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Structural Variants in Advanced Cancers Point to Effect of Treatment, Suggest Resistance Mechanisms

DNA Structure

NEW YORK — Some structural variants that arise in advanced cancers can be traced to the treatments the patient has received but may point to how treatment resistance develops and approaches to counter such resistance.

Researchers from the US and Canada analyzed 570 advanced and metastatic cancers from the Personalized OncoGenomics Program at BC Cancer to identify hundreds of genes whose expression is altered by a nearby structural variant breakpoint. The researchers also found that these SV-mediated gene expression changes were associated with worse patient survival and that a high SV burden was associated with prior treatment with DNA alkylating agents or taxanes.

"Treatment resistance is a big problem in cancer as it leads to the worst outcomes," senior author Chad Creighton, a professor of medicine and co-director of cancer bioinformatics at Baylor College of Medicine, said in a statement. "Often, we don't know what made the tumor resistant. Our approach is a way to answer that question, as it provides a strategy to identify the genes that might be involved and may suggest alternative therapeutic approaches."

The analysis appeared Tuesday in the journal Cell Reports.

Within the POG570 dataset — which includes DNA and RNA sequencing data on advanced and metastatic tumors from 18 organ groups — the researchers examined associations between gene expression and nearby SV breakpoints. Across the cohort, they identified more than 68,500 somatic SVs and homed in on hundreds of genes whose expression changed in relation to those SVs.

The researchers suggested the mechanisms behind these events could include the disruption of topologically associating domains, enhancer hijacking, and translocated retrotransposons, though they also identified a role for long interspersed elements and short interspersed elements.

These genes included ones involved in signaling receptor activity, G-protein-coupled receptor signaling pathways, and the detection of chemical stimuli, and included PLEKHG2, the increased mRNA expression of which has been linked to worse patient outcome in a range of tumor types.

A number of genes with SV-associated expression changes further correlated with patient survival. Of the 80 such genes the researchers identified, three — EGFR, FANCA, and PIM1 — had well established cancer links. A signature of these 80 genes were further associated with worse patient outcomes in the Cancer Genome Atlas dataset and across tumor types like lung cancer, pediatric brain cancer, and breast cancer.

As most of the patients in the POG570 cohort received systemic therapy before biopsy and genomic analysis, the researchers examined the influence of treatment on SV development. They found that patients treated with taxanes or DNA alkylating agents had higher tumor SV burdens, particularly SVs that affected the expression of metabolism-related genes. At the same time, patients treated with topoisomerase I inhibitors had SV-related expression changes affecting chromatin-related genes. These, the researcher noted, could point to potential treatment resistance pathways.

"Our findings can help identify potential mechanisms of cancer resistance to therapy in terms of the genes that might be involved. These genes can represent potential new therapeutic targets in the advanced cancer setting," Creighton said. "In addition, the findings can offer suggestions for combinations of current therapies that have not been previously considered."