DNA methylation array analyses to identify HYAL2 methylation in peripheral blood as a marker for the detection of early breast cancer.

2014 ◽  
Vol 32 (26_suppl) ◽  
pp. 26-26
Author(s):  
Rongxi Yang ◽  
Katrin Pfuetze ◽  
Manuela Zucknick ◽  
Christian Sutter ◽  
Frederik Marme ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Methylation ◽  
T Cells ◽  
Peripheral Blood ◽  
Methylation Level ◽  
Cpg Island ◽  
Early Stage ◽  
Strong Association ◽  
Cell Type ◽  
Increased Risk

26 Background: Early detection is crucial to improve the survival rate and quality of life of breast cancer (BC) patients. Changes in DNA methylation in peripheral blood could be associated with malignancy at early stage. We aim to identify BC-associated DNA methylation signatures in peripheral blood. Methods: We identified a BC-associated differentially methylated locus by genome-wide investigation using Illumina 27K Methylation Assay. Two validation studies and replications in leucocytes and T cells were carried out using MassARRAY. The RNA expression levels were measured by real-time PCR. Results: The methylation level of CpG site cg27091787 in hyaluronoglucosaminidase 2 gene (HYAL2) in peripheral blood was significantly lower in BC cases than in controls (discovery round, 72 BC case and 24 controls, p = 2.61 × 10-9 adjusted for cell-type proportions; first validation round,338 BC case and 507 controls, p < 0.0001; second validation round,189 BC case and 189 controls, p < 0.0001). Compared to the highest quartile, the lowest quartile of cg27091787 methylation was associated with a more than 40-fold increased risk of BC (p < 0.0001). In addition to cg27091787, the decreased methylation of a 650 bp CpG island shore of HYAL2 was also associated with BC. Moreover, the expression and methylation of HYAL2 in leucocytes were inversely correlated (p = 0.006). To note, the BC-associated decreased HYAL2 methylation was replicated in T cell fraction (p = 0.034). The cg27091787 methylation level enabled a powerful discrimination of early stage BC cases from healthy controls (area under curve (AUC) = 0.88), and was also robust for the detection of BC in younger women (AUC = 0.87). Conclusions: Validating the epigenome-wide study by independent cohorts, we have revealed a strong association between decreased HYAL2 methylation in peripheral blood and BC. Our results have given an answer to the debate on the origin of BC-associated differential methylation in blood, which is not only because of the change of cell type proportions, but more importantly due to altered methylation in specific blood cell fragments, like in T cells. And thus, we provide a promising blood-based marker for the detection of early BC.

scholarly journals Role of CD4+ CD25+ FOXP3+ regulatory T-cells and human papilloma virus infection in Egyptian Women with breast cancer

2019 ◽  
Author(s):  
Amany Tawfeik ◽  
Ahmed Mora ◽  
Ahmed Osman ◽  
Nabila Elsheikh ◽  
Mohamed Elrefaei
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
High Risk ◽  
Human Papilloma Virus ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Early Stage ◽  
Significant Proportion ◽  
Papilloma Virus ◽  
Egyptian Women

Abstract Several subsets of regulatory CD4+ T cells (CD4+ Tregs) have been described in peripheral blood and tumor microenvironment and blood of breast cancer (BC) patients and may play a key role in the progression of BC. High-risk human papilloma virus (HPV) have a causal role in a significant proportion of cervical, and head, and neck tumors and may play an important role in evoking neoplasia in BC. In this study we assessed the prevalence of CD4+Tregs (CD4+CD25+ FOXP3+ cells) and CD8+T cells by flow cytometry in peripheral blood from a total of 55 Egyptian women, including 20 treatment-naïve BC, 15 with breast benign lesions (BBL) and 20 healthy volunteers (HV). High-risk HPV genotype type 16, 18, and 31 was investigated in breast tissue from all BC and BBL patients using Real-Time PCR. HPV was detected in 4 BC, but in none of BBL patients. The frequency of CD4+ Tregs was significantly higher in BC compared to BBL and HV, (p < 0.001). In addition, we observed a significantly higher frequency of CD8+ T cells in peripheral blood of patients with late stage III compared to early stage I and II BC (p = 0.011). However, there was no significant association between the ratio of CD8+ T cell to CD4+ Tregs frequencies and the expression of Estrogen Receptor (ER), Progesterone Receptor (PR), and Human Epidermal Growth Factor Receptor 2 (HER2). In conclusion, CD4+ Tregs may contribute to progression BC in Egyptian women with HPV infection. The potential role CD4+ Tregs as a prognostic or predictive parameter should be analyzed in a larger longitudinal study with sufficient follow-up time.

