reduced complexity in the caudate, putamen, and pallidum at baseline in SZ patients compared to HC, with reduced complexity in the left caudate positively correlated with Continuous Performance Test (CPT) and Category Fluency Test scores. After treatment, the complexity of the left caudate increased. Regions with abnormal complexity showed decreased functional connectivity, with complexity positively correlated with connectivity strength. We observed that the dynamic complexity of the brain exhibited the characteristic of spontaneous, recurring “complexity drop”, potentially reflecting transient state transitions in the resting brain. Compared to HC, patients exhibited reduced scope, intensity, and duration of complexity drop, all of which improved after treatment. Reduced duration was negatively correlated with CPT scores and positively with clinical symptoms. The results suggest that abnormalities in brain activity complexity and its dynamic changes may underlie cognitive deficits and clinical symptoms in SZ patients. Antipsychotic treatment partially restores these abnormalities, highlighting their potential as indicators of treatment efficacy and biomarkers for personalized therapy.

Significance of PBRM1 mutation in disease progress and drug selection in clear cell renal cell carcinoma

ABSTRACT Clear cell renal cell carcinoma (ccRCC) is the predominant type of kidney cancer, and the mutation of PBRM1 (Polybromo 1) gene is a commonly observed genetic alteration. The high frequency of PBRM1 mutation in ccRCC suggests its potential use as a biomarker for personalized therapy. In this study, we aimed to investigate the significance of PBRM1 mutation in disease progression and drug sensitivity in ccRCC. Additionally, we analyzed the critical pathways and genes associated with PBRM1 mutation to understand its potential mechanisms. Our findings show that PBRM1 mutation was observed in 38% of ccRCC patients and correlated with advanced disease stages. We also identified selective inhibitors for ccRCC with PBRM1 mutation using online databases such as PD173074 and AGI-6780. Furthermore, we identified 1253 genes as differentially expressed genes (DEGs) that were significantly enriched in categories such as metabolic progression, cell proliferation, and development. Although PBRM1 mutation did not show an association with ccRCC prognosis, a lower PBRM1 expression level correlated with worsened prognosis. Our study provides insights into the association of PBRM1 mutation with disease progression in ccRCC and suggests potential gene and signaling pathways for personalized treatment in ccRCC with PBRM1 mutation.

Abstract 6164: NF-κB and NRF2 signaling pathways affect prognosis in HPV-associated head and neck cancer

Abstract Incidence of HPV associated head and neck squamous cell carcinoma (HNSCC) is on the rise, displaying a significantly favorable prognosis and overall better survival as compared to HPV negative HNSCC. Intense radiotherapy is the primary medical care leading to treatment associated morbidity in patients, thereby generating a need for de-intensification strategies. Biomarkers that can identify patients with less aggressive tumors as candidates for de-escalation therapy would revolutionize treatment. We applied an unbiased approach (weighted gene correlation network analysis (WGCNA)) that allows detection of autocorrelated gene sets on 3 independent cohorts of HPV+ HNSCC and created 22 consensus transcriptional modules by selecting genes that grouped together in WGCNA analyses from all 3 cohorts. Interestingly, only 1 module intrinsically divided HPV+ HNSCC into 2 subtypes, displaying different mutational profiles, mutational signatures, HPV gene expression patterns, HPV integration status, and patient survival. Gene set enrichment analysis revealed that this module was enriched in NF-kB genes and strongly associated with NF-κB signaling, confirming our prior findings that defined HPV+ HNSCC subtypes by presence or absence of NF-kB regulators, TRAF3 or CYLD defects and by the NF-κB activity classifier. Our studies show that NF- κB -driven intrinsic tumor characteristics contribute to increased sensitivity of NF- κB active HPV+ head and neck tumors to radiation, providing patients survival benefits. Indeed, TRAF3 or CYLD deletion activated NF-kB and dramatically increased radiation sensitivity of HPV+ head and neck cancer cells. In line with our RNA seq analysis, we found that activation of NF-κB via TRAF3/CYLD deletion significantly correlated with marked downregulation of NRF2 activity and reduced nuclear localization in in HPV+ HNSCC cells. Interestingly, TRAF3 CRISPR KO cells had lower NRF2 protein levels that were restored by MG132 treatment, indicating an involvement of KEAP1/CUL3 mediated proteasomal degradation of NRF2. In summary, our data unveils a unique relation between NF-κB pathway and radiosensitivity in HPV+ HNSCC. The distinct biological characteristics that separate patients into two subclasses associated with favorable prognosis could serve as a biomarker for personalized therapy. Citation Format: Aditi Kothari, Travis Parke Schrank, Wendell Gray Yarbrough, Natalia Isaeva. NF-κB and NRF2 signaling pathways affect prognosis in HPV-associated head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6164.

