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Identification of FUT7 hypomethylation as the blood biomarker in the prediction of early-stage lung cancer

Journal of Genetics and Genomics 2023年第8期50卷 573-581页

作者： Rong Qiao Feifei Di Jun Wang Yujie Wei Tian Xu Liping Dai Wanjian Gu Baohui Han rongxi yang Department of Pulmonary Medicine Shanghai Chest HospitalShanghai Jiaotong UniversityShanghai 200030China Nanjing TANTICA Biotechnology Co.Ltd NanjingJiangsu 210061China Department of Clinical Laboratory Jiangsu Province Hospital of Chinese MedicineNanjingJiangsu 210029China Henan Institute of Medical and Pharmaceutical Sciences Academy of Medical ScienceZhengzhou UniversityZhengzhouHenan 450001China Department of Epidemiology and Biostatistics School of Public HealthNanjing Medical UniversityNanjingJiangsu 211166China Department of Environmental Genomics Jiangsu Key Laboratory of Cancer BiomarkersPrevention and TreatmentCollaborative Innovation Center for Cancer Personalized MedicineNanjing Medical UniversityNanjingJiangsu 211166China Department of Genetic Toxicology The Key Laboratory of Modern Toxicology of Ministry of EducationCenter for Global HealthSchool of Public HealthNanjing Medical UniversityNanjingJiangsu 211166China

Early detection of lung cancer (LC) is vital for reducing LC-related mortality. However, noninvasive diagnostic tools remain a great challenge. We aim to identify blood-based biomarkers for the early detection of LC. Here, LC-associated hypomethylation in alpha-1,3-fucosyltransferase VII (FUT7) is identified via the Illumina 850K array in a discovery study and validated by mass spectrometry in two independent casecontrol studies with blood samples from 1720 LC patients (86.8% LC at stage I, blood is collected before surgery and treatment) and 3143 healthy controls. Compared to the controls, blood-based FUT7 hypomethylation is identified in LC patients at stage I, and even in LC patients with malignant nodules ≤1 cm and in patients with adenocarcinoma in situ. Gender plays a role in the LC-associated FUT7 hypomethylation in blood, which is more significant in males than in females. We also reveal that FUT7 hypomethylation in LC could be enhanced by the advanced stage of cancer, involvement of lymph nodes, and larger tumor size. Based on a large sample size and semi-quantitative methods, our study reveals a strong association between blood-based FUT7 hypomethylation and LC, suggesting that methylation signatures in blood may be a group of potential biomarkers for detection of early-stage LC.

关键词： Lung cancer Early detection DNA methylation FUT7 Mass spectrometry

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Identification and Validation of HYAL1 DNA Methylation in Differentiating Malignant from Benign Thyroid Nodules

Identification and Validation of HYAL1 DNA Methylation in Di...

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2021年中国肿瘤标志物学术大会暨第十五届肿瘤标志物青年科学家论坛

作者： Mengxia Li Yin Yifei Li Hong yang rongxi 徐州医科大学附属淮安医院淮安市第二人民医院

Background: Thyroid cancer(TC) is the most common endocrine cancer around the world, of which papillary thyroid cancer(PTC) accounts for about 85%. Fine-needle aspiration biopsy(FNAB) is the preferred method for the diagnosis of thyroid nodules in the clinical application. However, about 20-30% of cases are indeterminate nodules according to FNAB, of which approximately 69% are classified as benign by postoperative pathology. Besides, the sensitivities of FNAB are 65-99% across studies. It is thus of great importance to develop novel biomarkers to distinguish the malignant tumors from the benign ones. DNA methylation is commonly dysregulated in a variety of diseases including cancers. Our previous Infinium Methylation EPIC 850 K beadchip assay indicated a differentially methylated CpG site(cg02183083) within hyaluronidase 1(HYAL1) gene. Here, we conducted a validation study to explore the association between HYAL1 and thyroid *** and methods: We measured the HYAL1 methylation level in formalin-fixed paraffin-embedded(FFPE) tissues of 195 early-stage PTC(91.05% PTC at stage Ⅰ) and 195 age-and gender-matched benign tumors collected during 2019-2020. The median(interquartile range, IQR) ages of malignant and benign cases were 51.00(44.00-57.00) and 53.00(46.00-60.25) years old, respectively. Females accounted for 78.95%(150/190) in both PTC and benign cases. Protein expression of HYAL1 was evaluated in another 55 pairs of early-stage PTC(89.09% PTC at stage Ⅰ) and benign tumors collected during 2013-2016, of which 34 pairs of cases were females. The median age was 43.00(31.00-51.00)and 47.00(36.00-52.00) years in PTC and benign *** methylation was quantified by matrixassisted laser desorption ionization time-of-flight mass spectrometry and protein expression was detected by immunohistochemical(IHC) staining. Binary logistic regression and Mann-Whitney U test were used for the data analysis. Two-sided P values < 0.05 were considered as statistically