scholarly journals Frequency of CD4+ regulatory T cells, CD8+ T cells, and human papilloma virus infection in Egyptian Women with breast cancer

2020 ◽  
Vol 34 ◽  
pp. 205873842096682
Author(s):  
Amany M Tawfeik ◽  
Ahmed Mora ◽  
Ahmed Osman ◽  
Manar M Moneer ◽  
Nabila El-Sheikh ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Regulatory T Cells ◽  
Human Papilloma Virus ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Early Stage ◽  
Hpv Infection ◽  
Papilloma Virus ◽  
Egyptian Women

Several subsets of regulatory CD4+ T cells (CD4+ Tregs) have been described in peripheral blood and tumor microenvironment of breast cancer (BC) patients and may play a role in the progression of BC. High-risk human papilloma virus (HR-HPV) has a causal role in cervical, head, and neck tumors but the role of HR-HPV in evoking neoplasia in BC is still unclear. In this study we assessed the prevalence of CD4+CD25+ FOXP3+ regulatory T cells (CD4+Tregs) and CD3+ CD8+ T cells by flow cytometry in peripheral blood from a total of 55 Egyptian women, including 20 treatment-naïve BC, 15 with breast benign lesions (BBL), and 20 healthy volunteers (HV). HR-HPV genotypes type 16, 18, and 31 were investigated in breast tissue from all BC and BBL patients using Real-Time PCR. HR-HPV was detected in 4/20 (20%) and 0/15 (0%) BC and BBL patients respectively. The frequency of CD4+ Tregs was significantly higher in BC compared to BBL and HV, ( P < 0.001). In addition, we observed a significantly higher frequency of CD3+ CD8+ T cells in peripheral blood of patients with late stage III BC compared to early stage I and II BC ( P = 0.011). However, there was no significant association between the ratio of CD8+ T cell to CD4+ Tregs frequencies and the expression of Estrogen Receptor (ER), Progesterone Receptor (PR), and Human Epidermal Growth Factor Receptor 2 (HER2). These results lead us to postulate that the association between the frequency of CD4+ Tregs and CD8+ T cells in the peripheral blood may be a prognostic or predictive parameter in Egyptian women with BC. In addition, HR-HPV infection may be implicated in the development of some types of BC in Egyptian women.

scholarly journals 94 Effects of chemoimmunotherapy on the peripheral blood: insights from immune monitoring of a phase Ib trial of pembrolizumab and paclitaxel or capecitabine for triple-negative breast cancer (TNBC)

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A103-A103
Author(s):  
Brie Chun ◽  
Joanna Pucilowska ◽  
Shu Ching Chang ◽  
Isaac Kim ◽  
Benjamin Nikitin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
Triple Negative Breast Cancer ◽  
Peripheral Blood ◽  
Triple Negative ◽  
Early Stage ◽  
Medical Center ◽  
T Cell Subsets

