The first large-scale analysis of repeat amplification in the cancer genome is expected to reveal therapeutic targets

Researchers from Stanford University, Columbia University, the New York Genome Center and other institutions have recently identified somatic tandem repeat expansion of somatic cells in a variety of cancer types
.
Among them, repeated amplification in a kidney cancer is expected to be a therapeutic target
.
The results were published Dec.
14 in the journal Nature
.

Professor Michael Snyder, chair of the Department of Genetics at Stanford University School of Medicine, is one
of the corresponding authors of the paper.
He and colleagues wrote in the paper: "Our findings reveal a genetic alteration in the cancer genome that has little exploration and has important research and therapeutic implications
.
"To our knowledge, this is the first genome-wide investigation
of repeat amplification other than neurological disorders.
" ”

The researchers performed genomic analysis on 2,622 tumor samples from more than 2,500 patients from the International Cancer Genome Alliance and the Cancer Genome Atlas Project, covering 29 cancer types
.
Using the ExpansionHunter Denovo bioinformatics tool and reading depth-based filtering and other analysis, they found 160 recurring repeat amplification (rREs)
in 7 cancer types.

The researchers noted that all but five of the rREs appeared to be specific to cancer subtypes, appearing in
different subtypes of prostate, liver, brain, ovarian, kidney, and lung cancers.
Many replicate amplifications are located in or around gene regulatory sequences, particularly genes
in the Cancer Somatic Mutation Catalog Database (COSMIC).

For example, they focused specifically on GAAA repeat amplification in the regulatory element of the UGT2B7 gene in renal cell carcinoma, which has been validated by long-read sequencing and PCR
.
After their analysis, they found that more than one-third of kidney cancer patients had this recurring repeat amplification
.

Given that Friedreich's ataxia, a neurological disorder, is associated with GAA trinucleotide duplications within the FXN gene, and that a small molecule called Syn-TEF1 is able to transcribe across GAA repeats, the researchers speculate that a similar strategy may be feasible
in the treatment of kidney cancer.

In subsequent cell line experiments, the researchers found that in renal cell carcinoma containing GAAA repeat expansion, Syn-TEF3, targeting the GAAA molecule, was able to inhibit cell proliferation
in a dose-dependent manner.

"The most dramatic result is that you can really target them and stop cells from proliferating," Snyder said, arguing that "it's quite unusual to jump from discovery to treatment.
"

The researchers believe that from the current results, similar analyses have the potential to find repeat amplifications that can be targets from other cancer types
.
Some diseases that are not cancers are also expected to benefit from this approach
.

"Repeat amplification in neurodegenerative diseases has been studied the most so far, but studies of repeat amplification should not be limited to that," they said
.
"Many diseases currently have thousands of high-quality whole genome sequences, and our results provide a framework
for analyzing WGS datasets for complex diseases such as cancer.
"

Original search

Erwin, G.
S.
, Gürsoy, G.
, Al-Abri, R.
et al.
Recurrent repeat expansions in human cancer genomes.
Nature (2022).
https://doi.
org/10.
1038/s41586-022-05515-1