关键词： Thyroid nodules HYAL1 Identification DNA methylation Protein

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Novel blood-based hypomethylation of DYRK4 is associated with very early stage lung cancer

Novel blood-based hypomethylation of DYRK4 is associated wit...

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2021年中国肿瘤标志物学术大会暨第十五届肿瘤标志物青年科学家论坛

作者： Chunlan Liu Qiang Zhu Qong Qiao Runbo Zhong rongxi yang Nanjing Medical University 上海交通大学附属上海胸科医院

Objective: Early detection is essential to improve the survival of lung cancer. The quantitative measurement of specific DNA methylation changes in the peripheral blood could provide an efficient strategy for the detection of early cancer. We applied a candidate approach and assess the association between blood-based DYRK4 methylation and the risk of lung cancer in a case-control ***: The methylation level of three CpG sites in the promoter of DYRK4 gene was quantitatively determined by mass spectrometry in 845 very early stage lung cancer patients(91.8% lung cancer at stage I) and 1000 healthy controls. The correlations between DNA methylation and the disease status were analyzed by binary logistic regression adjusted for possible co-founding effects of age, gender and different measurement batches. The comparisons between two or multiple groups were analyzed by non-parametric ***: All three investigated CpG sites in DYRK4 gene showed lower methylation levels in lung cancer cases than in control group(Figure 1 A-1 C), and decreased methylation of all these CpG loci showed significant association with lung cancer(odds ratio(ORs) per-10% methylation ranging from 1.17 to1.43, P<0.00017 for all, Figure 1 D). Interquartile analysis showed that compared to the quartile with the highest methylation level(Q4), the three lower quartiles of methylation levels(Q1-Q3) of all three CpG loci were highly associated with an increased risk of lung cancer, and this association was especially pronounced in the lowest quartile(P trend<0.001 for all, Figure 2). Further investigation disclosed that the hypomethylation of DYRK4 was associated with lung cancer with even larger ORs in the male group than that of the female group(OR per-10% methylation from 1.33 to1.66, P<0.000088 for all in males, Figure 3), which is in accordance with the fact the men have higher risk to lung cancer. The relationship between DYRK4 methylation and the clinical characteristics of845 lung

关键词： lung cancer DNA methylation DYRK4 gene early detection peripheral blood

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The association between MGRN1 methylation in peripheral blood and breast cancer in the Chinese population

The association between MGRN1 methylation in peripheral bloo...

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2021年中国肿瘤标志物学术大会暨第十五届肿瘤标志物青年科学家论坛

作者： Shuifang Lei Lixi Li Qiming Yin Yifei Yin Fei Ma rongxi yang Nanjing Medical University 国家癌症中心肿瘤内科徐州医科大学附属淮安医院淮安市第二人民医院甲状腺与乳腺外科