Diagnostic and therapeutic potential of circular RNA in brain tumors.

Circular RNAs (circRNAs) are a class of RNA with a stable cyclic structure. They are expressed in various tissues and cells with conserved, specific characteristics. CircRNAs have been found to play critical roles in a wide range of cellular processes by regulating gene expression at the epigenetic, transcriptional, and posttranscriptional levels. There is an accumulation of evidence on newly discovered circRNAs, their molecular interactions, and their roles in the development and progression of human brain tumors, including cell proliferation, cell apoptosis, invasion, and chemoresistance. Here we summarize the current state of knowledge of the circRNAs that have been implicated in brain tumor pathogenesis, particularly in gliomas and medulloblastomas. In providing a comprehensive overview of circRNA studies, we highlight how different circRNAs have oncogenic or tumor-suppressive roles in brain tumors, making them attractive therapeutic targets and biomarkers for personalized therapy and precision diagnostics. This review article discusses circRNAs' functional roles and the prospect of using them as diagnostic biomarkers and therapeutic targets in patients with brain tumors.

Free Water Volume Fraction: An Imaging Biomarker to Characterize Moderate-to-Severe Traumatic Brain Injury.

Traumatic brain injury (TBI) is a major clinical and public health problem with few therapeutic interventions successfully translated to the clinic. Identifying imaging-based biomarkers characterizing injury severity and predicting long-term functional and cognitive outcomes in TBI patients is crucial for treatment. TBI results in white matter (WM) injuries, which can be detected using diffusion tensor imaging (DTI). Trauma-induced pathologies lead to accumulation of free water (FW) in brain tissue, and standard DTI is susceptible to the confounding effects of FW. In this study, we applied FW DTI to estimate free water volume fraction (FW-VF) in patients with moderate-to-severe TBI and demonstrated its association with injury severity and long-term outcomes. DTI scans and neuropsychological assessments were obtained longitudinally at 3, 6, and 12 months post-injury for 34 patients and once in 35 matched healthy controls. We observed significantly elevated FW-VF in 85 of 90 WM regions in patients compared to healthy controls (p < 0.05). We then presented a patient-specific summary score of WM regions derived using Mahalanobis distance. We observed that MVF at 3 months significantly predicted functional outcome (p = 0.008), executive function (p = 0.005), and processing speed (p = 0.01) measured at 12 months and was significantly correlated with injury severity (p < 0.001). Our findings are an important step toward implementing MVF as a biomarker for personalized therapy and rehabilitation planning for TBI patients.

Pushing the Proteomics Envelope: More sensitive technology spurs proteomic and metabolomic biomarker identification, clinical use

Pushing the Proteomics Envelope: More sensitive technology spurs proteomic and metabolomic biomarker identification, clinical use

Long non-coding RNAs in brain tumors.

Long non-coding RNAs (lncRNAs) have been found to be central players in the epigenetic, transcriptional and post-transcriptional regulation of gene expression. There is an accumulation of evidence on newly discovered lncRNAs, their molecular interactions and their roles in the development and progression of human brain tumors. LncRNAs can have either tumor suppressive or oncogenic functions in different brain cancers, making them attractive therapeutic targets and biomarkers for personalized therapy and precision diagnostics. Here, we summarize the current state of knowledge of the lncRNAs that have been implicated in brain cancer pathogenesis, particularly in gliomas and medulloblastomas. We discuss their epigenetic regulation as well as the prospects of using lncRNAs as diagnostic biomarkers and therapeutic targets in patients with brain tumors.

