On Feb. 17, 2025, Stanford researchers have conducted the first large-scale screen of these inherited changes, called single nucleotide variants, and homed in on fewer than 400 that are essential to initiate and drive cancer growth. These variants control several common biological pathways, including those governing whether and how well a cell can repair damage to its DNA, how it produces energy, and how it interacts with and moves through its microenvironment.

The study focused on DNA sequences inherited at conception, known as a person’s germline genome, rather than on mutations that can accumulate during a person’s lifetime as cells divide during development or to repair injury. Examples of well-known inherited cancer-associated mutations are the BRCA1 and BRCA2 genes that confer a significantly increased risk of breast and ovarian cancers. But only a few of these high-profile mutations are currently used to predict cancer risk.

The researchers amassed over 4,000 suspect variants identified by genome-wide association studies, or GWAS, in 13 types of cancer and tacked those regulatory regions — along with control sequences — to DNA sequences, each with a unique bar code. They then conducted what are known as massively parallel reporter assays to determine which variants changed the expression of the bar-tagged sequence in the relevant cell type, testing variants associated with lung cancer in human lung cells, for example.

Winnowing thousands of potential variants down to a few hundred functional regulatory regions allowed the researchers to combine information from pre-existing databases about DNA folding, tissue-specific gene expression profiles and others to identify about 1,100 target genes likely to play a role in cancer development. Some are specific to a certain type of cancer while others appear to increase the risk of several cancers.

Finally, the researchers used gene editing techniques in laboratory-grown cancer cells to show that as many as half of the variants are required to support ongoing cancer growth. They expect the study’s findings will be a springboard for researchers around the world seeking to understand inherited cancer risk and develop new therapies.