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  • Recurrent repeat expansions...
    Erwin, Graham S; Gürsoy, Gamze; Al-Abri, Rashid; Suriyaprakash, Ashwini; Dolzhenko, Egor; Zhu, Kevin; Hoerner, Christian R; White, Shannon M; Ramirez, Lucia; Vadlakonda, Ananya; Vadlakonda, Alekhya; von Kraut, Konor; Park, Julia; Brannon, Charlotte M; Sumano, Daniel A; Kirtikar, Raushun A; Erwin, Alicia A; Metzner, Thomas J; Yuen, Ryan K C; Fan, Alice C; Leppert, John T; Eberle, Michael A; Gerstein, Mark; Snyder, Michael P

    Nature (London), 01/2023, Volume: 613, Issue: 7942
    Journal Article

    Expansion of a single repetitive DNA sequence, termed a tandem repeat (TR), is known to cause more than 50 diseases . However, repeat expansions are often not explored beyond neurological and neurodegenerative disorders. In some cancers, mutations accumulate in short tracts of TRs, a phenomenon termed microsatellite instability; however, larger repeat expansions have not been systematically analysed in cancer . Here we identified TR expansions in 2,622 cancer genomes spanning 29 cancer types. In seven cancer types, we found 160 recurrent repeat expansions (rREs), most of which (155/160) were subtype specific. We found that rREs were non-uniformly distributed in the genome with enrichment near candidate cis-regulatory elements, suggesting a potential role in gene regulation. One rRE, a GAAA-repeat expansion, located near a regulatory element in the first intron of UGT2B7 was detected in 34% of renal cell carcinoma samples and was validated by long-read DNA sequencing. Moreover, in preliminary experiments, treating cells that harbour this rRE with a GAAA-targeting molecule led to a dose-dependent decrease in cell proliferation. Overall, our results suggest that rREs may be an important but unexplored source of genetic variation in human cancer, and we provide a comprehensive catalogue for further study.