How Does Our Personal Genetic Makeup Shape Cancer's Course and Treatment Response?

Each Person May Be Born With a Unique Genetic Background for Cancer

A groundbreaking study showing that cancer development and progression may be shaped not only by mutations accumulated through environmental factors and aging, but also by inherited genetics, was published on April 14, 2025 in Cell . By showing how germline (inherited) genetic variantsmay affect cancer development and treatment response, it adds a new dimension to personalized oncology.

New Research From a Turkish Scientist: Inherited Variants May Directly Influence Cancer Biology

From the Department of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai in New York, Associate Professor Dr. Zeynep H. Gümüşcommented as a study coauthor:

“Each person carries a unique combination of genetic variants from birth. These inherited differences are not merely background features; they may directly affect how tumors form, evolve and respond to treatment.”

The findings suggest that cancer care could be shaped by both tumor molecular features and the patient's inherited genetic background, again highlighting the importance of treatment tailored to the whole patient rather than only the tumor .

Graphical Abstract

The main messages of the graphical abstract can be summarized in 3 sentences:

1. Inherited genetic variantsmay directly influence cancer development and progression, not just as risk factors but by producing protein-level functional effects .

2. These variants can destabilize proteins, alter post-translational modifications (phosphorylation, acetylation), affect gene expression levels, and create differences between the proteomic effects of common or rare variants.

3. The research demonstrates a direct relationship between inherited genetic background and tumor biology , emphasizing the need to consider inherited variants in personalized oncology.

Research Method: What Did “Precision Peptidomic” Analysis Reveal?

The collaboration involved Mount Sinai, Washington University, the Clinical Proteomic Tumor Analysis Consortium and other leading centers. The study examined 1065 patients across 10 cancer types and analyzed their inherited genetic variants.

A total of 337469 inherited variantswere evaluated in detail for:

• Protein stability

• Allele-specific gene expression

• Post-translational modifications, particularly phosphorylation

• Disruptions in protein structure

Key Findings:

• Variants in ERBB2 and MAP2K2 were shown potentially to affect phosphorylation.

• SIRPA and GFAP variantsmay destabilize proteins in ways that reduce tumor visibility to the immune system, particularly in brain tumors such as glioblastoma.

• Inherited risk scores (polygenic risk scores)correlated with distal effects of certain variants.

Why Do These Findings Matter?

The inherited genome sets the stage for cancer evolution and may determine which somatic mutations matter, how aggressively the tumor behaves and how immunity responds.

This may explain a situation physicians often encounter: why do two patients with the same cancer stage and genetic mutation have such different disease courses?

What Is New in the Work by Zeynep Gümüş and Colleagues?

1. The Proteomic Effects of Inherited Variants Were Examined on an Unprecedented Scale

Earlier studies mainly examined germline effects on cancer risk at the genomic level, such as BRCA1/2 mutations. This study analyzed the protein-level effects of germline variants— particularly protein abundance, phosphorylation, acetylation and other post-translational modifications — across cancers. This is a major step toward understanding how germline variants may disrupt cancer-related signaling pathways .

2. Germline Variants + 3D Protein Structures + PTMs Were Combined for the First Time

The study analyzed germline variants and post-translational modification (PTM) sites not only by their linear sequence relationships, but also by their spatial proximity within 3D protein structures . For example, even if a germline variant does not directly affect a phosphorylation site, it may have functional effects if it lies nearby in the protein's three-dimensional structure.

3. Links Between Individual Risk Scores (PRS) and Protein Levels Were Revealed

Clinically used polygenic risk scores (PRS) had previously generally served only as diagnostic tools. This study showed biological effects not only at the gene level, but also at protein and proteomic pathway levels . This suggests that an individual's genetic risk may be reflected in measurable protein-level biology, with the ability to measure its biological effects at the protein level as a potential application.

By showing how inherited variants operate beyond DNA, at RNA, protein and even post-translational modification levels, and how they shape cancer's molecular evolution, the study fills an important gap in the literature.

Next Steps: Where Could This Knowledge Be Used?

The team is continuing research into inherited variants, particularly how they shape immunotherapy (immune-based treatment) responses. The findings may also have applications in predicting lung cancer risk , according to the researchers.

However, the researchers emphasize that the data came largely from people of European ancestry and must be validated in multiracial populations. This is an important caution for fairer and more inclusive genetic oncology.

Conclusion: Inherited Genes Shape Cancer's Fingerprint

This groundbreaking study shows that inherited variants may help determine not only risk but also how cancer arises, progresses and responds to treatment. In cancer care, “personalization” is being redefined around both tumor molecular analysis and the individual's inherited genetic makeup.

With this study, we can say:

Cancer is a product not only of our cells but also of our genetic inheritance. Future treatments will be shaped by a more holistic approach that considers this inheritance.