Oncogenic structural aberration landscape in gastric cancer genomes
Abstract Structural variants (SVs) are responsible for driver events in gastric cancer (GC); however, their patterns and processes remain poorly understood. Here, we examine 170 GC whole genomes to unravel the oncogenic structural aberration landscape in GC genomes and identify six rearrangement sig...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-06-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-39263-1 |
| _version_ | 1797795599143141376 |
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| author | Mihoko Saito-Adachi Natsuko Hama Yasushi Totoki Hiromi Nakamura Yasuhito Arai Fumie Hosoda Hirofumi Rokutan Shinichi Yachida Mamoru Kato Akihiko Fukagawa Tatsuhiro Shibata |
| author_facet | Mihoko Saito-Adachi Natsuko Hama Yasushi Totoki Hiromi Nakamura Yasuhito Arai Fumie Hosoda Hirofumi Rokutan Shinichi Yachida Mamoru Kato Akihiko Fukagawa Tatsuhiro Shibata |
| author_sort | Mihoko Saito-Adachi |
| collection | DOAJ |
| description | Abstract Structural variants (SVs) are responsible for driver events in gastric cancer (GC); however, their patterns and processes remain poorly understood. Here, we examine 170 GC whole genomes to unravel the oncogenic structural aberration landscape in GC genomes and identify six rearrangement signatures (RSs). Non-random combinations of RSs elucidate distinctive GC subtypes comprising one or a few dominant RS that are associated with specific driver events (BRCA1/2 defects, mismatch repair deficiency, and TP53 mutation) and epidemiological backgrounds. Twenty-seven SV hotspots are identified as GC driver candidates. SV hotspots frequently constitute complexly clustered SVs involved in driver gene amplification, such as ERBB2, CCNE1, and FGFR2. Further deconstruction of the locally clustered SVs uncovers amplicon-generating profiles characterized by super-large SVs and intensive segmental amplifications, contributing to the extensive amplification of GC oncogenes. Comprehensive analyses using adjusted SV allele frequencies indicate the significant involvement of extra-chromosomal DNA in processes linked to specific RSs. |
| first_indexed | 2024-03-13T03:20:23Z |
| format | Article |
| id | doaj.art-a521e2d770ec44e0b630ad375453251d |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-13T03:20:23Z |
| publishDate | 2023-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-a521e2d770ec44e0b630ad375453251d2023-06-25T11:21:22ZengNature PortfolioNature Communications2041-17232023-06-0114111310.1038/s41467-023-39263-1Oncogenic structural aberration landscape in gastric cancer genomesMihoko Saito-Adachi0Natsuko Hama1Yasushi Totoki2Hiromi Nakamura3Yasuhito Arai4Fumie Hosoda5Hirofumi Rokutan6Shinichi Yachida7Mamoru Kato8Akihiko Fukagawa9Tatsuhiro Shibata10Division of Cancer Genomics, National Cancer Center Research InstituteDivision of Cancer Genomics, National Cancer Center Research InstituteDivision of Cancer Genomics, National Cancer Center Research InstituteDivision of Cancer Genomics, National Cancer Center Research InstituteDivision of Cancer Genomics, National Cancer Center Research InstituteDivision of Cancer Genomics, National Cancer Center Research InstituteDivision of Cancer Genomics, National Cancer Center Research InstituteDivision of Cancer Genomics, National Cancer Center Research InstituteDivision of Bioinformatics, National Cancer Center Research InstituteDivision of Cancer Genomics, National Cancer Center Research InstituteDivision of Cancer Genomics, National Cancer Center Research InstituteAbstract Structural variants (SVs) are responsible for driver events in gastric cancer (GC); however, their patterns and processes remain poorly understood. Here, we examine 170 GC whole genomes to unravel the oncogenic structural aberration landscape in GC genomes and identify six rearrangement signatures (RSs). Non-random combinations of RSs elucidate distinctive GC subtypes comprising one or a few dominant RS that are associated with specific driver events (BRCA1/2 defects, mismatch repair deficiency, and TP53 mutation) and epidemiological backgrounds. Twenty-seven SV hotspots are identified as GC driver candidates. SV hotspots frequently constitute complexly clustered SVs involved in driver gene amplification, such as ERBB2, CCNE1, and FGFR2. Further deconstruction of the locally clustered SVs uncovers amplicon-generating profiles characterized by super-large SVs and intensive segmental amplifications, contributing to the extensive amplification of GC oncogenes. Comprehensive analyses using adjusted SV allele frequencies indicate the significant involvement of extra-chromosomal DNA in processes linked to specific RSs.https://doi.org/10.1038/s41467-023-39263-1 |
| spellingShingle | Mihoko Saito-Adachi Natsuko Hama Yasushi Totoki Hiromi Nakamura Yasuhito Arai Fumie Hosoda Hirofumi Rokutan Shinichi Yachida Mamoru Kato Akihiko Fukagawa Tatsuhiro Shibata Oncogenic structural aberration landscape in gastric cancer genomes Nature Communications |
| title | Oncogenic structural aberration landscape in gastric cancer genomes |
| title_full | Oncogenic structural aberration landscape in gastric cancer genomes |
| title_fullStr | Oncogenic structural aberration landscape in gastric cancer genomes |
| title_full_unstemmed | Oncogenic structural aberration landscape in gastric cancer genomes |
| title_short | Oncogenic structural aberration landscape in gastric cancer genomes |
| title_sort | oncogenic structural aberration landscape in gastric cancer genomes |
| url | https://doi.org/10.1038/s41467-023-39263-1 |
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