Research into germline genetic variants has identified ways that an individual’s genetic makeup can shape the biology of their cancer. The report, published in Cell, shows how these findings could potentially be applied to future treatment strategies to make cancer treatment more personalized.
A global collaboration of investigators mapped coding germline variants, termed “precision peptidomics,” onto peptides from mass spectrometry data to determine the impact of these variants on the proteomes of patients with cancer.
“Every person carries a unique combination of genetic variants from birth, and these inherited differences quietly shape how our cells function throughout life,” stated co-corresponding study author Zeynep H. Gümüş, PhD, Associate Professor of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai in New York. “What we’ve shown is that these variants don’t just sit in the background—they can play an active role in how tumors form, how they evolve, and even how they respond to treatment. This opens new possibilities for tailoring cancer care based not only on the tumor itself, but also on the patient’s underlying genetic makeup.”
Study Methods and Results
Investigators from Washington University in St. Louis, the Icahn School of Medicine at Mount Sinai, the Clinical Proteomic Tumor Analysis Consortium, and other institutions, analyzed the germline variants from 1,065 patients with 10 different types of cancer.
Precision peptidomics looked at 337,469 germline variants to see how they can alter post-translational modifications, protein stability, allele-specific expression, and protein structure.
Rare pathogenic and common germline variants in cancer genes were found that could impact proteomic features. For example, variants in ERBB2 and MAP2K2 were found that can affect phosphorylation. Additionally, destabilizing events in SIRPA and GFAP were predicted, which affects immunomodulation specifically in glioblastoma.
Polygenic risk scores were calculated and found to correlate with distal effects from risk variants.
“Our study flips the script by showing that inherited DNA changes can influence how genes are expressed and how proteins—key drivers of cancer behavior—are produced and modified in tumors. In doing so, these variants help explain some of the wide variation doctors see in how cancer appears, progresses, and responds to therapies from one patient to another,” Dr. Gümüş said.
“This is a major step toward precision medicine that considers the whole individual—not just the cancer,” stated co-first author Myvizhi Esai Selvan, PhD, Instructor of Genetics and Genomics at the Icahn School of Medicine at Mount Sinai. “In the evolution of cancer, the inherited genome sets the stage. It helps determine which mutations matter, how aggressive a tumor might become, and how the body’s immune system will respond.”
Going forward, the collaborative team is applying these insights toward immunotherapy responses in patients with cancer as well as toward lung cancer prediction.
The investigators did caution, however, that these findings are based on data from a primarily European-ancestry cohort and require further validation among multi-ancestry populations.
Disclosure: For full disclosures of the study authors, visit cell.com.
