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Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition.

Bernardo Rodriguez-MartinEva G AlvarezAdrian Baez-OrtegaJorge ZamoraFran SupekJonas DemeulemeesterMartin SantamarinaYoung Seok JuJavier TemesDaniel Garcia SoutoHarald DeteringYilong LiJorge Rodriguez-CastroAna Dueso-BarrosoAlicia L BruzosStefan C DentroMiguel G BlancoGianmarco ContinoDaniel ArdeljanMarta TojoNicola D RobertsSonia ZumalavePaul A W EdwardsJoachim WeischenfeldtMontserrat PuiggròsZechen ChongKen ChenEunjung Alice LeeJeremiah A WalaKeiran M RaineAdam ButlerSebastian M WaszakFábio C P NavarroSteven E SchumacherJean MonlongFrancesco MauraNiccolo BolliGuillaume BourqueMark GersteinPeter J ParkDavid C WedgeRameen BeroukhimDavid TorrentsJan O KorbelInigo MartincorenaRebecca C FitzgeraldPeter Van LooHaig H KazazianKathleen H Burnsnull nullPeter J CampbellJose M C Tubionull null
Published in: Nature genetics (2020)
About half of all cancers have somatic integrations of retrotransposons. Here, to characterize their role in oncogenesis, we analyzed the patterns and mechanisms of somatic retrotransposition in 2,954 cancer genomes from 38 histological cancer subtypes within the framework of the Pan-Cancer Analysis of Whole Genomes (PCAWG) project. We identified 19,166 somatically acquired retrotransposition events, which affected 35% of samples and spanned a range of event types. Long interspersed nuclear element (LINE-1; L1 hereafter) insertions emerged as the first most frequent type of somatic structural variation in esophageal adenocarcinoma, and the second most frequent in head-and-neck and colorectal cancers. Aberrant L1 integrations can delete megabase-scale regions of a chromosome, which sometimes leads to the removal of tumor-suppressor genes, and can induce complex translocations and large-scale duplications. Somatic retrotranspositions can also initiate breakage-fusion-bridge cycles, leading to high-level amplification of oncogenes. These observations illuminate a relevant role of L1 retrotransposition in remodeling the cancer genome, with potential implications for the development of human tumors.
Keyphrases
  • papillary thyroid
  • squamous cell
  • squamous cell carcinoma
  • genome wide
  • endothelial cells
  • childhood cancer
  • gene expression
  • radiation therapy
  • rectal cancer
  • locally advanced
  • nucleic acid