A LARGE-SCALE study has identified 380 single-nucleotide variants (SNV) linked to inherited cancer risk, highlighting potential therapeutic targets and opportunities for improved genetic screening.
Inherited genetic variations play a crucial role in cancer susceptibility, but pinpointing which variants actively contribute to cancer development has remained a challenge. Researchers at Stanford conducted an extensive screen of 4,041 SNVs associated with 13 major cancer types, representing over 90% of human malignancies. Using massively parallel reporter assays in relevant primary human cell types, they integrated chromatin accessibility, DNA looping, and expression quantitative trait loci data to identify SNVs with regulatory potential. These findings provide insights into the genetic mechanisms driving cancer initiation and progression, offering a clearer understanding of inherited cancer risk.
The study identified 380 SNVs with potential regulatory functions, linked to key cellular pathways such as mitochondrial translation, DNA damage repair, and Rho GTPase signalling. A CRISPR knockout screen revealed that several germline risk genes not only predispose individuals to cancer but also contribute to tumour growth once cancer is established. Notably, editing the SNV rs10411210 demonstrated that its risk allele increases expression of rhophilin RHPN2, enhancing stimulus-responsive RhoA activation. This suggests that individual SNVs may upregulate cancer-linked pathways, providing a mechanistic link between genetic risk and tumour progression. These functional data offer a valuable resource for prioritising variants in future research.
These findings have significant implications for clinical practice, particularly in cancer prevention and personalised medicine. Identifying SNVs that drive cancer initiation may refine genetic screening, allowing for more accurate risk assessment and early interventions. Additionally, understanding how specific SNVs influence tumour biology could lead to targeted therapies that disrupt cancer-promoting pathways before or after tumour development.
Jenna Lorge, EMJ
Reference
Kellman LN et al. Functional analysis of cancer-associated germline risk variants. Nat Genet. 2025;DOI:10.1038/s41588-024-02070-5.
