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An Integrated Approach For Uncovering Novel DNA Methylation Biomarkers For Non-small Cell Lung Carcinoma

為了解決rd-200hh的問題，作者VAIBHAV KUMAR SUNKARIA 這樣論述：

Introduction - Lung cancer is one of primal and ubiquitous cause of cancer related fatalities in the world. Leading cause of these fatalities is non-small cell lung cancer (NSCLC) with a proportion of 85%. The major subtypes of NSCLC are Lung Adenocarcinoma (LUAD) and Lung Small Cell Carcinoma (LUS

C). Early-stage surgical detection and removal of tumor offers a favorable prognosis and better survival rates. However, a major portion of 75% subjects have stage III/IV at the time of diagnosis and despite advanced major developments in oncology survival rates remain poor. Carcinogens produce wide

spread DNA methylation changes within cells. These changes are characterized by globally hyper or hypo methylated regions around CpG islands, many of these changes occur early in tumorigenesis and are highly prevalent across a tumor type.Structure - This research work took advantage of publicly avai

lable methylation profiling resources and relevant comorbidities for lung cancer patients extracted from meta-analysis of scientific review and journal available at PubMed and CNKI search which were combined systematically to explore effective DNA methylation markers for NSCLC. We also tried to iden

tify common CpG loci between Caucasian, Black and Asian racial groups for identifying ubiquitous candidate genes thoroughly. Statistical analysis and GO ontology were also conducted to explore associated novel biomarkers. These novel findings could facilitate design of accurate diagnostic panel for

practical clinical relevance.Methodology - DNA methylation profiles were extracted from TCGA for 418 LUAD and 370 LUSC tissue samples from patients compared with 32 and 42 non-malignant ones respectively. Standard pipeline was conducted to discover significant differentially methylated sites as prim

ary biomarkers. Secondary biomarkers were extracted by incorporating genes associated with comorbidities from meta-analysis of research articles. Concordant candidates were utilized for NSCLC relevant biomarker candidates. Gene ontology annotations were used to calculate gene-pair distance matrix fo

r all candidate biomarkers. Clustering algorithms were utilized to categorize candidate genes into different functional groups using the gene distance matrix. There were 35 CpG loci identified by comparing TCGA training cohort with GEO testing cohort from these functional groups, and 4 gene-based pa

nel was devised after finding highly discriminatory diagnostic panel through combinatorial validation of each functional cluster.Results – To evaluate the gene panel for NSCLC, the methylation levels of SCT(Secritin), FOXD3(Forkhead Box D3), TRIM58(Tripartite Motif Containing 58) and TAC1(Tachikinin

1) were tested. Individually each gene showed significant methylation difference between LUAD and LUSC training cohort. Combined 4-gene panel AUC, sensitivity/specificity were evaluated with 0.9596, 90.43%/100% in LUAD; 0.949, 86.95%/98.21% in LUSC TCGA training cohort; 0.94, 85.92%/97.37 in GEO 66

836; 0.91,89.17%/100% in GEO 83842 smokers; 0.948, 91.67%/100% in GEO83842 non-smokers independent testing cohort. Our study validates SCT, FOXD3, TRIM58 and TAC1 based gene panel has great potential in early recognition of NSCLC undetermined lung nodules. The findings can yield universally accurate

and robust markers facilitating early diagnosis and rapid severity examination.

探討 Selective serotonin reuptake inhibitors對慢性阻塞性肺病患者罹患肺癌風險性的影響

為了解決rd-200hh的問題，作者林志翰 這樣論述：

慢性阻塞性肺病患者因疾病特性關係多是抽菸者，相較於非患者罹患肺癌的機率更高。而慢性阻塞性肺病患者也有較高比例會產生憂鬱相關疾病，依現行的治療指引中常會使用選擇性血清素回收抑制劑(Selective serotonin reuptake inhibitors, SSRIs)來治療。早期的研究中顯示SSRIs可能具有促進細胞凋亡的作用，進而降低癌症發生風險，然而這些結果多數來自於細胞、動物實驗或流行病學研究，且綜合各項研究結果，SSRIs對於癌症之作用仍未完全被掌握並依舊存在矛盾。因此，SSRIs對於人體產生肺癌之影響，是否為保護或是有害仍未有定論。本研究旨在藉由台灣全國性資料庫，探討初次診斷慢

性阻塞性肺病之患者使用SSRIs，其後續發生肺癌之風險影響。本研究為一回溯性世代研究，所使用之資料來源為衛生福利部資料科學中心所提供之2000年200萬人抽樣檔，篩選出於2001年至2013年間初次診斷為慢性阻塞性肺病之患者，並串聯到其2000年至2018年間的醫療紀錄。定義初次診斷慢性阻塞性肺病者並有使用SSRIs者為實驗組；對照組則為初次診斷慢性阻塞性肺病者但未使用SSRIs之患者。兩組再依年齡、性別、共病症、使用藥物，以1：1之比例進行配對。兩組研究對象皆追蹤五年。兩組間發生癌症之風險及相關之干擾因子，以Cox比例風險回歸模型(Cox proportional hazards regre

ssion model)進行分析，並利用Kaplan-Meier法檢測實驗組和對照組之間五年肺癌發生率的差異。由於追蹤時間可能影響結果，於敏感性分析中將追蹤時間延長為十年。為了進一步分析劑量依存性 (Dose-dependent relationship)，使用條件式邏輯斯回歸模型估計勝算比以表示SSRIs類藥物累積暴露劑量與肺癌之關聯性。本研究使用雙尾檢定，將p值小於0.05定為具有統計學上之顯著差異。在1：1傾向分數配對後，本研究共收錄4,088位SSRIs使用者及4,088位非SSRIs使用者，經校正所有共變項及干擾因子後觀察到使用SSRIs者後續罹患肺癌的風險與非SSRIs使用者並無顯

著差異(aHR, 0.98; 95% CI, 0.62-1.57)。在敏感性分析中，將兩組追蹤時間皆延長為十年，結果也與主要研究類似(aHR, 0.95; 95% CI, 0.57-1.56)。而針對累積暴露劑量進行分析，依照SSRIs使用量多寡其風險比分別為，28-83個DDD (aHR, 1.21; 95% CI, 0.64-2.29)、84-167個DDD (aHR, 1.12; 95% CI, 0.50-2.52)、168-335個DDD (aHR, 0.85; 95% CI, 0.33-2.17)、336個DDD以上 (aHR, 0.79; 95% CI, 0.39-1.59)。SS

RIs之累積暴露劑量多寡與肺癌的風險之間並無存在顯著的劑量依存性。在本研究中，台灣慢性阻塞性肺病患者族群使用SSRIs類藥物並不會增加後續罹患肺癌的風險，但亦無觀察到保護效果。在累積暴露劑量的分析上，兩者之間無存在顯著劑量依存性，但隨著累積暴露劑量增加，約略呈現肺癌風險下降之趨勢。而SSRIs類藥物與肺癌確切的相關性，仍待未來進一步的研究證實。