한빛사 논문
Jae Won Yun1,2,3, Lixing Yang4,5, Hye-Young Park6, Chang-Woo Lee6, Hongui Cha1,2, Hyun-Tae Shin1,2, Ka-Won Noh7, Yoon-La Choi7,8, Woong-Yang Park1,2* and Peter J. Park4*
1 Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul, South Korea.
2 Samsung Genome Institute, Samsung Medical Center, Seoul, South Korea.
3 Veterans Medical Research Institute, Veterans Health Service Medical Center, Seoul, South Korea.
4 Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
5 Ben May Department for Cancer Research and Department of Human Genetics, The University of Chicago, Chicago, IL, USA.
6 Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi, South Korea.
7 Laboratory of Cancer Genomics and Molecular Pathology, Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, South Korea.
8 Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University College of Medicine, Seoul, South Korea.
*Corresponding author
Abstract
Background
Gene fusions have been studied extensively, as frequent drivers of tumorigenesis as well as potential therapeutic targets. In many well-known cases, breakpoints occur at two intragenic positions, leading to in-frame gene-gene fusions that generate chimeric mRNAs. However, fusions often occur with intergenic breakpoints, and the role of such fusions has not been carefully examined.
Results
We analyze whole-genome sequencing data from 268 patients to catalog gene-intergenic and intergenic-intergenic fusions and characterize their impact. First, we discover that, in contrast to the common assumption, chimeric oncogenic transcripts—such as those involving ETV4, ERG, RSPO3, and PIK3CA—can be generated by gene-intergenic fusions through splicing of the intervening region. Second, we find that over-expression of an upstream or downstream gene by a fusion-mediated repositioning of a regulatory sequence is much more common than previously suspected, with enhancers sometimes located megabases away. We detect a number of recurrent fusions, such as those involving ANO3, RGS9, FUT5, CHI3L1, OR1D4, and LIPG in breast; IGF2 in colon; ETV1 in prostate; and IGF2BP3 and SIX2 in thyroid cancers.
Conclusion
Our findings elucidate the potential oncogenic function of intergenic fusions and highlight the wide-ranging consequences of structural rearrangements in cancer genomes.
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