Author Manuscript Published OnlineFirst on June 17, 2019; DOI: 10.1158/0008-5472.CAN-18-3663 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
1 The Open Chromatin Landscape of Non-small Cell Lung
2 Carcinoma
3 Zhoufeng Wang1†, Kailing Tu2†, Lin Xia2†, Kai Luo2†, Wenxin Luo1†, Jie Tang2, Keying Lu2,
4 Xinlei Hu2, Yijing He2, Wenliang Qiao3, Yongzhao Zhou1, Jun Zhang2, Feng Cao2, Shuiping
5 Dai1, Panwen Tian1, Ye Wang1, Lunxu Liu4, Guowei Che4, Qinghua Zhou3, Dan Xie2 * and
6 Weimin Li1 *
7
8 1. Department of Respiratory and Critical Care Medicine, State Key Laboratory of Biotherapy,
9 West China Hospital, Sichuan University, Chengdu, Sichuan, China
10 2. National Frontier Center of Disease Molecular Network, State Key Laboratory of
11 Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
12 3. Lung Cancer Center, West China Hospital Sichuan University, Chengdu, Sichuan, China
13 4. Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu,
14 Sichuan, China
15 † These authors contributed equally to this work.
16
17 Running title: Open Chromatin Landscape of Non-small Cell Lung Carcinoma
18 * Corresponding Author ：Dan Xie, No. 17, Section 3, Renmin South Road, Chengdu,
19 China, 610041. Phone: 86-028-86118673. E-mail: [email protected]; Weimin Li, No. 37,
20 Guoxue Lane, Wuhou District, Chengdu, China, 610041. Phone: 86-028-81812009. E-mail:
22 23 Conflict of Interest statement: No potential conflicts of interest were disclosed.
24
Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 17, 2019; DOI: 10.1158/0008-5472.CAN-18-3663 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
25 Abstract
26 Non-small cell lung carcinoma (NSCLC) is a major cancer type whose epigenetic alteration
27 remains unclear. We analyzed open chromatin data with matched whole-genome sequencing
28 and RNA-seq data of 50 primary NSCLC cases. We observed high inter-patient heterogeneity of
29 open chromatin profiles and the degree of heterogeneity correlated to several clinical parameters.
30 Lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) exhibited distinct open
31 chromatin patterns. Beyond this, we uncovered that the broadest open chromatin peaks
32 indicated key NSCLC genes and led to less stable expression. Furthermore, we found that the
33 open chromatin peaks were gained or lost together with somatic copy number alterations and
34 affected the expression of important NSCLC genes. In addition, we identified 21 joint-QTLs that
35 correlated to both ATAC-seq peak intensity and gene expression levels. Finally, we identified 87
36 regulatory risk loci associated with lung cancer-related phenotypes by intersecting the QTLs with
37 GWAS significant loci. In summary, this compendium of multi-omics data provides valuable
38 insights and a resource to understand the landscape of open chromatin features and regulatory
39 networks in NSCLC.
40 Statement of Significance
41 This study utilizes state of the art genomic methods to differentiate lung cancer subtypes.
42 43 44
Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 17, 2019; DOI: 10.1158/0008-5472.CAN-18-3663 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
45 Introduction
46 Lung cancer is one of the leading causes of cancer-related death worldwide (1). Non-small
47 cell