BackgroundPembrolizumab plus curative-intent dose-dense anthracycline-based chemotherapy (ddAC) is associated with improved outcome in PD-L1-negative TNBC,1 whereas in the metastatic setting, clinical benefit of chemoimmunotherapy (taxane or gemcitabine/carboplatin) is restricted to PD-L1-positive patients.2 We hypothesize that this discordance could be related to immunomodulatory differences of the various chemotherapies. On-treatment serial monitoring of peripheral blood and tumoral T cells can be used to compare the effects of various regimens. We also hypothesize that T cell clonal expansion may differ across the regimens, and that tumor-enriched T cell clones are more likely to be tumor-reactive and expand following chemoimmunotherapy.MethodsBlood and tumor samples were collected from patients enrolled in a phase Ib clinical trial of palliative pembrolizumab and paclitaxel or capecitabine for metastatic TNBC, and from a contemporaneous cohort of patients treated with ddAC. T-cells were characterized using fresh whole blood flow cytometry and T-cell receptor (TCR) immunosequencing (immunoSEQ, Adaptive Biotechnologies) of DNA digests. Longitudinal regression was used to test the hypothesis that tumor-enriched T-cell clonotypes are more likely to expand in peripheral blood following therapy.ResultsWhen combined with pembrolizumab, paclitaxel versus capecitabine had similar effects on T-cells, resulting in a time-dependent lymphodepletion across all major T cell subsets (average CD3+ T cell fold-change capecitabine: -0.42, paclitaxel: -0.56, p = 0.80 t-test), whereas ddAC was associated with more profound lymphodepletion (CD3+ average fold-change: -1.21). Notably, ddAC was associated with higher odds of novel clonotype detection compared to capecitabine (odds ratio (OR): 3.42, 95% CI: 3.34–3.5) as well as compared to paclitaxel (OR: 1.53, 95% CI: 1.47–1.60). Significant expansion of tumoral clonotypes occurred in five patients receiving chemoimmunotherapy (average 4.2 unique clonotypes per patient, range 2–11). These clonotypes did not significantly expand over time in the blood. Similarly, T-cell clonotypes that were enriched within tumor did not exhibit measurable differences in serial trend within the peripheral blood.ConclusionsEffects to T cell subsets and clonotypes are similar between capecitabine and paclitaxel when combined with pembrolizumab. ddAC was more profoundly lymphotoxic, but resulted in greater clonotype expansion. These findings offer mechanistic insight onto the differences in clinical activity observed with chemoimmunotherapy in early stage versus metastatic TNBC. We observed no strong association between tumor clonotype enrichment and peripheral clonotype expansion, highlighting the unmet need to develop methods of monitoring tumor-reactive T cell clones in the context of immunotherapy.AcknowledgementsThe authors would like to acknowledge collaborators at the Earle A. Chiles Research Institute and Adaptive Biotechnologies for mentorship and guidance. Support for the clinical trial (NCT02734290), which comprised the metastatic cohort was provided by Merck and the Providence Opportunity Fund. Laboratory services were provided at no cost by Adaptive BiotechnologiesTrial RegistrationNCT02734290ReferencesSchmid P, Cortes J, Pusztai L, et al. Pembrolizumab for early triple-negative breast cancer. N Engl J Med 2020 Feb 27;382(9):810–821. doi: 10.1056/NEJMoa1910549.Cortes J, Cescon DW, Rugo HS, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet 2020;396(10265):1817–1828. doi:10.1016/S0140-6736(20)32531-9Ethics ApprovalAll patients provided written, informed consent. The study protocols for the collection of specimens from the early-stage breast cancer cohort and from the metastatic TNBC clinical trial were separately approved by independent review boards at Providence Portland Medical Center and Cedars Sinai Medical Center (mTNBC clinical trial only).

scholarly journals Association of CD4+ CD25+ FOXP3+ regulatory T-cells and human papilloma virus infection in Egyptian Women with breast cancer

2020 ◽  
Author(s):  
Amany Tawfeik ◽  
Ahmed Mora ◽  
Ahmed Osman ◽  
Nabila Elsheikh ◽  
Mohamed Elrefaei
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
High Risk ◽  
Human Papilloma Virus ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Early Stage ◽  
Significant Proportion ◽  
Papilloma Virus ◽  
Egyptian Women

Abstract Several subsets of regulatory CD4+ T cells (CD4+ Tregs) have been described in peripheral blood and tumor microenvironment and blood of breast cancer (BC) patients and may play a key role in the progression of BC. High-risk human papilloma virus (HPV) have a causal role in a significant proportion of cervical, and head, and neck tumors and may play an important role in evoking neoplasia in BC. In this study we assessed the prevalence of CD4+Tregs (CD4+CD25+ FOXP3+ cells) and CD3+ CD8+ T cells by flow cytometry in peripheral blood from a total of 55 Egyptian women, including 20 treatment-naïve BC, 15 with breast benign lesions (BBL) and 20 healthy volunteers (HV). High-risk HPV genotype type 16, 18, and 31 was investigated in breast tissue from all BC and BBL patients using Real-Time PCR. HPV was detected in 4 BC, but in none of BBL patients. The frequency of CD4+ Tregs was significantly higher in BC compared to BBL and HV, (p < 0.001). In addition, we observed a significantly higher frequency of CD3+ CD8+ T cells in peripheral blood of patients with late stage III compared to early stage I and II BC (p = 0.011). However, there was no significant association between the ratio of CD8+ T cell to CD4+ Tregs frequencies and the expression of Estrogen Receptor (ER), Progesterone Receptor (PR), and Human Epidermal Growth Factor Receptor 2 (HER2). In conclusion, CD4+ Tregs may contribute to progression BC in Egyptian women with HPV infection. The potential role CD4+ Tregs as a prognostic or predictive parameter should be analyzed in a larger longitudinal study with sufficient follow-up time.