Aims: Mahogunin ring finger 1(MGRN1), an E3 ubiquitin ligase of the Really Interesting New Gene finger family, plays a pivotal role in many biological and cellular mechanisms. The DNA hypomethylation in MGRN1 has been reported to be associated with breast cancer(BC) in the Caucasian ***, the association has not been studied in other population. In this case-control study, we attempted to study the relationship between MGRN1 DNA methylation and BC in the Chinese *** and Methods: 4 MGRN1 CpG sites were quantitatively measured through mass spectrometry in the case-control study with 234 sporadic BC cases and 222 controls. The interquartile analysis was performed by calculating the quartiles from the methylation data from the total participants. The logistic regression adjusted for covariants and non-parametric tests were used to investigate the association between MGRN1 methylation level and the status of ***: We observed four MGRN1 CpG sites(MGRN1pG, MGRN1pG, MGRN1pG,4)were associated with BC. A significant tendency was also found for two MGRN1 CpG sites(P≤ 0.016,Table 1). In addition, we found significant associations between BC and altered MGRN1 methylation at different age groups, mostly in women at postmenopausal(age ≥ 50 years old, odds ratios(ORs)per-10% methylation: 1.58-1.85, P ≤ 0.031 for three of four CpG loci;age < 50 years old, ORs per-10% methylation = 0.77, P=0.033 for one CpG site, Table 2). This age-related MGRN1 methylation was also modified by the status of human epidermal growth factor receptor 2(HER2)(HER2 negative,ORs per-10% methylation: 0.86-1.28, P ≤ 0.045 for all four CpG loci;HER2 positive, ORs per-10%methylation = 0.79, P = 0.022 for one CpG site, Table 2).Conclusion: In the Chinese population, we reported a significant association between BC and the bloodbased MGRN1 methylation modified by age and the status of HER2. Above all, this study provided evidence of potential DNA methylation markers for early

关键词： Chinese population Breast cancer MGRN1 Methylation Blood

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大巴山陆内造山带高压古流体及其运移动力学机制研究

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地学前缘 2017年第2期24卷 123-129页

作者：覃小丽李荣西杨玲董树文何为杨清宇长安大学地球科学与资源学院陕西西安710054 国土资源部岩浆作用成矿与找矿重点实验室陕西西安710054 陕西省地质调查院陕西西安710065 中国地质科学院北京100037 中国石油长庆油田分公司勘探部陕西西安710021

陆内造山带普遍存在的高压流体与金属矿产与油气形成与分布关系十分密切。大巴山陆内造山带发育有大量同构造期方解石脉,碳氧同位素反映其为围岩碳酸盐岩成岩流体产物。通过对方解石脉中盐水包裹体分析测试,应用包裹体p-T-X相图确定的... 详细信息

陆内造山带普遍存在的高压流体与金属矿产与油气形成与分布关系十分密切。大巴山陆内造山带发育有大量同构造期方解石脉,碳氧同位素反映其为围岩碳酸盐岩成岩流体产物。通过对方解石脉中盐水包裹体分析测试,应用包裹体p-T-X相图确定的大巴山构造带同构造期古流体压力自北而南由高变低,即从大巴山逆冲构造带、大巴山前陆构造带到大巴山前陆坳陷古流体压力分别为240~270 MPa、220~240 MPa和170~190 MPa,而恢复的古流体压力梯度分别为2.2 MPa/100m、2.3 MPa/100m和2.0 MPa/100m,明显高于正常静水压力,表明大巴山陆内造山期古流体为典型异常高压流体。综合分析表明,大巴山陆内造山带和四川盆地自古至今普遍存在异常高压流体。结合区域地质研究认为,处于大巴山推覆体前缘、受志留系泥岩滑脱层和逆掩断层控制的高压体系具有压力封存箱特征。大巴山陆内造山带高压流体是在埋藏过程中形成的,其形成深度在2 800m左右,异常高压是大巴山构造带驱动流体迁移的主要动力之一。

关键词：方解石脉流体包裹体压力梯度陆内造山大巴山构造带

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城市规划与产业规划的互动协同

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开放导报 2015年第1期 36-38页

作者：薛富智杨荣喜深圳市城市规划设计研究院广东深圳518028 台州市住房和城乡建设规划局浙江台州318000

城市规划和产业规划的协同是当前"多规统筹"实践中的重要内容,对于已经进入空间紧约束阶段的城市,城市和产业的协同问题变得更加复杂。应从政策机制到工作方法全面创新,以更加协调、有序、精准的空间和产业协同规划,实现二者更紧密的融... 详细信息

城市规划和产业规划的协同是当前"多规统筹"实践中的重要内容,对于已经进入空间紧约束阶段的城市,城市和产业的协同问题变得更加复杂。应从政策机制到工作方法全面创新,以更加协调、有序、精准的空间和产业协同规划,实现二者更紧密的融合,推动城市和经济可持续发展。

关键词：空间紧约束协同规划

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Lung Cancer-associated Blood-based Hypomethylation of HYAL2 in Two Independent Case-control Studies as well as the Two Studies in Combination by Mass Spectrometry

Lung Cancer-associated Blood-based Hypomethylation of HYAL2 ...