Abstract 1875: Identification of LASEP3 as a serological and tissue biomarker and a therapeutic target for lung cancer

Abstract Lung cancer is the leading cause of cancer deaths worldwide. The prognosis of patients with lung cancer remains poor, because of its occult metastasis even at earlier stage of the disease and its resistance to conventional multimodal treatments. Therefore, this study aims to identify novel serum and tissue biomarkers for personalized therapy and/or therapeutic targets for lung cancers through screening and functional analyses of cancer-specific oncoproteins. We used cDNA microarrays for screening genes encoding transmembrane/secretory proteins that are up-regulated in lung cancers, and identified a secreted protein, LASEP3 (lung cancer-associated serum protein 3) as a candidate. Immunohistochemical staining of LASEP3 showed that LASEP3 expression was observed in 198 (54.8%) of 361 NSCLCs (non-small cell lung cancer) that had undergone curative surgery. High level of LASEP3 expression was associated with poor prognosis for NSCLC patients. (P = 0.0183 by log-rank test). Serum LASEP3 levels were higher in NSCLC patients than in healthy volunteers. The proportion of serum LASEP3-positive cases was 160 (61.8%) of 259 NSCLCs (49.4% for stage I-II, 67.4% for stage III-IV), while 6 (5.5%) of 109 healthy volunteers were falsely diagnosed. Moreover, reduction of LASEP3 expression by siRNAs suppressed lung cancer cell proliferation, probably through apoptosis as suggested by flow cytometric analysis and caspase-3 and 7 assays. Furthermore, subsequent microarray analysis of these cancer cells identified several candidate downstream genes of LASEP3 that relate to cell growth and invasion signals. LASEP3 is a possible diagnostic and prognostic biomarker and a therapeutic target for lung cancer. Citation Format: Atsushi Takano, Yusuke Nakamura, Yataro Daigo. Identification of LASEP3 as a serological and tissue biomarker and a therapeutic target for lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1875.

Abstract 2488: Novel candidate protein biomarkers for cisplatin response prediction in non-small cell lung cancer.

Abstract The five-year survival rate for non-small cell lung cancer (NSCLC) is still less than twenty percent in part due to treatment failure and lack of biomarkers for personalized therapy. Most NSCLC patients are treated by chemotherapy and cisplatin is still the major component of most chemotherapy regimens. However, resistance to cisplatin is a common phenomenon. Aim of this study was to identify protein biomarkers that can be used for cisplatin response prediction. The proteomes and secretomes1 of a series of human NSCLC cell lines with a range of IC50-values for cisplatin (1.5 - 15 μM) were analyzed by label-free proteomics based on GeLC-MS/MS and quantified by spectral counting. Significant differential expression of proteins was determined by the in-house developed beta-binomial statistical test2. Network and gene ontology analysis was performed, with STRING and DAVID respectively, to reveal cellular and molecular functions associated with the differential proteins. In total, 2885 and 2342 proteins were detected in the cell lysates and secretomes, respectively. The proteins with significantly higher expression in the resistant cell lines were associated RNA processing and vesicle transport, while the proteins with higher expression in the sensitive cell lines were known to be involved in RNA splicing, DNA damage repair and extracellular matrix organization. The most promising candidates are being validated in tissues and sputum of patients with known response to cisplatin. 1 Piersma SR et al. J Proteome Res. 2010 Apr 5;9(4):1913-22. 2 Pham TV et al. Bioinformatics. 2010 Feb 1;26(3):363-9. Citation Format: Tieneke B M Schaaij-Visser, Remco Nagel, Inge de Reus, Sander R. Piersma, Thang V. Pham, Egbert F. Smit, Frederik B. Thunnissen, Ruud H. Brakenhoff, Anton Berns, Connie R. Jimenez. Novel candidate protein biomarkers for cisplatin response prediction in non-small cell lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2488. doi:10.1158/1538-7445.AM2013-2488

Abstract 3463: Nuclear localization of S6K is associated with unfavorable disease-free survival in hormone-receptor positive breast cancer cases.

