Cancer genetics research has predominantly focused on identifying risk-increasing variants, implicitly treating genetic protection as the absence of risk. Here we show that cancer-protective and cancer-risk genetic variants operate through fundamentally distinct biological pathways. Analysing genome-wide association summary statistics from FinnGen (N=500, 348) across 19 cancer endpoints, we separated significant variants (P 0; 1, 335 genes) sets after LD clumping. Pathway enrichment analysis revealed that protective genes uniquely enrich for xenobiotic detoxification (cytochrome P450 metabolism, glucuronidation), cell adhesion and tissue integrity (adherens junctions), and positive regulation of apoptosis — mechanisms that prevent cancer initiation. Risk genes uniquely enrich for transcriptional regulation, DNA replication, and kinase signalling — mechanisms that cancer co-opts for progression. The two pathway profiles are significantly distinct (Fisher's exact P = 8. 57 x 10^-24; Jaccard similarity = 0. 320). This finding replicates in an independent East Asian cohort (BioBank Japan, 7 cancer types; Fisher's P = 4. 12 x 10^-9; Jaccard = 0. 425). At the variant level, a Polygenic Protection Score (PPS) constructed from protective variants shares virtually no variants with a standard Polygenic Risk Score (Jaccard = 0. 005) and only 21. 7% of genes, with gene-level contributions anti-correlated (Spearman ρ = -0. 306, P = 7. 7 x 10^-104). These results demonstrate that cancer protection has its own genetic architecture, distinct from the inverse of cancer risk, with implications for risk stratification and chemoprevention.
Avram Score (Mon,) studied this question.