scholarly journals The Genome-Wide Impact of Trisomy 21 on DNA Methylation and Its Implications for Hematologic Malignancies

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2510-2510
Author(s):  
Joseph L. Wiemels ◽  
Ivo S Muskens ◽  
Shaobo Li ◽  
Priyatama Pandey ◽  
Ritu Roy ◽  
...  
Keyword(s):  
Dna Methylation ◽  
T Cells ◽  
Linear Regression ◽  
Blood Cell ◽  
Trisomy 21 ◽  
Chromosome 21 ◽  
Small Scale ◽  
Cell Type ◽  
Genome Wide ◽  
Increased Risk

Children with Down syndrome (DS), caused by constitutive trisomy of chromosome 21, have a 20-fold increased risk of acute lymphoblastic leukemia (DS-ALL) and 500-fold increased risk of acute megakaryoblastic leukemia (DS-AMKL). At least 10-15% of DS neonates are born with the pre-leukemic syndrome transient abnormal myelopoiesis (TAM). Trisomy 21 affects hematopoiesis and leukemia risk; however, the underlying mechanisms are not fully understood. Previous small-scale studies (sample N<30) revealed genome-wide epigenetic effects of trisomy 21. We conducted a comprehensive and multi-ethnic study of neonatal DNA methylation in DS. DNA was extracted from newborn dried bloodspots from 196 children born with DS and 442 non-DS controls from the California Biobank Program, and assayed using Illumina Infinium MethylationEPIC arrays containing >850,000 CpG probes. Data preprocessing was performed using the SeSAMe R package, and the conumee package confirmed trisomy 21 or euploidy in DS and non-DS subjects. Cell type deconvolution was performed, and blood cell proportions compared between DS and non-DS newborns using linear regression adjusting for covariates. ReFACTor principal components (PCs) were used to adjust for cell type heterogeneity and EPISTRUCTURE PCs to adjust for ancestry. Epigenome-wide association studies (EWAS) were performed overall, and stratified by ethnicity, using linear regression models adjusting for sex, plate, first six ReFACTor PCs, and first six ancestry-related PCs. Differentially methylated regions (DMRs) were evaluated using DMRcate and comb-p, with a consensus list of significant DMRs using the overlap. Deconvolution of blood cell proportions revealed highly significant (P<5x10-7) differences across most cell types, with lower B-cells, CD4 T-cells, monocytes, but higher CD8 T-cells and nucleated red blood cells (nRBCs) in DS than in non-DS newborns. Our EWAS of DS revealed 710 CpGs associated at genome-wide significant levels (P<5x10-8). CpGs in the hematopoietic transcription factor RUNX1 on chromosome 21 were highly significantly hypermethylated in DS neonates, including 2 of the top 3 CpG associations (with P<10-20). Significant CpGs were found in additional genes involved in hematopoiesis, including hypermethylation at the promoter of FLI1, which plays a critical role in megakaryopoiesis. Additionally, we identified 847 significant DMRs (containing two or more proximal CpGs with coordinate methylation status), with the top 2 DMRs residing in RUNX1 (DMRcate derived Stouffer-P=8.0x10-92) and FLI1 (P=1.6x10-79). The RUNX1 DMR, containing 16 CpGs, overlaps a super-enhancer in hematopoietic stem cells (HSCs) and demonstrated a profoundly increased mean beta value (+0.30) among DS compared to non-DS subjects. We also found significant enrichment for the overlap of hypermethylated DMRs with super-enhancers genome-wide in HSCs (P<10-20). EWAS and DMR results in ethnicity-stratified analyses were highly correlated between Latinos and non-Latino whites. Intriguingly, PC analysis and hierarchical clustering of DNA methylation data identified a subset of DS subjects (N=34/196, 17%) that clustered separately: these all had significantly higher nRBC proportions than other subjects and possibly represent DS neonates with TAM, although further investigation is needed for confirmation. Removing this cluster did not affect our main findings in our EWAS or DMR analyses. Constitutive trisomy 21 has profound effects on DNA methylation across the genome, in particular resulting in repression of known regulators of hematopoiesis including RUNX1 and FLI1. Our findings highlight potential mechanisms for the increased risk of both lymphoid and myeloid malignancies in children with DS. Disclosures No relevant conflicts of interest to declare.

scholarly journals Profile of copper-associated DNA methylation and its association with incident acute coronary syndrome

