These variations, discovered in what is known as the germline genome (the DNA inherited at birth), control critical biological pathways. These pathways include DNA repair, energy production, and cell movement through the microenvironment. The insights gained from this research could pave the way for new treatments and genetic screenings to assess a person’s cancer risk.

Breaking Down the Study

The study’s authors, led by Paul Khavari, MD, PhD, analyzed data from over a million people with 13 of the most common cancer types, representing 90% of all human malignancies. They identified 380 variants that influence the expression of genes linked to cancer. Khavari emphasizes that these variations, inherited from parents, can significantly elevate the risk of developing multiple types of cancer.

The Role of Regulatory Regions

Interestingly, the variants identified by the Stanford team are not part of protein-coding genes. Instead, they reside in regulatory regions, controlling how genes are expressed. These regulatory areas can influence both nearby and distant genes. The research builds on Khavari’s 2020 project funded by the National Human Genome Research Institute, which aimed to identify variants associated with 42 common diseases.

A Fresh Approach to Genetic Research

Previous studies, known as genome-wide association studies (GWAS), have identified variations found more frequently in people with specific cancers compared to those without. However, these studies often fall short in demonstrating how these changes affect gene activity. In contrast, Khavari and his team used a different method called massively parallel reporter assays to test over 4,000 suspect variants from 13 types of cancer.

The researchers tested the variants in relevant cell types, such as lung cells for lung cancer, to see if they altered gene expression. This approach narrowed down the number of variants to about 400 functional regulatory regions. The team then used existing databases to identify approximately 1,100 genes likely involved in cancer development. Some genes were specific to certain cancer types, while others increased the risk of several cancers.

Paths to Cancer Growth

The identified genes make sense in the context of cancer development. For example, some affect pathways involved in cell death, while others impact how cells interact with their surroundings. Another significant pathway is associated with the function of mitochondria, the cell’s powerhouses that support growth and division.

Surprising Findings

One unexpected pathway includes genes linked to inflammation, long known to be associated with cancer. However, the exact role of inflammation in the disease process has been unclear. This finding suggests that communication between cells and the immune system might maintain chronic inflammation, contributing to increased cancer risk.

Implications for Future Research

The study’s authors also used gene editing techniques to demonstrate that about half of the identified variants are necessary to sustain cancer growth. This discovery provides a foundation for future research into inherited cancer risk and potential new therapies.

“Now we have a first-generation cartographic map of functional single nucleotide variants that determine a person’s lifetime cancer risk,” Khavari commented. “We expect this information to be incorporated into increasingly informative genetic screening tests available over the next decade. These tests could help determine who is at higher risk for many types of common diseases, including cancer, guiding interventions like lifestyle changes, pharmacological preventatives, and diagnostic screening.”

Conclusion

This groundbreaking study marks a significant milestone in the quest to understand and combat cancer. By identifying crucial single nucleotide variants, researchers can develop more precise genetic screenings and targeted treatments. As the research continues, we may see the advent of personalized medicine that can predict and prevent cancer before it takes hold.