Stanford researchers have made a groundbreaking discovery by identifying 380 key single nucleotide variants (SNVs) linked to inherited cancer risk, marking a significant advancement in understanding the genetic factors that drive cancer.

This pivotal research was published in Nature Genetics on February 17, 2025, and was led by former graduate student Laura Kellman alongside senior author Paul Khavari, MD, PhD.

The identified variants primarily reside in regulatory regions of DNA, influencing the expression of nearby or distant cancer-associated genes, rather than in coding sequences like the well-known BRCA1 and BRCA2 mutations.

Utilizing massively parallel reporter assays, the researchers tested over 4,000 candidate variants to confirm their functional impact on gene expression in relevant cell types, narrowing down to a functional subset.

The study analyzed genetic data from millions diagnosed with the 13 most common cancer types, which account for over 90% of all human malignancies, to pinpoint these influential variants.

Interestingly, the research revealed a connection between inflammation-related genes and cancer risk, suggesting that interactions between cancer cells and the immune system may drive chronic inflammation contributing to cancer.

Gene editing experiments indicated that nearly half of the identified variants are necessary for ongoing cancer growth, laying the groundwork for future research into inherited cancer risk and potential therapies.

These findings are expected to enhance genetic screening tests over the next decade, allowing for more personalized risk assessments for various complex diseases, including cancer.

The researchers emphasized the importance of these variants in controlling biological pathways related to DNA repair, energy production, and cellular interactions, which are crucial for cancer development.

Focusing on inherited DNA sequences known as the germline genome, this study highlights the significance of inherited genetic changes over mutations acquired during a person's lifetime.

While previously identified inherited mutations like BRCA1 and BRCA2 are well-known, only a few are currently utilized in risk prediction, underscoring the need for advancements in genetic screening.

This research is part of a larger initiative funded by the National Human Genome Research Institute aimed at mapping regulatory variants linked to various diseases, including cancers.