How do polygenic risk factors interact with monogenic pathogenic variants to shape cancer risk?

How do polygenic risk factors interact with monogenic pathogenic variants to shape cancer risk?

• A. Polygenic risk has no effect on risk in BRCA carriers.
• B. Polygenic risk always reduces risk in BRCA carriers.
• C. Polygenic risk can modulate risk in those with a pathogenic variant, potentially increasing or decreasing overall risk; the interaction is complex.
• D. Polygenic risk fully determines cancer risk regardless of BRCA status.

Answer: (C)

Genetic cancer risk comes from both rare, high-impact mutations and many common variants that each have a small effect. In someone who carries a pathogenic BRCA variant, the overall risk is not fixed by that single mutation alone. The broader genetic background, summarized as polygenic risk, can shift the expected risk up or down. A BRCA carrier with a high polygenic risk score can end up with a higher lifetime risk than a BRCA carrier with a low polygenic risk score, while still being higher than the general population. Conversely, a low polygenic risk background can temper the penetrance of the BRCA variant to some extent. The way these factors combine is complex and is thought to be roughly multiplicative on the relative risk scale rather than a simple add-on. So the best description is that polygenic risk can modulate risk in those with a pathogenic variant, potentially increasing or decreasing overall risk; the interaction is complex.

Genetic cancer risk comes from both rare, high-impact mutations and many common variants that each have a small effect. In someone who carries a pathogenic BRCA variant, the overall risk is not fixed by that single mutation alone. The broader genetic background, summarized as polygenic risk, can shift the expected risk up or down. A BRCA carrier with a high polygenic risk score can end up with a higher lifetime risk than a BRCA carrier with a low polygenic risk score, while still being higher than the general population. Conversely, a low polygenic risk background can temper the penetrance of the BRCA variant to some extent. The way these factors combine is complex and is thought to be roughly multiplicative on the relative risk scale rather than a simple add-on. So the best description is that polygenic risk can modulate risk in those with a pathogenic variant, potentially increasing or decreasing overall risk; the interaction is complex.