Recurrent repeat expansions in human cancer genomes

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.

Automated summary

In this study, repeat DNA sequence expansions were identified in 2,622 cancer genomes across 29 cancer types. Most of these expansions were specific to certain subtypes of cancer and were found to be distributed non-uniformly in the genome, showing enrichment near potential cis-regulatory elements. One specific expansion, a GAAA-repeat expansion, was detected in 34% of renal cell carcinoma samples and was shown to decrease cell proliferation in a dose-dependent manner when targeted with a GAAA-targeting molecule in preliminary experiments. Overall, this research suggests that repeat DNA sequence expansions may be an important and unexplored source of genetic variation in human cancer, providing a comprehensive catalogue for further study.