PO.MCB08.02 · 分子与细胞生物学

Pan-cancer LINE-1 retrotransposition landscapes in TCGA whole-genome sequences

编号 1980 展板 6 时间 4/20 09:00–12:00 区域 Section 23 主讲 Beomki Lee, MD

分会场 Genomic Drivers of Cancer Pathogenesis

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作者与单位

Beomki Lee¹, Ryul Kim², Chunyang Bao², Hansol Park², Gang-Hee Lee², Jonghoon Lee², Yoonsuh Lee², Won-Chul Lee², David Lehotzky³, Ron Solan³, Antonia Kowalewski³, Xavi Loinaz³, Vasuki Narasimha Swamy³, David I. Heiman³, Samantha Van Seters³, Saveliy Belkin³, Sam Wiseman³, Andrew D. Cherniack³, Luis Antonio Corchete Sanchez³, Brian P. Danysh³, Zachary Everton³, Chip Stewart³, Haruna Tomono³, Gengchao Wang³, Esther Rheinbay³, Gad Getz³, Cheng-Zhong Zhang³, Young Seok Ju²

¹Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea, Republic of,²Inocras Inc., San Diego, CA,³Broad Institute, Cambridge, MA

摘要 Abstract

Overexpression of LINE-1 (L1) elements is recognized as a hallmark of many cancers, yet their activity and the number of somatic LINE-1 retrotranspositions (soL1Rs) vary markedly across tumor types. Despite their ubiquity in certain cancers, such as esophageal and colorectal carcinomas, the biological significance of transposable elements in cancer development remains underappreciated. To elucidate the contribution of L1 activity to oncogenesis, we analyzed whole-genome sequencing (WGS) data from >8,000 tumor-normal pairs in The Cancer Genome Atlas (TCGA). In total, we identified over 132,000 soL1R events, with their distribution differing widely across cancer types. The highest soL1R burdens were observed in esophageal carcinoma (ESCA, 134.2 events per case), bladder carcinoma (BLCA, 74.0), head and neck squamous cell carcinoma (HNSC, 56.3), lung squamous cell carcinoma (LUSC, 53.3), colon adenocarcinoma (COAD, 29.7), and rectal adenocarcinoma (READ, 16.8). The number of transductions correlated strongly with the overall soL1R burden in each cohort. Activity of germline LINE-1 source elements, inferred from transduction counts, identified 22q12.1-2 as the most active locus, followed by Xp22.2-2, 5q14.3-2, and 14q23.1. Using L1 transduction events, we further discovered 12 previously unreported germline LINE-1 source loci. Functional analysis revealed that soL1R events contribute to oncogenesis through both direct disruption of tumor suppressor genes and complex genomic rearrangements mediated by retrotransposition. In summary, this population-scale WGS analysis delineates the pan-cancer landscape of somatic LINE-1 retrotranspositions, uncovers novel germline source elements, and highlights the multifaceted role of soL1R activity in cancer genome evolution.

利益披露 Disclosure

B. Lee, None.. R. Kim, None.. C. Bao, None.. H. Park, None.. G. Lee, None.. J. Lee, None.. Y. Lee, None.. W. Lee, None.. D. Lehotzky, None.. R. Solan, None.. A. Kowalewski, None.. X. Loinaz, None.. V. Narasimha Swamy, None.. D. I. Heiman, None.. S. Van Seters, None.. S. Belkin, None.. S. Wiseman, None. A. D. Cherniack, Bayer ). L. Corchete Sanchez, None.. B. P. Danysh, None.. Z. Everton, None.. C. Stewart, None.. H. Tomono, None.. G. Wang, None. E. Rheinbay, Inocras Inc. ). G. Getz, IBM ). Pharmacyclics/Abbvie ). Bayer ). Genentech ). Calico ). Ultima Genomics ). Inocras Inc. ). Google ). Kite ). Novartis ). Scorpion Therapeutics g., Board of Directors, non-salaried role), Stock Option. Predicta Biosciences g., Board of Directors, non-salaried role), Stock Option. Antares Therapeutics Stock Option. C. Zhang, None. Y. Ju, Inocras Inc. Employment, g., Board of Directors, non-salaried role), Stock Option.

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