ECG2Gene: Deep Learning-Based Germline Tumor Susceptibility Gene Risk Assessment Using Electrocardiograms

Electrocardiograms (ECGs) may contain physiological information related to hereditary cancer susceptibility, but its relationship with future cancer risk remains unclear. Here, we present ECG2Gene, a two-stage deep-learning framework that derives digital phenotypes related to germline tumor susceptibility from routine 12-lead ECGs and predicts future cancer risk. In Stage 1, carrier status for pathogenic or likely pathogenic variants in ATM, BRIP1, CHEK2, PALB2, BRCA1, and BRCA2 supervises a multitask model that generates six continuous ECG-derived gene scores. In Stage 2, XGBoost integrates these scores with clinical variables to predict subsequent breast and ovarian cancer in women and prostate cancer in men. We also introduce ECG-Wide Association Analysis (EWAS) to characterize associations between ECG-derived gene scores and ECG waveforms. Across the clinical feature combinations evaluated in UK Biobank, the best-performing sex-specific models achieve AUROCs of 0.683, 0.633, and 0.660 for breast, ovarian, and prostate cancer, respectively. In external evaluations, models combining ECG-derived gene scores with age achieve prostate cancer AUROCs of 0.709 and 0.579 among men in the overall China Kadoorie Biobank and MIMIC-IV-ECG cohorts, respectively. ECG2Gene links genetically supervised ECG phenotyping and waveform association analysis to future cancer outcomes, demonstrating the potential of routine ECGs combined with clinical information for non-invasive, opportunistic cancer risk assessment.