PO.MCB08.02 · 分子与细胞生物学

对调控区域的拷贝数分析揭示超过8,000例TCGA样本中反复出现的启动子/增强子体细胞拷贝数改变

Copy number analysis of regulatory regions reveal recurrent promoter/enhancer somatic copy number alterations across >8,000 TCGA samples

编号 1978 展板 4 时间 4/20 09:00–12:00 区域 Section 23 主讲 Haruna Tomono, BS

分会场 Genomic Drivers of Cancer Pathogenesis

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作者与单位 Authors & Affiliations

Haruna Tomono¹, Chunyang Bao², Antonia Kowalewski¹, David Lehotzky¹, Ron Solan¹, Matthew Leventhal¹, Luis Antonio Corchete Sanchez¹, David I. Heiman¹, Samantha Van Seters¹, Saveliy Belkin¹, Sam Wiseman¹, Brian P. Danysh¹, Chip Stewart¹, Vasuki Narasimha Swamy¹, Gengchao Wang¹, Xavi Loinaz¹, Zachary Everton¹, Gang-Hee Lee², Won-Chul Lee², Hansol Park², Ryul Kim², Young Seok Ju², Esther Rheinbay¹, Gad Getz¹, Andrew D. Cherniack¹, Matthew L. Meyerson³, Rameen Beroukhim³

¹Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA,²Inocras Inc., San Diego, CA,³Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA

摘要 Abstract

中文摘要

体细胞拷贝数改变（SCNA）是常见的致癌事件。以往的研究利用DNA微阵列和全外显子组测序数据识别了反复出现的基因水平SCNA。这些研究还识别出调控区域的局灶性扩增。高通量全基因组测序能够对非编码区域的这些局灶性SCNA进行更深入、更全面的分析，有可能揭示致癌过程的新型驱动因素。为此，我们利用GISTIC2.0系统地分析了来自癌症基因组图谱（TCGA）31种癌症类型、超过8,000对肿瘤-正常配对的WGS数据中的SCNA和结构变异，以识别已知癌基因和抑癌基因附近局灶性、反复出现的启动子和增强子SCNA。我们利用结构变异检出结果对主要的局灶性SCNA发现进行正交验证。我们识别出一个在一部分IDH野生型胶质母细胞瘤样本中特异性发生的、位于EGFR启动子/增强子区域的反复扩增事件。这提示在一部分此类侵袭性肿瘤中，存在一种由SCNA驱动的EGFR上调机制，不同于经典的基因体扩增或点突变。我们正在进行的工作旨在拓宽各类癌症中调控性SCNA的图景，并验证其转录影响，以提供新的生物学见解和候选治疗靶点。

查看英文原文 English abstract

Somatic copy number alterations (SCNAs) are frequent oncogenic events. Previous studies have identified recurrent gene-level SCNAs using DNA microarray and whole exome sequencing data. These studies have also identified focal amplifications of regulatory regions. High-throughput whole genome sequencing enables deeper, comprehensive analysis of these focal SCNAs in non-coding regions, potentially revealing novel drivers of oncogenesis. To this end, we systematically analyzed SCNAs and structural variants in WGS data from >8,000 tumor-normal pairs across 31 cancer types from The Cancer Genome Atlas (TCGA) using GISTIC2.0 to identify focal, recurrent promoter and enhancer SCNAs near known oncogenes and tumor suppressor genes. We leveraged structural variant calls to orthogonally validate our primary focal SCNA findings. We identified a recurrent amplification event specific to the EGFR promoter/enhancer region in a subset of IDH-wildtype glioblastoma samples. This suggests an additional SCNA-driven mechanism for EGFR upregulation, distinct from canonical gene body amplification or point mutations, in a fraction of these aggressive tumors. Our ongoing work aims to broaden the landscape of regulatory SCNAs across cancers and validate their transcriptional impact to provide new biological insights and candidate therapeutic targets.

利益披露 Disclosure

H. Tomono, None. C. Bao, Inocras Employment. A. Kowalewski, None.. D. Lehotzky, None.. R. Solan, None.. M. Leventhal, None.. L. Corchete Sanchez, None.. D. I. Heiman, None.. S. Van Seters, None.. S. Belkin, None.. S. Wiseman, None.. B. P. Danysh, None.. C. Stewart, None.. V. Narasimha Swamy, None.. G. Wang, None.. X. Loinaz, None.. Z. Everton, None. G. Lee, Inocras Employment. W. Lee, Inocras Employment. H. Park, Inocras Employment. R. Kim, Inocras Employment. Y. Ju, Inocras Employment. E. Rheinbay, Inocras ). G. Getz, IBM ). Pharmacyclics/Abbvie ). Bayer ). Genentech ). Calico ). Ultima Genomics ). Inocras ). Google ). Kite ). Novartis ). Scorpion Therapeutics Other Securities, Other, Founder, Consultant. Predicta Biosciences Other Securities, Other, Founder. Antares Therapeutics Other Securities. A. D. Cherniack, Bayer ). M. L. Meyerson, Bayer ), Patent, Other. Janssen ). Delve Bio Other. Isabl Other. Karyoverse Other. R. Beroukhim, KaryoVerse Therapeutics Stock. LOH Therapeutics Stock.

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