Kara N Maxwell | Search PubMed

PubMed2026

Cross-Ancestry and Phenome-Wide Associations of Cancer-Specific Polygenic Risk Scores.

PURPOSE: Genome-wide association studies have identified many common variants associated at low effect sizes with various cancers. Summing the effects of these variants into polygenic risk scores (PRS) can improve cancer risk prediction. However, cross-cancer and cross-phenotype pleiotropic associations of cancer-specific PRS are limited. METHODS: Using logistic regression models, we tested the association of 13 cancer-specific PRS with curated phenotypes representing the same 13 cancers and 340 cancer and cardiometabolic phecodes in 560,287 individuals (114,255 African ancestry [AFR] and 446,032 European ancestry [EUR]) from the Million Veteran Program. Models were stratified by ancestry and used age, principal components, and cancer-specific PRS per standard deviation as independent variables, and correction was applied for multiple comparisons. RESULTS: All 13 cancer-specific PRS were significantly associated with their respective cancers among EUR individuals with odds ratios per standard deviation of PRS (odds ratio [OR]) 1.05-1.70. Among AFR individuals, the effect sizes of the cancer PRS were lower, with OR 1.01-1.48, and cancer-specific PRS were significantly associated with their respective cancers for five of 13 cancers (bladder, breast in female patients, colorectal, prostate, and thyroid). In cancer-cancer pleiotropy studies, only the renal cancer-specific PRS was significantly associated with skin cancer (OR = 1.04, P = 4.5 × 10-06) among EUR individuals. PheWAS demonstrated five positive pleotropic associations with cardiometabolic conditions (thyroid cancer PRS with thyroid goiter, oral cancer PRS with diabetes phenotypes, and hypothyroidism) and two negative associations (oral and lung cancer PRS separately with coronary artery disease). CONCLUSION: Cancer PRS have stronger associations per cancer among EUR versus AFR individuals. In contrast to PRS of other chronic diseases, the majority of cancer-related PRS are highly specific and pleiotropic associations with other cancers and cardiometabolic traits are uncommon.

Female↗

PubMed2026

The 'Prostate Cancer Screening for People at Genetic Risk of Aggressive Disease' (PATROL) study.

BACKGROUND: Inherited (germline) pathogenic and likely pathogenic variants (gPVs) in key genes associated with increased risk of prostate cancer (PCa) now warrant more attentive PCa screening per National Comprehensive Cancer Network (NCCN) guidelines-e.g., BRCA2, HOXB13, ATM, BRCA1, MSH2, MSH6, CHEK2 and TP53. However, the optimal early detection strategy for gPV carriers, including use of age-adjusted PSA thresholds and prostate imaging may be refined. and as a means to investigate novel biomarkers. STUDY DESIGN: 'Prostate Cancer Screening for People at Genetic Risk of Aggressive Disease' (PATROL) is a multicentre, prospective early detection study for individuals at increased risk for PCa due to carrying a gPV in a PCa risk gene. ENDPOINTS: The primary endpoint is to determine the positive predictive value of pre-defined age-directed prostate-specific antigen (PSA) level thresholds and prostate-specific imaging, e.g., multiparametric magnetic resonance imaging (MRI) for clinically significant PCa on biopsy for individuals at risk of PCa due to a gPV. Exploratory endpoints include characterising clinicopathological characteristics of PCa and patient-reported outcomes. Biospecimens will be collected to evaluate emerging clinical and research biomarkers. PATIENTS AND METHODS: Key eligibility includes: individuals aged ≥40 years who carry a gPV in an eligible gene, who have no prior diagnosis of PCa, do not have another active malignancy, and provide informed consent. Study procedures include annual physical examination and PSA. Imaging with MRI is optional at baseline and recommended if the PSA level is above the protocol-recommended PSA level threshold. Participants will be offered prostate biopsy for any clinical concern, PSA level >1.0 ng/mL if aged <50 years; PSA level >1.5 ng/mL if aged 50-59 years; PSA level >2.0 ng/mL if aged ≥60 years. If PCa is diagnosed, clinical care is determined by the participant and treating physician. If opting for active surveillance, study procedures will be collected annually for 10 years or until definitive treatment. If definitive treatment, study procedures will be collected for an additional 1 year. Long-term clinical outcomes will be collected annually until the study closes.

Humans↗