PO.MCB08.02 · 分子与细胞生物学

TCGA全基因组序列中的泛癌种LINE-1逆转座图景

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 Authors & Affiliations

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

中文摘要

LINE-1（L1）元件的过表达被公认为许多癌症的一个标志，然而其活性和体细胞LINE-1逆转座（soL1R）的数量在不同肿瘤类型间差异显著。尽管转座元件在某些癌症（如食管癌和结直肠癌）中普遍存在，但其在癌症发生中的生物学意义仍未得到充分认识。为阐明L1活性对致癌过程的贡献，我们分析了来自癌症基因组图谱（TCGA）超过8,000对肿瘤-正常配对的全基因组测序（WGS）数据。我们总共识别出超过132,000个soL1R事件，其分布在不同癌症类型间差异极大。最高的soL1R负荷见于食管癌（ESCA，每例134.2个事件）、膀胱癌（BLCA，74.0）、头颈部鳞状细胞癌（HNSC，56.3）、肺鳞状细胞癌（LUSC，53.3）、结肠腺癌（COAD，29.7）和直肠腺癌（READ，16.8）。转导的数量与每个队列中的总体soL1R负荷密切相关。通过转导计数推断的胚系LINE-1源元件活性识别出22q12.1-2为最活跃的位点，其次为Xp22.2-2、5q14.3-2和14q23.1。利用L1转导事件，我们进一步发现了12个此前未报道的胚系LINE-1源位点。功能分析表明，soL1R事件通过直接破坏抑癌基因以及由逆转座介导的复杂基因组重排两种方式促进致癌过程。总之，这项人群规模的WGS分析勾勒了体细胞LINE-1逆转座的泛癌种图景，揭示了新型胚系源元件，并强调了soL1R活性在癌症基因组进化中的多方面作用。

查看英文原文 English 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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