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Pinpin Long ◽  
Qiuhong Wang ◽  
Yizhi Zhang ◽  
Xiaoyan Zhu ◽  
Kuai Yu ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Acute Coronary Syndrome ◽  
Methylation Level ◽  
Meta Analysis ◽  
Regulation Of Gene Expression ◽  
Density Lipoprotein ◽  
Blood Leukocytes ◽  
Coronary Syndrome ◽  
A Genome ◽  
Increased Risk

Abstract Background Acute coronary syndrome (ACS) is a cardiac emergency with high mortality. Exposure to high copper (Cu) concentration has been linked to ACS. However, whether DNA methylation contributes to the association between Cu and ACS is unclear. Methods We measured methylation level at > 485,000 cytosine-phosphoguanine sites (CpGs) of blood leukocytes using Human Methylation 450 Bead Chip and conducted a genome-wide meta-analysis of plasma Cu in a total of 1243 Chinese individuals. For plasma Cu-related CpGs, we evaluated their associations with the expression of nearby genes as well as major cardiovascular risk factors. Furthermore, we examined their longitudinal associations with incident ACS in the nested case-control study. Results We identified four novel Cu-associated CpGs (cg20995564, cg18608055, cg26470501 and cg05825244) within a 5% false discovery rate (FDR). DNA methylation level of cg18608055, cg26470501, and cg05825244 also showed significant correlations with expressions of SBNO2, BCL3, and EBF4 gene, respectively. Higher DNA methylation level at cg05825244 locus was associated with lower high-density lipoprotein cholesterol level and higher C-reactive protein level. Furthermore, we demonstrated that higher cg05825244 methylation level was associated with increased risk of ACS (odds ratio [OR], 1.23; 95% CI 1.02–1.48; P = 0.03). Conclusions We identified novel DNA methylation alterations associated with plasma Cu in Chinese populations and linked these loci to risk of ACS, providing new insights into the regulation of gene expression by Cu-related DNA methylation and suggesting a role for DNA methylation in the association between copper and ACS.

scholarly journals De-escalation of radiation therapy in patients with stage I, node-negative, HER2-positive breast cancer

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Jose G. Bazan ◽  
Sachin R. Jhawar ◽  
Daniel Stover ◽  
Ko Un Park ◽  
Sasha Beyer ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Early Stage ◽  
Local Therapy ◽  
Adjuvant Radiation ◽  
Her2 Positive ◽  
Node Negative ◽  
Risk Of Death ◽  
Her2 Breast Cancer ◽  
Neoadjuvant Systemic Therapy ◽  
Increased Risk

AbstractIn the modern era, highly effective anti-HER2 therapy is associated with low local-regional recurrence (LRR) rates for early-stage HER2+ breast cancer raising the question of whether local therapy de-escalation by radiation omission is possible in patients with small-node negative tumors treated with lumpectomy. To evaluate existing data on radiation omission, we used the National Cancer Database (NCDB) to test the hypothesis that RT omission results in equivalent overall survival (OS) in stage 1 (T1N0) HER2+ breast cancer. We excluded patients that received neoadjuvant systemic therapy. We stratified the cohort by receipt of adjuvant radiation. We identified 6897 patients (6388 RT; 509 no RT). Patients that did not receive radiation tended to be ≥70 years-old (odds ratio [OR] = 3.69, 95% CI: 3.02–4.51, p < 0.0001), to have ≥1 comorbidity (OR = 1.33, 95% CI: 1.06–1.68, p = 0.0154), to be Hispanic (OR = 1.49, 95% CI: 1.00–2.22, p = 0.049), and to live in lower income areas (OR = 1.32, 95% CI: 1.07–1.64, p = 0.0266). Radiation omission was associated with a 3.67-fold (95% CI: 2.23–6.02, p < 0.0001) increased risk of death. While other selection biases that influence radiation omission likely persist, these data should give caution to radiation omission in T1N0 HER2+ breast cancer.

scholarly journals DNA methylation mediated RSPO2 to promote follicular development in mammals

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Xiaofeng Zhou ◽  
Yingting He ◽  
Nian Li ◽  
Guofeng Bai ◽  
Xiangchun Pan ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Wnt Signaling ◽  
Signaling Pathway ◽  
Methylation Level ◽  
Molecular Mechanisms ◽  
Cpg Island ◽  
Wnt Signaling Pathway ◽  
Follicular Development ◽  
Expression Level

