A new study published in Nature Genetics presents a large-scale functional analysis of single-nucleotide variants (SNVs) associated with cancer risk. Gaining insight into inherited cancer risk, researchers hope to progress with new diagnostic targets for genetic screening.
The researchers focused on SNVs in noncoding regions of DNA, which control gene activity. Although these regions have been connected to cancer susceptibility, it’s been difficult to tell which SNVs actually change gene expression. To tackle this, the team used a high-throughput method called massively parallel reporter assay (MPRA) to test thousands of SNVs at once.
The variants were inserted into a lentiviral library and expressed in 13 types of human cells related to cancer (including cells from breast, lung, colon, prostate, and pancreatic tissues). This approach revealed several regulatory SNVs that affect how transcription factors bind to DNA and control gene activity, with some variants showing different effects depending on whether they increase or decrease cancer risk.
“One pathway that really popped out includes a number of genes closely associated with inflammation,” said Paul Khavari, senior author of this study in the press release. “While a connection has been established between inflammation and cancer, it’s not been clear what was driving this process – the cancer cells or the immune system. This finding suggests there may be cross talk between cells and the immune system that drives chronic inflammation and increases cancer risk.”
Overall, this extensive dataset provides a valuable resource for prioritizing cancer-risk variants and understanding their biological roles. By integrating MPRA, chromatin interaction, and gene expression data, the study establishes a framework that could improve cancer diagnostics, guide genetic screening, and support precision medicine.
Khavari concluded, “Now we have a first-generation cartographic map of functional single nucleotide variants that determine a person’s lifetime cancer risk. We expect that this information will be incorporated into increasingly informative genetic screening tests that will become available over the next decade to help determine who is most at risk for many types of genetically complex diseases, including cancer. This general approach may help provide an individualized risk assessment for common diseases to guide interventions, such as lifestyle changes, pharmacologic preventatives and diagnostic screening.”
Future research will aim to validate these findings in larger populations and explore their potential for early cancer detection.
Image Credit: Collage created using Adobe Stock images
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