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2021年中国肿瘤标志物学术大会暨第十五届肿瘤标志物青年科学家论坛

作者： Liya Zhu Xiajie Zhou rongxi yang Baohui Han Rong Qiao Runbo Zhong Yue Wang Tian Xu Wanjian Gu Liping Dai Department of Epidemiology and Biostatistics School of Public Health Nanjing Medical University Nanjing Medical University Shanghai Chest Hospital Shanghai Jiaotong University Department of Clinical Laboratory Jiangsu Province Hospital of Chinese Medicine Henan Institute of Medical and Pharmaceutical Sciences Academy of Medical Science Zhengzhou University

Background and aim: Lung cancer(LC) is the second commonly diagnosed cancer and the leading cause of cancer-related mortality worldwide, with 2.2 million new cases and 1.8 million deaths in 2020. The median survivals and 5-year survival rates of LC decrease with increasing stage, from 21 months to 12 months and 50-65% to 2-3% at stage I and IV, respectively. Thus, early detection is essential to improve the survival and life quality of LC patients. Changes in DNA methylation in peripheral blood could be associated with malignancy at early stage. Previous works have shown that blood-based hyaluronoglucosaminidase 2 gene(HYAL2) methylation was associated with a variety of cancers, but not with LC. Here, we aim to investigate the association between blood-based methylation of HYAL2 and LC in the Chinese *** and methods: The methylation levels of two HYAL2 CpG sites were quantified via MALDITOF mass spectrometry in two independent case-control studies of the Chinese population with a total of 960 LC cases and 1472 age and gender matched controls. The association between methylation intensities and LC was estimated by interquartile analysis using the logistic regression model adjusted for age, gender, and batch effect in Study Ⅰ, Study Ⅱ as well as combining Study Ⅰ and Ⅱ. The logistic regression analysis was performed to compare the DNA methylation differences between early-stage LC cases(Stage Ⅰ LC cases) and intermediate & advanced LC cases(Stage Ⅱ&Ⅲ LC cases) adjusted for age, gender, and batch ***: In Study Ⅰ, the hypomethylation of HYAL2pG and HYAL2pG(cg27091787) showed a significant association with LC in most of the lower quartiles of methylation levels(Q1-Q3) compared to the quartile with the highest methylation level(Q4) using the logistic regression model adjusted for covariants(Odds ratios(ORs) for Q1 of HYAL2pG = 2.74, P = 6.30 E-05;OR for Q1 of HYAL2pG(cg27091787) = 2.30, P = 0.001). This association was enhanced with lower quart

关键词： Lung cancer early detection DNA methylation HYAL2 peripheral blood

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自适应阵列天线中应用Kalman补偿算法的探讨

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南京航空航天大学学报 1986年第4期 95-103页

作者：高扬华荣喜

为了补偿在自适应阵列天线中应用Kalman算法时,由于模型误差和计算误差所引起的自适应阵列天线性能的损失,本文引入Kalman补偿算法,即自适应Kalman渐消记忆滤波算法及自适应Kalman参量识别滤波算法,获得了有益的结果。最后在上述两种算... 详细信息

为了补偿在自适应阵列天线中应用Kalman算法时,由于模型误差和计算误差所引起的自适应阵列天线性能的损失,本文引入Kalman补偿算法,即自适应Kalman渐消记忆滤波算法及自适应Kalman参量识别滤波算法,获得了有益的结果。最后在上述两种算法的基础上,导出了一种新的算法,该算法具有上述两种算法的优点。

关键词：天线自适应阵滤波理论补偿

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HYAL2基因DNA甲基化水平可用于甲状腺良恶性肿瘤的鉴别诊断

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南方医科大学学报 2022年第1期42卷 123-129页

作者：殷益飞李红杨春生张敏敏黄选东李梦夏杨蓉西张正东徐州医科大学附属淮安医院甲状腺乳腺外科江苏淮安223001 南京医科大学公共卫生学院江苏南京211166

目的通过比较甲状腺良恶性肿瘤组织样本中HYAL2基因CpG位点甲基化水平的差异,评估其作为甲状腺癌鉴别诊断分子标志物的潜在价值。方法采用飞行时间质谱检测190对甲状腺乳头状癌(PTC)病例和年龄、性别配对的甲状腺腺瘤中HYAL2基因启动子... 详细信息