AbstractIn female mammals, the proliferation, apoptosis, and estradiol-17β (E2) secretion of granulosa cells (GCs) have come to decide the fate of follicles. DNA methylation and RSPO2 gene of Wnt signaling pathway have been reported to involve in the survival of GCs and follicular development. However, the molecular mechanisms for how DNA methylation regulates the expression of RSPO2 and participates in the follicular development are not clear. In this study, we found that the mRNA and protein levels of RSPO2 significantly increased during follicular development, but the DNA methylation level of RSPO2 promoter decreased gradually. Inhibition of DNA methylation or DNMT1 knockdown could decrease the methylation level of CpG island (CGI) in RSPO2 promoter and upregulate the expression level of RSPO2 in porcine GCs. The hypomethylation of −758/−749 and −563/−553 regions in RSPO2 promoter facilitated the occupancy of transcription factor E2F1 and promoted the transcriptional activity of RSPO2. Moreover, RSPO2 promoted the proliferation of GCs with increasing the expression level of PCNA, CDK1, and CCND1 and promoted the E2 secretion of GCs with increasing the expression level of CYP19A1 and HSD17B1 and inhibited the apoptosis of GCs with decreasing the expression level of Caspase3, cleaved Caspase3, cleaved Caspase8, cleaved Caspase9, cleaved PARP, and BAX. In addition, RSPO2 knockdown promoted the apoptosis of GCs, blocked the development of follicles, and delayed the onset of puberty with decreasing the expression level of Wnt signaling pathway-related genes (LGR4 and CTNNB1) in vivo. Taken together, the hypomethylation of −758/−749 and −563/−553 regions in RSPO2 promoter facilitated the occupancy of E2F1 and enhanced the transcription of RSPO2, which further promoted the proliferation and E2 secretion of GCs, inhibited the apoptosis of GCs, and ultimately ameliorated the development of follicles through Wnt signaling pathway. This study will provide useful information for further exploration on DNA-methylation-mediated RSPO2 pathway during follicular development.

PS02.176: LINE-1 METHYLATION LEVEL AND LOCAL IMMUNE RESPONSE IN ESOPHAGEAL CANCER

2018 ◽  
Vol 31 (Supplement_1) ◽  
pp. 172-172
Author(s):  
Yoshifumi Baba ◽  
Taisuke Yagi ◽  
Yuki Kiyozumi ◽  
Yukiharu Hiyoshi ◽  
Masaaki Iwatsuki ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Immune Response ◽  
Esophageal Cancer ◽  
Methylation Level ◽  
Cpg Island ◽  
Surrogate Marker ◽  
Esophageal Tumor ◽  
Local Immune Response ◽  
Dna Hypomethylation ◽  
Response Status

Abstract Background In cancer cells, DNA methylation may be altered in two principle ways; global DNA hypomethylation and site-specific CpG island promoter hypermethylation. Since Long interspersed element-1 (LINE-1 or L1; a repetitive DNA retrotransposon) constitutes a substantial portion (approximately 17%) of the human genome, the extent of LINE-1 methylation is regarded as a surrogate marker of global DNA methylation. In previous studies, we demonstrated that LINE-1 hypomethylation was strongly associated with a poor prognosis in esophageal cancer, supporting its potential role as a prognostic marker (Ann Surg 2012). We also found that LINE-1-hypomethylated tumors showed highly frequent genomic gains at various loci containing candidate oncogenes such as CDK6 (Clin Cancer Res 2014). Given that immunotherapy, as represented by PD-1/PD-L1-targeting antibodies, has increasingly gained attention as a novel treatment strategy for esophageal cancer, better understanding of local immune response status in esophageal cancer is important. The aim of this study is to evaluate the relationship between LINE-1 methylation level and local immune response in esophageal cancer. Methods Using a non-biased database of 305 curatively resected esophageal cancers, we evaluated PD-L1 expression and TIL status (CD8 expression) by immunohistochemical analysis (Ann Surg 2017). Results TIL positivity was significantly correlated with longer overall survival (log-rank P < 0.0001). TIL-negative cases demonstrated significantly lower LINE-1 methylation level compared with TIL-positive cases (P = 0.012). This finding certainly supports that LINE-1 methylation level may influence the local immune response status. Conclusion PD-L1 expression was not related with LINE-1 methylation level. Further investigations in this field would provide deeper insights into esophageal tumor immunology and assist the development of new therapeutic strategies against esophageal cancer. Disclosure All authors have declared no conflicts of interest.

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