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. 2025 Aug 28;25(1):1393.
doi: 10.1186/s12885-025-14640-9.

Association between polygenic risk and survival in breast cancer patients

Danielle E Kurant  1 , Stefan Groha  2 , Yi Ding  2 , Chris German  3 , Wei Wang  3 , Julie M Granka  3 , Michael V Holmes  3 ; 23andMe Research Team; Suyash S Shringarpure  3 , Alexander Sasha Gusev  4
Collaborators, Affiliations

Association between polygenic risk and survival in breast cancer patients

Danielle E Kurant et al. BMC Cancer. .

Abstract

Background: Polygenic risk scores (PRS) estimate an individual’s germline genetic predisposition to a quantitative trait and/or risk of disease. Several PRS have been developed for cancer risk with the goal of improved risk screening. Here, we sought to establish whether PRS for cancer risk and other common traits may influence survival for patients with cancer.

Methods: We conducted a PRS survival analysis using 23,770 cancer patients of European ancestry from the Dana-Farber Cancer Institute Profile cohort.

Results: We identified an association between PRS for breast cancer risk and longer patient survival (HR = 0.89 (95% CI: 0.84–0.95), p = 1.50 × 10–4, < 5% FDR), implying that individuals at high genetic risk had better outcomes. High PRS individuals were also significantly less likely to harbor somatic TP53 mutations, consistent with having less aggressive tumors. This association persisted when including tumor grade and became more protective when restricting to ER-negative tumors (HR = 0.78 (95% CI: 0.68–0.89), p = 1.69 × 10–4). Potential confounders such as hormone receptor status, age, grade, stage, and ER-targeted therapy did not fully explain this association, nor was there statistical evidence of index event bias at individual variants. We did not observe significant associations between cancer risk and survival for other cancers, suggesting that this mechanism may be largely unique to breast cancer. However, we did observe associations between shorter survival and type 2 diabetes, bipolar, and pancreatitis PRS (1% FDR).

Conclusions: These findings suggest that higher germline risk may predispose individuals to less aggressive breast cancer tumors and provide novel insights into breast cancer development and prognosis.

Supplementary Information: The online version contains supplementary material available at 10.1186/s12885-025-14640-9.

Keywords: Breast Cancer; Cancer Survival; Polygenic Risk Scores (PRS).

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: This study was approved by DFCI IRB Protocol 19–033. All participants provided informed consent for research. The research conformed to the principles of the Declaration of Helsinki. Consent for publication: Not applicable. Competing interests: Some authors are employees of 23andMe, Inc., as designated in the author list.

Figures

Fig. 1
Fig. 1
Study cohort and time definitions. a Breakdown of sample counts in this study. b Survival analyses were performed using multiple index dates. The earliest sequencing date was used as the time of cohort entry, and the latest diagnosis before cohort entry was used as the diagnosis in the cohort. Earlier diagnoses and diagnoses after sequencing date were not used in the model. In patients who had multiple biopsies of the same tumor, only the first sample was included in the evaluation. As sequencing panels have varying levels of accuracy, the best sequencing panel was used to generate the PRS
Fig. 2
Fig. 2
Somatic TP53 mutations versus PRS quartile. Association between somatic TP53 mutations and PRS_ER +. Patients in the highest quartile of polygenic risk demonstrated the fewest TP53 mutations. Patients with the lowest polygenic risk had the highest rate of TP53 mutations
See this image and copyright information in PMC

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