Oncogenic structural aberration landscape in gastric cancer genomes

Mihoko Saito-Adachi, Natsuko Hama, Yasushi Totoki, Hiromi Nakamura, Yasuhito Arai, Fumie Hosoda, Hirofumi Rokutan, Shinichi Yachida, Mamoru Kato, Akihiko Fukagawa and Tatsuhiro Shibata ()
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Mihoko Saito-Adachi: Division of Cancer Genomics, National Cancer Center Research Institute
Natsuko Hama: Division of Cancer Genomics, National Cancer Center Research Institute
Yasushi Totoki: Division of Cancer Genomics, National Cancer Center Research Institute
Hiromi Nakamura: Division of Cancer Genomics, National Cancer Center Research Institute
Yasuhito Arai: Division of Cancer Genomics, National Cancer Center Research Institute
Fumie Hosoda: Division of Cancer Genomics, National Cancer Center Research Institute
Hirofumi Rokutan: Division of Cancer Genomics, National Cancer Center Research Institute
Shinichi Yachida: Division of Cancer Genomics, National Cancer Center Research Institute
Mamoru Kato: Division of Bioinformatics, National Cancer Center Research Institute
Akihiko Fukagawa: Division of Cancer Genomics, National Cancer Center Research Institute
Tatsuhiro Shibata: Division of Cancer Genomics, National Cancer Center Research Institute

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-39263-1

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