A new pan-cancer study from the National Institute of Health’s Clinical Proteomic Tumor Analysis Consortium (CPTAC) explores how inherited genetic variants shape protein function in cancer. Using a method called precision peptidomics, CPTAC researchers mapped over 337,000 coding germline variants to peptides detected in tumor samples and normal adjacent tissues across ten cancer types. Their work, published in Cell, has revealed how these variants might alter protein structure, allele-specific expression, post-translational modifications, and ultimately contribute to oncogenesis.
A person’s germline genome carries a unique mix of millions of genetic variants that shape biological processes, including cancer evolution. Many of these variants are thought to influence cancer risk and progression through diverse mechanisms, including interactions with somatic alterations or by shaping the immune response against cancer cells. Despite significant advances in cataloging germline variants, their functional impact has remained largely unexplored.
In this study, researchers identified 119 rare, low-frequency germline variants in cancer associated genes that, in combination with common variants, are predicted to affect protein abundance, stability, and PTM states. This includes specific germline variants capable of disrupting, deleting, or even creating phosphorylation sites, as well as alterations that can significantly affect protein structure, function, and downstream signaling pathways.
Researchers illuminated allele-specific expression (ASE) and allele-specific protein (ASP) effects of germline insertions and deletions — alterations not typically detectable at the RNA level. For example, an indel in SIRPA was found to lead to altered peptide abundance in lung squamous cell carcinoma and glioblastoma, potentially affecting immune checkpoint signaling.
Large genome-wide association studies for each cancer type were leveraged to calculate polygenic risk scores (PRSs), which were then linked to broader pathway-level effects. For instance, high PRSs in pancreatic ductal adenocarcinoma were associated with immune-related pathways, particularly antigen presentation, and other processes including platelet function.
By connecting germline variation to protein-level changes, the study opens new possibilities for assessing cancer risk, improving diagnostics, and developing targeted therapies. On the importance of the study, first author Dr. Fernanda Martins Rodrigues commented:
“Ultimately, this research advances our understanding of inherited cancer susceptibility and informs the development of personalized strategies for cancer prevention and treatment—particularly for individuals with hereditary predispositions. Working on this project within the CPTAC consortium was an incredible experience, particularly as an early-career scientist. Collaborating with experts from across institutions provided invaluable mentorship and insight. We hope this work lays the foundation for future studies and serves as a valuable resource for the research community, driving progress in precision oncology and reducing disparities in genetic risk assessment.”