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Hotspots of Tandem Duplications Might Drive Breast Cancer

NEW YORK (GenomeWeb) – Hotspots of tandem duplications in breast cancer genomes often affect cancer susceptibility genes and super-enhancers, according to a new analysis.

A Wellcome Trust Sanger Institute-led team of researchers examined genomic rearrangements within 560 breast cancers and they uncovered 33 hotspots of large tandem duplications. As they reported in Nature Genetics today, these duplications often affected germline cancer susceptibility genes and breast cancer super-enhancers, suggesting that they might be drivers of disease.

"DNA in breast cancers is heavily restructured by many tandem duplications," first author Dominik Glodzik from the Sanger Institute said in a statement. "From our research, it now looks like some of these tandem duplications are not just unimportant passenger mutations, but actually create new driver mutations for cancer."

Nearly 78,000 intrachromosomal rearrangements and six rearrangement signatures were previously found in this cohort of breast cancer patients. For this study, Glodzik and his colleagues focused on two — RS1 and RS3 — that were marked by large and small duplications, respectively.

After gauging the background distribution of rearrangements, the researchers used two approaches — the principle of intermutation distance and piecewise constant fitting — to search for rearrangement hotspots. RS1 tandem duplications formed 33 hotspots, while the smaller RS3 tandem duplications formed four.

These four RS3 tandem duplication hotspots were highly focused, arose in small genomic windows, and harbored a high density of rearrangements, the researchers noted. Two of the four RS3 tandem duplication hotspots affected the known tumor suppressor genes PTEN and RB1.

The 33 RS1 tandem duplication hotspots, meanwhile, had lower rearrangement densities and sometimes included nested tandem duplications. While cancer susceptibility loci were also enriched among RS1 tandem duplication hotspots, slightly more than half of these hotspots also contained at least one breast super-enhancer.

One RS1 hotspot occurs at the known breast cancer gene ESR1, which is near to both a breast cancer susceptibility locus and a breast-specific super-enhancer. When the researchers examined gene expression data from six patients who harbored this hotspot, all had significantly elevated expression of ESR1, even with a small increase in copy number. Most of the samples with this hotspot were estrogen-receptor positive tumors, while tumors with the 32 other rearrangements were triple-negative tumors. Based on this, Glodzik and his colleagues proposed that duplications in the ESR1 hotspot might drive disease.

Through a global gene-expression approach and mixed effects model, the researchers found that tandem duplications near super-enhancers or breast cancer susceptibility genes also led to an increase of global gene expression. Based on this, they noted that tandem duplications of cancer genes affect those individual genes, while tandem duplications of super-enhancers have a more modest, but wider effect on gene expression.

Glodzik and his colleagues likewise uncovered rearrangement hotspots among smaller cohorts of ovarian and pancreatic cancers that also appeared to overlap with super-enhancers and oncogenes.

This enrichment of breast cancer susceptibility loci, oncogenes, and breast super-enhancers at hotspots suggested to the researchers that this increase in copy number might bestow a selective advantage.

"This research has shown a new genetic mechanism for generating drivers in cancer, which we have found not only in breast cancers, but also other cancers," senior author Serena Nik Zainal from the Sanger Institute said in a statement. "It is really important to identify and study tumors with this mutational signature of tandem duplications, because if it can create many new drivers, then it has potentially devastating consequences making tumors more aggressive."