Abstract [Background&amp; Aim]mTOR signaling pathway (mTOR-S6K-pS6) plays important roles in translation process from RNA to protein and proliferation in many cancers. This pathway works as a hub, where various signals come from growth factors, energy loss and hypoxia and are transmitted to the translation process. Among this pathway, S6K (Ribosomal Protein S6 Kinase) is a key molecule. S6K is phosphorylated not only by mTOR, but also by other molecules. Moreover, S6K itself regulates various other molecules. S6K is the substrate of mTOR, and phospholyrates S6. Among these complicated networks, signal through the mTOR-S6K-S6 pathway contributes to cell. Thus, in breast cancer, this pathway is an important therapeutic target. mTOR pathway functions in the downstream of the HER2-PI3K-Akt signaling and it is known that this pathway is involved in therapeutic resistance, such as hormone resistance and anti-HER2 resistance. However, still many remain unknown about the clinical significance of mTOR related pathways. Therefore we investigated this pathway in breast cancer tissues by immunohistochemistry to find the biomarker for personalized therapy. [Methods]One-hundred and three formalin-fixed, paraffin-embedded tissue specimens were collected from the Department of Breast Surgery, Kyoto University Hospital between July 2000 and December 2005. The median follow up was 78 months (range, 3-120 months). For mTOR signaling pathway, the expression of S6K, phospho-S6K and phospho-S6 was examined using immunohistochemistry. The correlation between each expression pattern, clinico-pathological characteristics, and prognosis was evaluated statistically. [Results]In the normal mammary glands, S6K and phospho-S6K were not stained, or stained weakly both in the nucleus and/or the cytoplasm. Phospho-S6 was not detected. In breast cancer cells, S6K and phospho-S6K were detected in the nucleus and/or the cytoplasm as reported previously. Phospho-S6 was detected in the cytoplasm. Staining of these molecules has the heterogeneous pattern. Hormone-receptor negative HR(-) cases had higher expression of phospho-S6 than HR(+) cases (p=0.0276). Cases with weak S6K staining in cytoplasm but strong in the nucleus had shorter DFS (Wilcoxon test, p=0.0304). This trend was clear in the subgroup of HR(+) cases (Wilcoxon test, p=0.0243). There was no significant correlation between the clinical outcome and other expression profile. [Discussion &amp; Conclusion]It is reported that mTOR regulates nuclear localization of S6K. Although the function of S6K in nucleus is largely unknown, the result of this study suggests that nuclear S6K may play a crucial role in the progression of breast cancer. It is warranted to conduct further investigation. However, nuclear localization of S6K may be a potential biomarker of activated mTOR in breast cancer patients particularly having HR(+) disease. Citation Format: Nobuko Kawaguchi-Sakita, Rafaat Abd El-Aal Bakheet Mohamed, Fumiaki Sato, Takayuki Ueno, Masahiro Kawashima, Noriyuki Yoshida, Wen Zhao Li, Tomoharu Sugie, Yoshiki Mikami, Shigehira Saji, Takashi Inamoto, Masakazu Toi. Nuclear localization of S6K is associated with unfavorable disease-free survival in hormone-receptor positive breast cancer cases. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3463. doi:10.1158/1538-7445.AM2013-3463

Genomic Profiling of Liver Cancer

Development of liver cancers is driven largely by genomic alterations that deregulate signaling pathways, influencing growth and survival of cancer cells. Because of the hundreds or thousands of genomic/epigenomic alterations that have accumulated in the cancer genome, it is very challenging to find and test candidate genes driving tumor development and progression. Systematic studies of the liver cancer genome have become available in recent years. These studies have uncovered new potential driver genes, including those not previously known to be involved in the development of liver cancer. Novel approaches combining multiple datasets from patient tissues have created an unparalleled opportunity to uncover potential new therapeutic targets and prognostic/predictive biomarkers for personalized therapy that can improve clinical outcomes of the patients with liver cancer.