目的通过比较甲状腺良恶性肿瘤组织样本中HYAL2基因CpG位点甲基化水平的差异,评估其作为甲状腺癌鉴别诊断分子标志物的潜在价值。方法采用飞行时间质谱检测190对甲状腺乳头状癌(PTC)病例和年龄、性别配对的甲状腺腺瘤中HYAL2基因启动子区域CpG位点的甲基化水平。采用免疫组化检测另外55对匹配的甲状腺良恶性肿瘤患者的HYAL2蛋白表达水平。Logistic回归分析用于评估甲基化水平每降低10%与早期PTC之间的关联并计算比值比(OR)。受试者工作特征曲线及曲线下面积(AUC)用于评估HYAL2基因特定CpG位点甲基化水平改变作为分子标志物的效能。结果HYAL2_CpG_3位点低甲基化与早期PTC显著相关(OR=1.51,P=0.001),且该关联在Ⅰ期PTC中依旧显著(OR=1.42,P=0.007)。年龄分层分析显示HYAL2_CpG_3甲基化水平降低与早期PTC关联在年龄小于50岁的人群中显著高于高年龄组(OR:1.89 vs 1.37;P<0.05),且低年龄组人群中AUC最高,为0.787。免疫组化结果显示早期PTC中HYAL2蛋白表达水平显著高于甲状腺良性肿瘤。结论HYAL2基因启动子区域甲基化水平改变与早期PTC的关联,并为DNA甲基化改变作为甲状腺良恶性肿瘤鉴别诊断的标志物提供了新思路。

关键词： HYAL2基因 DNA甲基化甲状腺肿瘤鉴别诊断分子标志物

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外周血中KCNMA1基因甲基化水平与肺癌的发生和发展相关

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南方医科大学学报 2023年第3期43卷 349-359页

作者：臧紫珊乔荣朱强周夏婕顾万建韩宝惠杨蓉西南京医科大学公共卫生学院流行病与卫生统计学系江苏南京211166 上海交通大学上海胸科医院肺内科上海200030 江苏省中医院检验科江苏南京210029

目的探究外周血中KCNMA1基因的甲基化水平与肺癌的相关性。方法应用基质辅助激光解吸电离飞行时间质谱(MALDI-TOF-MS)技术对285例肺癌患者、186例年龄、性别匹配的良性肺结节患者和278例匹配的健康对照外周血中KCNMA1基因上4个CpG位点... 详细信息

目的探究外周血中KCNMA1基因的甲基化水平与肺癌的相关性。方法应用基质辅助激光解吸电离飞行时间质谱(MALDI-TOF-MS)技术对285例肺癌患者、186例年龄、性别匹配的良性肺结节患者和278例匹配的健康对照外周血中KCNMA1基因上4个CpG位点甲基化水平进行半定量检测。使用Logistic回归模型校正协变量分析DNA甲基化水平与肺癌的相关性。使用Mann-Whitney U检验分析不同临床特征组别的甲基化水平差异。结果在>55岁和女性人群中,KCNMA1_CpG_5甲基化水平最高四分位Q4 vs最低四分位Q1均与肺癌显著相关(>55岁人群:OR=2.60,95%CI:1.25~5.41,P=0.011;女性人群:OR=2.09,95%CI:1.03~4.26,P=0.042),且KCNMA1_CpG_5甲基化的相关性从Q2到Q4逐渐增强(P=0.003,0.038)。与良性患者相比,KCNMA1_CpG_5最高四分位Q4在男性肺癌患者中的OR值为0.35(95%CI:0.16~0.79,P=0.012)。浸润性腺癌中KCNMA1_CpG_3甲基化水平显著低于非浸润性腺癌(P=0.028),较大肿瘤(T2-4)中KCNMA1_CpG_1甲基化水平显著高于较小肿瘤(T1)(P=0.021)。结论外周血中KCNMA1甲基化水平的改变可能与肺癌发生和发展相关。

关键词：肺癌 KCNMA1 DNA甲基化外周血病例对照研究

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