Journal Article

Recurrent repeat expansions in human cancer genomes

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

2023

Overview

Expansion of a single repetitive DNA sequence, termed a tandem repeat (TR), is known to cause more than 50 diseases 1 , 2 . 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 3 – 8 . 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. An atlas explores the landscape of recurrent repeat expansions in human cancer genomes.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 38/39 / 45 / 45/23 / 45/29 / 45/77 / 631/208/457/649 / 631/208/726 / 692/699/67/69 / Base Sequence / Cancer / Carcinoma, Renal Cell - genetics / Carcinoma, Renal Cell - pathology / Cell proliferation / Cell Proliferation - drug effects / Deoxyribonucleic acid / Disease / DNA / DNA Repeat Expansion - genetics / DNA sequencing / Gene Expression Regulation / Gene regulation / Genetic diversity / Genome, Human - genetics / Genomes / Humanities and Social Sciences / Humans / Introns - genetics / Kidney cancer / Mann-Whitney U test / Microsatellite instability / multidisciplinary / Mutation / Neoplasms - classification / Neoplasms - genetics / Neoplasms - pathology / Neurodegenerative diseases / Neurological diseases / Nucleotide sequence / Prostate / Regulatory Elements, Transcriptional - genetics / Regulatory sequences / Renal cell carcinoma / Reproducibility of Results / Science / Science (multidisciplinary) / Sequence Analysis, DNA / Stability analysis