Abstract
Recurrent repeat expansions were identified near known regulatory elements across seven cancer types.
Major Finding: Recurrent repeat expansions were identified near known regulatory elements across seven cancer types.
Concept: A GAAA-repeat expansion was found in 34% of renal cell carcinomas, and its targeting reduced cell proliferation.
Impact: This study revealed a new class of recurrent genomic changes that could be therapeutically vulnerable.
Expansion of tandem repeat (TR) DNA sequences can cause disease, but their identification using short-read DNA sequencing is difficult, leading to many large TRs going undetected. To determine the frequency and function of these recurrent repeat expansions (rRE) in cancer, Erwin, Gürsoy, and colleagues analyzed 2,622 human cancer genomes with matched normal samples from the International Cancer Genome Consortium and The Cancer Genome Atlas to identify somatic repeat expansions and found 160 rREs in seven cancer types. Most of these rREs were cancer subtype specific with a known pathogenic motif being observed in six rREs, all of which were GAA. Evaluation of rRE distribution revealed that many were located in or near known regulatory elements, suggesting that rREs may play a functional role in regulating gene expression. Further investigation into a specific rRE showed that, in 34% of renal cell carcinoma (RCC) samples, a GAAA expansion was noted in the intron of UGT2B7, which encodes for a small molecule–clearing glucuronidase. Most of these expansions were heterozygous in nature, with results also indicating that this rRE possibly alters UGT2B7 expression. Additionally, Syn-TEF3, which contains a GAAA-targeting polyamide linked to the bromodomain ligand JQ1, was used to determine the effects of this GAAA-repeat expansion on cell proliferation. Treatment of cells with Syn-TEF3 led to a dose-dependent reduction in cell proliferation in cell lines with the largest GAAA repeats, while having little effect on a cell line with the smallest repeats, supporting the potential therapeutic vulnerability of these GAAA-repeat expansions in RCC. In summary, this study identified 160 rREs that are enriched near gene regulatory elements and demonstrated that, in RCC, GAAA-repeat expansions can be targeted with small molecules. Together, these results suggest that these genetic alterations could have both mechanistic and therapeutic implications in cancer.
Note:Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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