Epigenomics and Interindividual Differences in Drug Response

Epigenomics is a rapidly growing field. New developments in epigenetics, such as the recently described modified cytosine variants (e.g., 5-hydroxymethylcytosine, 5hmC) and an arsenal of novel noncoding forms of RNA, can be applied in the area of drug pharmacokinetics and pharmacodynamics. Epigenetic aberrations can affect drug treatment by modulating the expressions of key genes involved in the metabolism and distribution of drugs as well as drug targets, thereby contributing to interindividual variation in drug response. These epigenetic alterations, along with the epigenetic profiles of circulating nucleic acids, have great potential to be used as biomarkers for personalized therapy, particularly in the treatment of cancer. In this review we present an update of pharmacoepigenetics with respect to epigenetic regulation of ADME genes (genes related to drug absorption, distribution, metabolism, and excretion) and drug targets, and we illustrate how this information can be used for predicting interindividual variations in drug response.

Identification of a new insertion in exon 20 of EGFR in a woman with NSCLC

Mutations of epidermal growth factor receptor 1 (EGFR) gene occur in about 15 % of all NSCLCs in Western Europe and are frequently located in exons 19 and 21, being associated with high sensitivity to EGFR tyrosine kinase inhibitors (TKIs). By contrast, exon 20 insertions account for up to 10 % of all EGFR mutations and are correlated to EGFR TKI resistance. Herein, we describe a novel mutation in EGFR exon 20 in a female non-smoker bearing a lung adenocarcinoma, characterized by the insertion of a nucleotide triplet GTT, which translates into a protein with an additional Valine between Proline 772 and Histidine 773 (p.P772_H773insV-c.2316_2317insGTT). The patient was treated with cisplatin/pemetrexed 1st-line and docetaxel 2nd-line chemotherapies, reporting a prolonged disease stabilization of 25 months. The identification and the biological and clinical characterization of novel EGFR mutations represent a prerequisite for their wide use as predictive biomarkers for personalized therapy in NSCLC.

Abstract 5100: Secretome proteomics to identify indicators for lung cancer treatment response prediction and monitoring

Abstract Lung cancer is currently the number one cause of cancer-related deaths worldwide. Five-year survival rates for both non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) are still less than twenty percent due to late stage of presentation, treatment failure and lack of biomarkers for personalized therapy. Aim of this study is to identify protein biomarkers that can be used for treatment response prediction and therapy monitoring. Rather than following a broad strategy by analyzing the proteome of whole cell or tissue lysates, we chose to use a more specific approach based on the assumption that the best tumor markers are shed or secreted by the tumor and can be detected in blood. Secretome (i.e. all proteins shed from or secreted by a cell or tissue) proteomics (Piersma SR et al. J Proteome Res. 2010 Apr 5;9(4):1913-22.) was performed on a set of tumors from conditional mouse models for SCLC and NSCLC (Meuwissen R et al. Oncogene. 2001 Oct 4;20(45):6551-8; Meuwissen R et al. Cancer Cell. 2003 Sep;4(3):181-9.), a set of human and mouse SCLC and NSCLC cell lines and a series of human NSCLC cell lines with a range of IC50-values for cisplatin (1.5 – 15 µM). Secretomes were obtained by collecting serum-free media from the cell lines or collecting PBS in which a tumor tissue piece had been incubated. In the secretome samples, up to 2,000 proteins can be identified with 80% reproducibility by label-free, shotgun nanoLC tandem mass spectrometry and quantified by spectral counting. The beta-binomial test (Pham TV et al. Bioinformatics. 2010 Feb 1;26(3):363-9.) is used to find significant differences in protein expression between the different secretomes and network analysis is performed to provide insight into the underlying cellular mechanisms. The secretomes from the mouse models are used to find proteins specifically secreted by either NSCLC or SCLC, while the comparison between the secretomes of the several human and mouse cell lines allows extrapolation of the results from the mouse models to the human situation. Furthermore, the analysis of the cell lines with various cisplatin IC50-values permits selection of the protein markers that are indicative of sensitivity or resistance. The results of the different proteomics analyses will be presented along with the most promising biomarker candidates and an overview of the functional network analysis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5100. doi:10.1158/1538-7445.AM2011-5100

