Polygenic risk and rare variant gene clustering enhance cancer risk stratification for breast and prostate cancers

Sep 21, 2026

Uploaded by Rowan

Polygenic risk score (PRS) and rare monogenic variant screening enable cancer risk prediction and highlight individuals at high risk, yet combining rare-variant effects with PRS remains difficult. Using 454,711 exome sequencing and 487,409 array UK Biobank samples, the study analyzes breast and prostate cancers to develop an expanded PRS (EPRS). By clustering cancer-specific rare-variant genes with odds ratios and population-attributable fractions, EPRS refines risk stratification and shows markedly higher risks in high-PRS groups carrying rare high-impact variants.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages10

Reading Time25 min

AccessFree to download

Background

Methods and EPRS framework

Gene clustering with rare variants

Results and risk stratification performance

Implications

communications biology Article [https://doi.org/10.1038/s42003-024-06995-9](https://doi.org/10.1038/s42003-024-06995-9) Polygenic risk and rare variant gene clustering enhance cancer risk stratiﬁcation for breast and prostate cancers Check for updates | Joon Ho Kang , Youngkee Lee , Dong Jun Kim, Ji-Woong Kim, Myeong Jae Cheon & Byung-Chul Lee | | | --- | --- | | Polygenic risk score (PRS) and rare monogenic variant screening are valuable tools for predicting cancer risk and identifying individuals at high risk. Integrating both common and rare genetic variants is crucial for accurate risk assessment. However, estimating the impacts of rare variantson cancer and combining them with PRS remains challenging. Here, we analyze 454,711 exome sequencing and 487,409 array UK Biobank samples, focusing on breast and prostate cancers. We introduce an expanded PRS (EPRS) approach, yielding a systematic model for more effective risk stratiﬁcation. By prioritizing and clustering genes with cancer-speciﬁc rare variants based on odds ratios and population-attributable fraction, we reﬁne risk stratiﬁcation by combining both monogenic and polygenic effects. Individuals in high-PRS groups with rare high-impact gene variants show up to 15-and 22-fold higher risk for breast and prostate cancers, respectively, compared to those in the intermediate-PRS groups without rare variants. Combined risk proﬁles vary across distinct rare variant clusters within the same PRS group for both cancers. Our EPRS approach enhances risk stratiﬁcation for breast and prostate cancers, offering important insights for future research and potential applications to other cancer types. | | | Public health initiatives focus on reducing healthcare burdens by leveraging the social and ﬁnancial beneﬁts of disease prevention. Early disease detection facilitates timely interventions, thereby preventing disease progression and the development of symptoms1. Preventive measures involve identifying high-risk individuals for speciﬁc diseases by assessing their potential risk.
Breast and prostate cancers are highly prevalent, with breast cancer being the most common among female patients, while prostate cancer ranks the second most common among male patients2. The World Health Organization (WHO) advocates for organized, population-based mammography screenings every 2 years for women aged 50 to 69 years, highlighting the prospects for enhancing cost-effectiveness and beneﬁt-to-harm ratios through risk-stratiﬁed screening3. Women at increased risk of breast cancer have several options to reduce their risk, including surgery, medication and lifestyle modiﬁcations. Also, breast cancer risk estimation models now exist that attempt to quantify the risk accounting individual factors, breast-related factors, genetic testing and family history factors4. Prostate | cancer screening is recommended by different modalities, including prostate-speciﬁc antigen (PSA) serum levels, digital rectal examination, modern imaging techniques (for example, multiparametric MRI), prostate biopsy and liquid biopsy5. Despite the high prevalence of prostate cancer, its etiology is not well understood. Established risk factors remain limited to advancing age, family history of the malignancy, and speciﬁc genetic variants2. Importantly, both breast and prostate cancers exhibit high heritability estimated at 31% and 58%, respectively6,7. Consequently, incorporating genetic predisposition into risk stratiﬁcation for these cancers is crucial. Moreover, there is substantial potential to improve preventive measures for both conditions3,8. Therefore, further research is needed to develop more effective prevention and risk stratiﬁcation strategies for both breast and prostate cancers.
Genetic architecture studies play a crucial role in distinguishing individuals at potential risk for various diseases9–12. Particularly, predicting cancer risk, which has high heritability conferred by the genetic variants

FAQs

What problem does the study address regarding cancer risk prediction?

Estimating the impact of rare variants on cancer and combining those effects with polygenic risk scores (PRS) is challenging, limiting accurate risk assessment.

What data and cancers are analyzed in the research?

The study analyzes 454,711 exome sequencing and 487,409 array UK Biobank samples, focusing on breast and prostate cancers.

How does the proposed EPRS approach improve risk stratification?

EPRS prioritizes and clusters genes carrying cancer-specific rare variants using odds ratios and population-attributable fractions, then combines monogenic and polygenic effects to refine risk groups.

Sep 21, 2026

Uploaded by Rowan