Cancer Risk at the Genome–Exposome Interface: Toward Translational Composite Scoring

At the Human Genomics Conference 2026, held in Athens, Professor Dimosthenis Sarigiannis, Director and Chairman of the Board of the National Hellenic Research Foundation (NHRF), delivered an invited lecture in the Symposium on Environmental Genomics, presenting a critical review of Composite Risk Scores (CRS) – integrative metrics that combine inherited susceptibility (Polygenic Risk Scores) with an individual’s lifelong, multidomain exposome.

The presentation conveyed a dual message. On the one hand, genetic epidemiology robustly documents that the top PRS quintile carries a 3- to 4-fold increase in risk across several major cancers, while 40–60% of cancer incidence is shaped by modifiable environmental, behavioral and lifestyle factors. On the other hand, these strong etiologic associations translate into only incremental gains in predictive performance (ΔAUC 0.02–0.14), highlighting the central association – prediction gap that must guide any clinical translation.

The analysis identified three structural weaknesses across the international literature: chronic under-reporting of calibration – the most consequential yet most neglected metric for screening-age decisions; the declining portability of Eurocentric PRS to other populations, given that approximately 78% of GWAS discovery is of European ancestry; and the urgent need for longitudinal, multidomain exposome data, which will deliver the largest future gains in CRS methodology.

The proposed research agenda – mandatory external validation, multi-ancestry GWAS, TRIPOD-aligned reporting and implementation science – positions CRS as a tool for risk stratification, trial enrichment and population-level prevention planning, rather than as a standalone diagnostic instrument. NHRF’s contribution, in collaboration with AUTH, IUSS Pavia and Yale School of Public Health, consolidates an integrated genome–exposome approach to European oncology risk research.