Personalizing treatment with pemetrexed (PEM) in patients with malignant mesothelioma (MPM) and non-small cell lung cancer (NSCLC): The role of thimidylate synthase.

e21001 Background: PEM was first approved for the treatment of MPM in combination with cisplatin, more recently as first line and maintenance therapy for advanced nonsquamous NSCLC. TS levels may predict response to PEM; high levels of expression are speculated to predict resistance to PEM. To evaluate whether TS protein levels, rather than histologic type, could be used to select patients with NSCLC and MPM for treatment with PEM, we assessed the variability of expression of TS in NSCLC and MPM tissue samples. Methods: We pursued semi-quantification of TS protein levels by immunohistochemistry (IHC) on tissue microarrays from 83 adenocarcinoma, 92 squamous, large cell, not-other-specified (NOS) NSCLC and 40 MPM samples. An IHC scoring system (IRS) was implemented based on stains: IRS scores of 0-2, 3-7 and 8-12 signified low, moderate and high TS protein expression respectively. Results: Of 49 squamous-cell samples, 22% had low expression of TS, indicating that PEM could potentially be effective in a subset of patients with squamous lung cancer. 24% expressed high levels of TS, 55% had an IRS greater than 6, in contrast to 23% of the adenocarcinoma samples. Of 83 adenocarcinoma samples, 56.5% and 9.6% had moderate and high expression of TS respectively. Similarly, 47% and 35% of the MPM samples showed moderate and high levels of TS expression respectively (Table). Correlation of clinical response to PEM with levels of TS expression is ongoing. Conclusions: Based on these preliminary data, TS levels are highly variable across both NSCLC and MPM tissue samples, and a substantial minority of patients with squamous histology may have a molecular profile that correlates with sensitivity to PEM. The role of TS as a biomarker for personalized therapy with PEM in patients with NSCLC and MPM requires prospective validation. TS expression Tumor type Negative (IRS = 0-2) Low (IRS = 3-7) High (IRS = 8-12) Mesothelioma (n = 40) 17.5% 47.5% 35% Adeno (n = 83) 33.6% 56.5% 9.6% Squamous, large cell, and NOS (n=92) 23.8% 50.8% 25% Squamous (n = 49) 22.2% 50.8% 24.4% Large cell (n = 11) 18% 54% 27.2% NOS/BAC (n = 12) 16.6% 41.5% 41.6% No significant financial relationships to disclose.

Functional polymorphism in CTLA4 gene influences the response to therapy with inhaled corticosteroids in Slovenian children with atopic asthma

We genotyped CTLA4 CT60 (rs3087243) functional single nucleotide polymorphism (SNP) in children with asthma and in healthy controls and correlated the genotype data with asthma clinical data, including treatment response with inhaled corticosteroids measured by forced expiratory volume in the first second (FEV1). FEV1 increased by 21.7% after 4 weeks of therapy in atopic asthmatics with the A/A genotype compared with an 8.6% increase in heterozygotes and a 5.8% increase in G/G homozygotes (p <0.01). Genotype and allele frequencies in asthmatics did not differ significantly from those in the control group. SNP CT60 in the CTLA4 gene is significantly associated with the response to treatment with inhaled corticosteroids in children with atopic asthma and could be a useful biomarker for personalized therapy in asthmatic children. SNP CT60 in the CTLA4 gene plays only a minor role in genetic susceptibility to childhood asthma in the Caucasian population.