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Cancer Genome Analysis Unearths Potentially Targetable Tandem Repeat Expansions

NEW YORK – A team from Stanford University, Columbia University, the New York Genome Center, and elsewhere has uncovered somatic tandem repeat expansions in tumors from a wide range of cancer types, including a potentially targetable repeat expansion in a subset of kidney cancers.

"Taken together, our results uncover an unexplored genetic alteration in cancer genomes with important mechanistic and therapeutic implications," senior and co-corresponding author Michael Snyder, genetics chair at Stanford University, and his colleagues wrote in Nature on Wednesday, noting that "to our knowledge, this is the first genome-wide survey of repeat expansions beyond a neurological or neurodegenerative disorder."

Using the ExpansionHunter Denovo bioinformatics tool, along with read depth-based filtering and other analyses, the researchers searched for somatic repeat expansions in tumor genomes from more than two dozen cancer types that were not found in matched normal sequences.

With 2,622 tumor whole-genome sequences (WGS) from more than 2,500 patients profiled for the International Cancer Genome Consortium and the Cancer Genome Atlas projects, they unearthed 160 recurrent repeat expansions (rREs) in tumors from seven of the cancer types considered.

All but five of the rREs appeared to be cancer subtype-specific, the team noted, turning up in subtypes of prostate, liver, brain, ovarian, kidney, and lung cancer. Many of the rREs fell in and around gene regulatory sequences, particularly for genes linked to cancer in the Catalogue of Somatic Mutations in Cancer database.

For example, the researchers focused in on a long-read- and PCR-confirmed GAAA-repeat expansion falling near a UGT2B7 gene regulatory element in renal cell carcinomas. In their analyses of that rRE, the investigators found that it turned up in more than one-third of kidney cancers.

Because a targeted molecule dubbed Syn-TEF1 has shown promise for combating the FXN repeat expansions behind a neurological condition called Friedreich's ataxia, the researchers reasoned that a similar strategy may be feasible for the recurrent kidney cancer change.

Indeed, in their subsequent cell line experiments, the investigators found that a GAAA-targeting molecule known as Syn-TEF3 could curb cell proliferation in a dose-dependent manner in kidney cancer cell lines containing the GAAA-repeat expansion.

"The most dramatic result was that you could actually target them and stop cell proliferation," Snyder said in a statement, calling it "pretty unusual" to go "right from discovery to potential therapeutic avenue."

From their findings so far, the study's authors suggested, similar analyses may lead to potentially targetable repeat expansions in other yet-to-be-analyzed cancer types and in non-cancer conditions that have been assessed by genome sequencing.

"Thousands of high-quality whole-genome sequences exist for many diseases, and our data provide evidence that repeat expansions should be explored beyond the classical bounds of neurodegenerative diseases where they have been most investigated," the authors wrote. "Our results provide a framework to analyze WGS datasets from complex diseases such as cancer."